1
|
Trzeciak AJ, Liu ZL, Gatie M, Krebs AS, Saitz Rojas W, O'Neal AJ, Baako AK, Wang Z, Nelson J, Miranda IC, Uddin J, Lipshutz A, Xie J, Huang CL, Saavedra PHV, Hadjantonakis AK, Overholtzer M, Glickman MS, Subramanya AR, Vierbuchen T, Etchegaray JI, Lucas CD, Parkhurst CN, Perry JSA. WNK1 mediates M-CSF-induced macropinocytosis to enforce macrophage lineage fidelity. Nat Commun 2025; 16:4945. [PMID: 40436823 PMCID: PMC12120055 DOI: 10.1038/s41467-025-59901-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Accepted: 05/09/2025] [Indexed: 06/01/2025] Open
Abstract
Tissue-resident macrophages (TRM) are critical for mammalian organismal development and homeostasis. Here we report that with-no-lysine 1 (WNK1) controls myeloid progenitor fate, with Csf1riCre-mediated Wnk1 deletion in mice (WNK1-deficient mice) resulting in loss of TRMs and causing perinatal mortality. Mechanistically, absence of WNK1 or inhibition of WNK kinase activity disrupts macrophage colony-stimulating factor (M-CSF)-stimulated macropinocytosis, thereby blocking mouse and human progenitor and monocyte differentiation into macrophages and skewing progenitor differentiation into neutrophils. Treatment with PMA rescues macropinocytosis but not macrophage differentiation of WNK-inhibited progenitors, implicating that M-CSF-stimulated, macropinocytosis-induced activation of WNK1 is required for macrophage differentiation. Finally, M-CSF-stimulated macropinocytosis triggers WNK1 nuclear translocation and concomitant increased protein expression of interferon regulatory factor (IRF)8, whereas inhibition of macropinocytosis or WNK kinase activity suppresses IRF8 expression. Our results thus suggest that WNK1 and downstream IRF8-regulated genes are important for M-CSF/macropinocytosis-mediated regulation of myeloid cell lineage commitment during TRM development and homeostasis.
Collapse
Affiliation(s)
- Alissa J Trzeciak
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Zong-Lin Liu
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mohamed Gatie
- Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA
| | - Adam S Krebs
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY, USA
| | - Waleska Saitz Rojas
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anya J O'Neal
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ann K Baako
- Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY, USA
| | - Zhaoquan Wang
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY, USA
| | - Justin Nelson
- Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Isabella C Miranda
- Division of Pulmonary and Critical Care Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Jazib Uddin
- Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA
| | - Allie Lipshutz
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jian Xie
- Department of Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | - Chou-Long Huang
- Department of Medicine, Division of Nephrology, Carver College of Medicine, University of Iowa, Iowa City, IA, USA
| | | | - Anna-Katerina Hadjantonakis
- Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA
| | - Michael Overholtzer
- Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Cell Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA
| | - Michael S Glickman
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY, USA
- Division of Infectious Diseases, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Arohan R Subramanya
- Dept of Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Thomas Vierbuchen
- Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Developmental Biology Program, Sloan Kettering Institute for Cancer Research, New York, NY, USA
| | - Jon Iker Etchegaray
- Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
| | - Christopher D Lucas
- University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, Edinburgh, BioQuarter, UK
- Institute for Regeneration and Repair, Edinburgh, BioQuarter, UK
| | | | - Justin S A Perry
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Immunology and Microbial Pathogenesis, Weill Cornell Medicine, New York, NY, USA.
| |
Collapse
|
2
|
Stakenborg N, Viola MF, Boeckxstaens G. Intestinal neuron-associated macrophages in health and disease. Nat Immunol 2025:10.1038/s41590-025-02150-6. [PMID: 40399608 DOI: 10.1038/s41590-025-02150-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/14/2025] [Indexed: 05/23/2025]
Abstract
Neuron-macrophage cross-talk in the intestine plays a crucial role in the maintenance of tissue homeostasis and the modulation of immune responses throughout life. Here, we describe how gut neuron-macrophage interactions shift macrophage phenotype and function from early development to adulthood and how this cross-talk modulates the macrophage function in response to infection and inflammation. We highlight how a neural microenvironment instructs a neuron-associated macrophage phenotype in the gut and show that their phenotype may resemble nerve-associated macrophages in other organs. Finally, we note that the loss of neuron-associated macrophages or a shift in their phenotype can contribute to enteric neurodegeneration in the gastrointestinal tract, causing gut motility disorders.
Collapse
Affiliation(s)
- Nathalie Stakenborg
- Center of Intestinal Neuro-Immune Interactions, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium
| | - Maria Francesca Viola
- Developmental Biology of the Immune System, Life & Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany
| | - Guy Boeckxstaens
- Center of Intestinal Neuro-Immune Interactions, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, KU Leuven-University of Leuven, Leuven, Belgium.
| |
Collapse
|
3
|
Haranaka M, Kinami K, Yang YO, Li H, Pratta M, Suzukawa K. Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Axatilimab in Healthy Japanese Male Participants: Results from a Phase 1, Randomized, Double-Blind, Dose-Escalation Study. Clin Drug Investig 2025:10.1007/s40261-025-01438-7. [PMID: 40381116 DOI: 10.1007/s40261-025-01438-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/02/2025] [Indexed: 05/19/2025]
Abstract
BACKGROUND Axatilimab, an anti-colony-stimulating factor 1 receptor (CSF-1R) antibody, blocks colony-stimulating factor 1 (CSF-1) and interleukin-34 (IL-34) binding to CSF-1R on macrophages and monocytes. Axatilimab has demonstrated efficacy and safety in chronic graft-versus-host disease, and its safety, pharmacokinetics (PK), and pharmacodynamics (PD) were characterized in healthy Western participants. OBJECTIVE The objective of this study was to evaluate the safety, PK, and PD of axatilimab among healthy Japanese men. METHODS In this double-blind, randomized, dose-escalation study, eligible participants were healthy Japanese men aged 18-55 years, with a body weight of 50-100 kg, a body mass index of 18.0-30.0 kg/m2, and no clinically significant findings on screening evaluation (clinical, laboratory, electrocardiogram, and physical exam). Participants were randomized to receive axatilimab or placebo in a 3:1 ratio in a blinded manner. Safety (30 d follow-up; primary endpoint), PK, and PD were evaluated at a clinic in Japan following single-dose infusions of axatilimab 0.3 mg/kg (n = 6), axatilimab 1.0 mg/kg (n = 9), or placebo (n = 5). RESULTS Three participants receiving axatilimab experienced a nonserious treatment-emergent adverse event (nasopharyngitis [0.3-mg/kg dose], amylase level increased [1.0-mg/kg dose], and headache [1.0-mg/kg dose]), with no clinically meaningful trends in hematology, urinalysis, physiologic, and most clinical chemistry measures. PK exposure increased with the 1.0 mg/kg versus 0.3 mg/kg dose, with greater than dose-proportional increases in area under the curve. CSF-1 and IL-34 levels had dose-dependent increases following axatilimab infusion. A transient increase in nonclassical monocytes was observed for 8 h following axatilimab infusion and then decreased below baseline until day 8 (0.3 mg/kg) or day 15 (1.0 mg/kg). The inverse effect was observed with classical monocytes. Intermediate monocytes had similar transient increases as nonclassical monocytes. CONCLUSIONS A single dose of axatilimab 0.3 mg/kg and 1.0 mg/kg was generally well tolerated in healthy Japanese men. Safety, PK, and PD findings were consistent with those observed in healthy Western participants. TRIAL REGISTRATION Japan Registry for Clinical Trials, jRCT2071220109; 27 February 2023.
Collapse
Affiliation(s)
| | - Kenzo Kinami
- Incyte Biosciences Japan GK, Tokyo Midtown Hibiya, 12th Floor, 1-1-2 Yurakucho, Chiyoda-ku, Tokyo, 100-0006, Japan
| | | | | | | | - Kazumi Suzukawa
- Incyte Biosciences Japan GK, Tokyo Midtown Hibiya, 12th Floor, 1-1-2 Yurakucho, Chiyoda-ku, Tokyo, 100-0006, Japan.
| |
Collapse
|
4
|
Dhenni R, Hoppé AC, Reynaldi A, Kyaw W, Handoko NT, Grootveld AK, Keith YH, Bhattacharyya ND, Ahel HI, Telfser AJ, McCorkindale AN, Yazar S, Bui CHT, Smith JT, Khoo WH, Boyd M, Obeid S, Milner B, Starr M, Brilot F, Milogiannakis V, Akerman A, Aggarwal A, Davenport MP, Deenick EK, Chaffer CL, Croucher PI, Brink R, Goldstein LD, Cromer D, Turville SG, Kelleher AD, Venturi V, Munier CML, Phan TG. Macrophages direct location-dependent recall of B cell memory to vaccination. Cell 2025:S0092-8674(25)00407-6. [PMID: 40300604 DOI: 10.1016/j.cell.2025.04.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Revised: 08/31/2024] [Accepted: 04/02/2025] [Indexed: 05/01/2025]
Abstract
Vaccines generate long-lived plasma cells and memory B cells (Bmems) that may re-enter secondary germinal centers (GCs) to further mutate their B cell receptor upon boosting and re-exposure to antigen. We show in mouse models that lymph nodes draining the site of primary vaccination harbor a subset of Bmems that reside in the subcapsular niche, generate larger recall responses, and are more likely to re-enter GCs compared with circulating Bmems in non-draining lymph nodes. This location-dependent recall of Bmems into the GC in the draining lymph node was dependent on CD169+ subcapsular sinus macrophages (SSMs) in the subcapsular niche. In human participants, boosting of the BNT162b2 vaccine in the same arm generated more rapid secretion of broadly neutralizing antibodies, GC participation, and clonal expansion of SARS-CoV-2-specific B cells than boosting of the opposite arm. These data reveal an unappreciated role for primed draining lymph node SSMs in Bmem cell fate determination.
Collapse
Affiliation(s)
- Rama Dhenni
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia
| | - Alexandra Carey Hoppé
- Immunovirology and Pathogenesis Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Arnold Reynaldi
- Infection Analytics Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Wunna Kyaw
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia
| | - Nathalie Tricia Handoko
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia
| | - Abigail K Grootveld
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia
| | - Yuki Honda Keith
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia
| | - Nayan Deger Bhattacharyya
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia
| | - Holly I Ahel
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia
| | - Aiden Josiah Telfser
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia
| | - Andrew N McCorkindale
- Data Science Platform, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Seyhan Yazar
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia
| | - Christina H T Bui
- St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia; Cancer Plasticity and Dormancy Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - James T Smith
- St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia; Cancer Plasticity and Dormancy Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Weng Hua Khoo
- Cancer Plasticity and Dormancy Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Mollie Boyd
- Immunovirology and Pathogenesis Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Solange Obeid
- St. Vincent's Hospital Sydney, Sydney, NSW, Australia
| | - Brad Milner
- St. Vincent's Hospital Sydney, Sydney, NSW, Australia
| | - Mitchell Starr
- St. Vincent's Centre for Applied Medical Research, Sydney, NSW, Australia
| | - Fabienne Brilot
- Brain Autoimmunity Group, Kids Neuroscience Centre, The Children's Hospital at Westmead, Faculty of Medicine and Health, School of Medical Sciences, Sydney, NSW, Australia; School of Medical Science, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia
| | - Vanessa Milogiannakis
- Immunovirology and Pathogenesis Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Anouschka Akerman
- Immunovirology and Pathogenesis Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Anupriya Aggarwal
- Immunovirology and Pathogenesis Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Miles P Davenport
- Infection Analytics Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Elissa K Deenick
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; Immunovirology and Pathogenesis Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Christine L Chaffer
- St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia; Cancer Plasticity and Dormancy Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Peter I Croucher
- St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia; Cancer Plasticity and Dormancy Program, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Robert Brink
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; Immune Biotherapies Program, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Leonard D Goldstein
- St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia; Data Science Platform, Garvan Institute of Medical Research, Sydney, NSW 2010, Australia
| | - Deborah Cromer
- Infection Analytics Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Stuart G Turville
- Immunovirology and Pathogenesis Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia
| | - Anthony D Kelleher
- Immunovirology and Pathogenesis Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia; St. Vincent's Hospital Sydney, Sydney, NSW, Australia.
| | - Vanessa Venturi
- Immunovirology and Pathogenesis Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.
| | - C Mee Ling Munier
- Immunovirology and Pathogenesis Program, Kirby Institute, UNSW Sydney, Sydney, NSW, Australia.
| | - Tri Giang Phan
- Precision Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Healthcare Clinical Campus, School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia.
| |
Collapse
|
5
|
Chen YT, Lohia GK, Chen S, Liu Z, Wong Fok Lung T, Wang C, Riquelme SA. A host-pathogen metabolic synchrony that facilitates disease tolerance. Nat Commun 2025; 16:3729. [PMID: 40253414 PMCID: PMC12009439 DOI: 10.1038/s41467-025-59134-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 04/10/2025] [Indexed: 04/21/2025] Open
Abstract
Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, which mediates cooperative host-pathogen interactions. In P. aeruginosa, itaconate modifies key cysteine residues in TCA cycle enzymes critical for succinate metabolism, inducing bioenergetic stress and promoting the formation biofilms that are less immunostimulatory and allow the bacteria to integrate into the local microbiome. Itaconate incorporates into the central metabolism of the biofilm, driving exopolysaccharide production-particularly alginate-which amplifies airway itaconate signaling. This itaconate-alginate interplay limits host immunopathology by enabling pulmonary glutamine assimilation, activating glutaminolysis, and thereby restrain detrimental inflammation caused by the inflammasome. Clinical sample analysis reveals that P. aeruginosa adapts to this metabolic environment through compensatory mutations in the anti-sigma-factor mucA, which restore the succinate-driven bioenergetics and disrupt the metabolic synchrony essential for sustaining disease tolerance.
Collapse
Affiliation(s)
- Ying-Tsun Chen
- Department of Pediatrics, Columbia University, New York, NY, USA
| | | | - Samantha Chen
- Department of Pediatrics, Columbia University, New York, NY, USA
| | - Zihua Liu
- Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | | | - Chu Wang
- Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
| | | |
Collapse
|
6
|
Dexter T, Anthias C, Nicholson E. Evaluating Axatilimab as a treatment option for chronic graft-versus-host disease. Immunotherapy 2025; 17:409-418. [PMID: 40338737 DOI: 10.1080/1750743x.2025.2501928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2025] [Accepted: 05/01/2025] [Indexed: 05/10/2025] Open
Abstract
Allogeneic stem cell transplantation represents the only curative option for many patients with high risk hematological malignancies but is associated with a number of severe complications. Of these, chronic graft versus host disease (cGVHD) is the leading cause of late non-relapse mortality and of much morbidity. For over 30 years, glucocorticoids have been the mainstay of first line therapy, yet approximately 50% patients are refractory or dependent and traditionally there have been few options for these patients. In recent years, newer treatments including ruxolitinib and belumosudil have shown success in the second and third line settings. However, further effective nontoxic treatments are a necessary to address this complex debilitating disease. Axatilimab is an antibody to colony stimulating factor 1 (CSF-1), a tyrosine kinase receptor. CSF1R signaling dependent macrophages and monocytes are key mediators of inflammation and fibrosis in chronic GVHD, and thus, this therapy offers a targeted approach. Here we summarize the key clinical studies that have been performed to date of this novel therapy.
Collapse
Affiliation(s)
- Tania Dexter
- Department of Haemato-Oncology, Royal Marsden Hospital, London, UK
- Anthony Nolan, London, UK
- Institute of Cancer Research, London, UK
| | - Chloe Anthias
- Department of Haemato-Oncology, Royal Marsden Hospital, London, UK
- Anthony Nolan, London, UK
- Institute of Cancer Research, London, UK
| | - Emma Nicholson
- Department of Haemato-Oncology, Royal Marsden Hospital, London, UK
- Institute of Cancer Research, London, UK
| |
Collapse
|
7
|
Hume DA, Summers KM, O'Brien C, Pavli P. The Relationship Between CSF1R Signaling, Monocyte-Macrophage Differentiation, and Susceptibility to Inflammatory Bowel Disease. Cell Mol Gastroenterol Hepatol 2025; 19:101510. [PMID: 40154882 DOI: 10.1016/j.jcmgh.2025.101510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 04/01/2025]
Abstract
More than 300 genomic loci have been associated with increased susceptibility to inflammatory bowel disease (IBD) through genome-wide association studies. A major challenge in the translation of genome-wide association studies to mechanistic insights lies in connecting noncoding variants to function. For example, single-nucleotide variants (SNVs) in the vicinity of the gene encoding the transcription factor ETS2 on human chromosome 21 are associated with the risk of developing IBD in Europeans. The peak of SNV association lies within a distal enhancer that may regulate ETS2 transcription. The interpretation of this and many other SNV associations with IBD depends on a model linking variation in transcriptional regulation to the likelihood of developing chronic intestinal inflammation. One model for the ETS2 locus is that overexpression in monocytes is causally associated with the risk allele, which in turn leads to a hyperinflammatory state. Here we summarize evidence for an alternative mechanism focused on negative regulators of monocyte-macrophage activation. We argue that IBD susceptibility arises from dysregulation of monocyte adaptation in the intestinal milieu to form resident intestinal macrophages that are anergic to inflammatory stimuli. This process depends on signals initiated by macrophage colony-stimulating factor (CSF1) binding to its receptor (CSF1R). Within this framework, ETS2 is a myeloid-specific transcription factor, expressed in pluripotent and committed progenitors and monocytes, and is down-regulated by CSF1, in common with many genes associated with IBD susceptibility, including NOD2. ETS2 is also both a downstream target and a mediator of the CSF1/CSF1R signaling pathway. Therapeutic targeting of ETS2 and its upstream regulators has the potential to prevent CSF1-dependent monocyte differentiation toward a prorepair resident macrophage phenotype and consequently exacerbate intestinal inflammation.
Collapse
Affiliation(s)
- David A Hume
- Mater Research Institute, University of Queensland, Woolloongabba, Brisbane, Australia.
| | - Kim M Summers
- Mater Research Institute, University of Queensland, Woolloongabba, Brisbane, Australia
| | - Claire O'Brien
- Centre for Research in Therapeutics Solutions, Faculty of Science and Technology, University of Canberra, Canberra, Australian Capital Territory, Australia
| | - Paul Pavli
- School of Medicine and Psychology, The Australian National University, Canberra, Australian Capital Territory, Australia; Gastroenterology and Hepatology Unit, Canberra Hospital, Canberra, Australian Capital Territory, Australia.
| |
Collapse
|
8
|
Joalland N, Quéméner A, Deshayes S, Humeau R, Maillasson M, LeBihan H, Salama A, Fresquet J, Remy S, Mortier E, Blanquart C, Guillonneau C, Anegon I. New soluble CSF-1R-dimeric mutein with enhanced trapping of both CSF-1 and IL-34 reduces suppressive tumor-associated macrophages in pleural mesothelioma. J Immunother Cancer 2025; 13:e010112. [PMID: 40101804 PMCID: PMC11927444 DOI: 10.1136/jitc-2024-010112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2024] [Accepted: 02/18/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND Colony stimulating factor-1 receptor (CSF-1R) and its ligands CSF-1 and interleukin (IL)-34 have tumorigenic effects through both induction of suppressive macrophages, and survival/proliferation of tumor cells. In addition, the IL-34 tumorigenic effect can also be mediated by its other receptors, protein-tyrosine phosphatase zeta, Syndecan-1 (CD138) and triggering receptor expressed on myeloid cells 2. Small tyrosine kinase inhibitors are used to block CSF-1R signaling but lack specificity. Neutralizing anti-CSF-1 and/or IL-34 antibodies have been proposed, but their effects are limited. Thus, there is a need for a more specific and yet integrative approach. METHODS A human mutated form of the extracellular portion of CSF-1R was in silico modelized to trap both IL-34 and CSF-1 with higher affinity than the wild-type CSF-1R by replacing the methionine residue at position 149 with a Lysine (M149K). The extracellular portion of the mutated CSF-1R M149K was dimerized using the immunoglobulin Fc sequence of a silenced human IgG1 (sCSF-1RM149K-Fc). Signaling through CSF-1R, survival of monocytes and differentiation of suppressive macrophages were analyzed using pleural mesothelioma patient's samples and mesothelioma/macrophage spheroids in vitro and in vivo in the presence of sCSF-1RM149K-Fc or sCSF-1R-Fc wild type control (sCSF-1RWT-Fc). RESULTS We defined that the D1 to D5 domains of the extracellular portion of CSF-1R were required for efficient binding to IL-34 and CSF-1. The mutein sCSF-1RM149K-Fc trapped with higher affinity than sCSF-1RWT-Fc both CSF-1 and IL-34 added in culture and naturally produced in mesothelioma pleural effusions. sCSF-1RM149K-Fc inhibited CSF-1R signaling, survival and differentiation of human suppressive macrophage in vitro and in vivo induced by pleural mesothelioma cells. Neutralization of IL-34 and CSF-1 by sCSF-1RM149K-Fc also resulted in higher killing of pleural mesothelioma cells by a tumor-specific CD8+ T cell clone in mesothelioma/macrophage spheroids. CONCLUSIONS sCSF-1RM149K-Fc efficiently traps both CSF-1 and IL-34 and inhibits CSF-1R signaling, monocyte survival and suppressive macrophage differentiation induced by pleural mesothelioma cells producing CSF-1 and IL-34, as well as restores cytotoxic T-cell responses. sCSF-1RM149K-Fc has therapeutic potential vs other therapies under development targeting single components of this complex cytokine pathway involved in cancer.
Collapse
Affiliation(s)
- Noémie Joalland
- INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France
- LabEx IGO, Nantes Université, Nantes, France
| | - Agnès Quéméner
- LabEx IGO, Nantes Université, Nantes, France
- INSERM, UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, University of Nantes, Nantes, France
| | - Sophie Deshayes
- LabEx IGO, Nantes Université, Nantes, France
- INSERM, UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, University of Nantes, Nantes, France
| | - Romain Humeau
- INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France
- LabEx IGO, Nantes Université, Nantes, France
| | - Mike Maillasson
- LabEx IGO, Nantes Université, Nantes, France
- INSERM, UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, University of Nantes, Nantes, France
- INSERM, CNRS, SFR Bonamy, UMS BioCore, Imp@ct Platform, Nantes Université, Centre Hospitalo-Universitaire (CHU) Nantes, Nantes, France
| | - Héloïse LeBihan
- INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France
- LabEx IGO, Nantes Université, Nantes, France
| | - Apolline Salama
- INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France
- LabEx IGO, Nantes Université, Nantes, France
| | - Judith Fresquet
- LabEx IGO, Nantes Université, Nantes, France
- INSERM, UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, University of Nantes, Nantes, France
| | - Séverine Remy
- INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France
| | - Erwan Mortier
- LabEx IGO, Nantes Université, Nantes, France
- INSERM, UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, University of Nantes, Nantes, France
- INSERM, CNRS, SFR Bonamy, UMS BioCore, Imp@ct Platform, Nantes Université, Centre Hospitalo-Universitaire (CHU) Nantes, Nantes, France
| | - Christophe Blanquart
- LabEx IGO, Nantes Université, Nantes, France
- INSERM, UMR 1307, CNRS UMR 6075, Université d'Angers, CRCI2NA, University of Nantes, Nantes, France
| | - Carole Guillonneau
- INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France
- LabEx IGO, Nantes Université, Nantes, France
| | - Ignacio Anegon
- INSERM, Center for Research in Transplantation and Translational Immunology, UMR 1064, Nantes Universite, Nantes, France
- LabEx IGO, Nantes Université, Nantes, France
| |
Collapse
|
9
|
Yu B, Wang X, zheng Y, Wang W, Cheng X, Cao Y, Wei M, Fu Y, Chu Y, Wang L. M2 macrophages promote IL-10 +B-cell production and alleviate asthma in mice. IMMUNOTHERAPY ADVANCES 2025; 5:ltaf007. [PMID: 40342727 PMCID: PMC12059559 DOI: 10.1093/immadv/ltaf007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Accepted: 03/06/2025] [Indexed: 05/11/2025] Open
Abstract
Introduction B cells have a central regulatory role in various diseases. While macrophages are found in the disease microenvironment and interact with tissue and diverse immune cells, their relationship with B cells remains poorly explored. Methods This study used an asthma animal model and macrophage depletion and demonstrated a significant exacerbation of asthma symptoms upon macrophage removal, coupled with a marked reduction in IL-10+ B-cell expression. Results Further analysis revealed that the macrophages interacting with IL-10+ B cells in the asthma microenvironment were of the M2 subtype. Furthermore, our sequencing data indicated a potential mechanism wherein M2 macrophages promote IL-10+ B-cell activity through the TGF-β pathway and oxidative phosphorylation pathways. Conclusion These findings suggest that M2 macrophages modulate IL-10+ B cells, ultimately mitigating asthma symptoms in mouse models.
Collapse
Affiliation(s)
- Baichao Yu
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xueqi Wang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yongkun zheng
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wenjun Wang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xiaoqin Cheng
- Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yue Cao
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Mingxing Wei
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ying Fu
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yiwei Chu
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Luman Wang
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
- Shanghai Fifth People’s Hospital, Fudan University, Shanghai, China
| |
Collapse
|
10
|
Adams RC, MacDonald KPA, Hill GR. The contribution of the monocyte-macrophage lineage to immunotherapy outcomes. Blood 2025; 145:1010-1021. [PMID: 39576958 DOI: 10.1182/blood.2024025680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Revised: 10/21/2024] [Accepted: 11/04/2024] [Indexed: 11/24/2024] Open
Abstract
ABSTRACT Macrophages execute core functions in maintaining tissue homeostasis, in which their extensive plasticity permits a spectrum of functions from tissue remodeling to immune defense. However, perturbations to tissue-resident macrophages during disease, and the subsequent emergence of monocyte-derived macrophages, can hinder tissue recovery and promote further damage through inflammatory and fibrotic programs. Gaining a fundamental understanding of the critical pathways defining pathogenic macrophage populations enables the development of targeted therapeutic approaches to improve disease outcomes. In the setting of chronic graft-versus-host disease (cGVHD), which remains the major complication of allogeneic hematopoietic stem cell transplantation, colony-stimulating factor 1 (CSF1)-dependent donor-derived macrophages have been identified as key pathogenic mediators of fibrotic skin and lung disease. Antibody blockade of the CSF1 receptor (CSF1R) to induce macrophage depletion showed remarkable capacity to prevent fibrosis in preclinical models and has subsequently demonstrated impressive efficacy for improving cGVHD in ongoing clinical trials. Similarly, macrophage depletion approaches are currently under investigation for their potential to augment responses to immune checkpoint inhibition. Moreover, both monocyte and tissue-resident macrophage populations have recently been implicated as mediators of the numerous toxicities associated with chimeric antigen receptor T-cell therapy, further highlighting potential avenues of macrophage-based interventions to improve clinical outcomes. Herein, we examine the current literature on basic macrophage biology and contextualize this in the setting of cellular and immunotherapy. Additionally, we highlight mechanisms by which macrophages can be targeted, largely by interfering with the CSF1/CSF1R signaling axis, for therapeutic benefit in the context of both cellular and immunotherapy.
Collapse
Affiliation(s)
- Rachael C Adams
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Kelli P A MacDonald
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, Australia
| | - Geoffrey R Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| |
Collapse
|
11
|
Yang Y, Sokolov V, Volkova A, Liu X, Leon C, Kosinsky Y, Barker B, Zhang X, Ordentlich P, Sheng J, Chen X. Semimechanistic Population PK/PD Modeling of Axatilimab in Healthy Participants and Patients With Solid Tumors or Chronic Graft-Versus-Host Disease. Clin Pharmacol Ther 2025; 117:704-715. [PMID: 39704205 PMCID: PMC11835428 DOI: 10.1002/cpt.3503] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 11/10/2024] [Indexed: 12/21/2024]
Abstract
Axatilimab, a high-affinity humanized immunoglobulin G4 monoclonal antibody against colony-stimulating factor 1 receptor (CSF-1R), is approved for the treatment of chronic graft-versus-host disease (cGVHD), and under investigation for idiopathic pulmonary fibrosis and solid tumors. The population pharmacokinetics (PK) and pharmacodynamics (PD) of axatilimab were characterized in healthy participants and patients with solid tumors or cGVHD using data from four clinical studies with 325 participants, including 278 patients with cGVHD. The model structure reflected the mechanism of action of axatilimab: blocking CSF-1R signaling with axatilimab reduces the circulating levels of cells in the mononuclear phagocytic cell lineage (including nonclassical monocytic cells (NCMCs) and Kupffer cells), resulting in increases in circulating enzymes owing to reduced clearance by Kupffer cells. The structural model consisted of a two-compartment axatilimab PK model and turnover PD models for CSF-1, NCMCs, aspartate transaminase (AST), and creatine phosphokinase (CPK). Axatilimab PK and CSF-1 equations also included saturable clearance components to reflect the competitive binding of axatilimab and CSF-1 to CSF-1R. Covariate search was conducted with the conditional sampling use for the stepwise approach based on correlation tests (COSSAC) approach. Covariate effects on model parameters, steady-state axatilimab exposure, and NCMC concentrations were assessed. The final population PK/PD model was mathematically described with 6 ordinary differential equations and 39 model parameters. Among the 11 statistically significant covariates, one (body weight) and two (participant population type and baseline CPK) covariates affected axatilimab steady-state exposure and steady-state NCMC levels by > 20%, respectively. These results informed the axatilimab dosing strategy in patients with cGVHD.
Collapse
MESH Headings
- Humans
- Male
- Adult
- Female
- Middle Aged
- Graft vs Host Disease/drug therapy
- Graft vs Host Disease/blood
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/pharmacology
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/therapeutic use
- Neoplasms/drug therapy
- Neoplasms/blood
- Models, Biological
- Aged
- Young Adult
- Healthy Volunteers
- Chronic Disease
- Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/antagonists & inhibitors
- Adolescent
- Receptor, Macrophage Colony-Stimulating Factor
Collapse
Affiliation(s)
| | - Victor Sokolov
- M&S Decisions FZ LLCDubaiUnited Arab Emirates
- Marchuk Institute of Numerical Mathematics RASMoscowRussia
| | - Alina Volkova
- M&S Decisions FZ LLCDubaiUnited Arab Emirates
- Marchuk Institute of Numerical Mathematics RASMoscowRussia
| | - Xing Liu
- Incyte CorporationWilmingtonDelawareUSA
| | | | | | | | | | | | | | | |
Collapse
|
12
|
Lehtonen H, Jokela H, Hofmann J, Tola L, Mehmood A, Ginhoux F, Becher B, Greter M, Yegutkin GG, Salmi M, Gerke H, Rantakari P. Early precursor-derived pituitary gland tissue-resident macrophages play a pivotal role in modulating hormonal balance. Cell Rep 2025; 44:115227. [PMID: 39841599 DOI: 10.1016/j.celrep.2024.115227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Revised: 11/26/2024] [Accepted: 12/30/2024] [Indexed: 01/24/2025] Open
Abstract
The pituitary gland is the central endocrine regulatory organ producing and releasing hormones that coordinate major body functions. The physical location of the pituitary gland at the base of the brain, though outside the protective blood-brain barrier, leads to an unexplored special immune environment. Using single-cell transcriptomics, fate mapping, and imaging, we characterize pituitary-resident macrophages (pitMØs), revealing their heterogeneity and spatial specialization. Microglia-like macrophages (ml-MACs) are enriched in the posterior pituitary, while other pitMØs in the anterior pituitary exhibit close interactions with hormone-secreting cells. Importantly, all pitMØs originate from early yolk sac progenitors and maintain themselves through self-renewal, independent of bone marrow-derived monocytes. Macrophage depletion experiments unveil the role of macrophages in regulating intrapituitary hormonal balance through extracellular ATP-mediated intercellular signaling. Altogether, these findings provide information on pituitary gland macrophages and advance our understanding of immune-endocrine system crosstalk.
Collapse
Affiliation(s)
- Henna Lehtonen
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Heli Jokela
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Julian Hofmann
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Lauriina Tola
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Arfa Mehmood
- Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Florent Ginhoux
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China; Singapore Immunology Network, Agency for Science, Technology and Research, Singapore 138648, Singapore; INSERM U1015, Gustave Roussy Cancer Campus, Villejuif 94800, France; Translational Immunology Institute, SingHealth Duke-NUS, Singapore 169856, Singapore; Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Burkhard Becher
- Institute of Experimental Immunology, University of Zürich, 8057 Zurich, Switzerland
| | - Melanie Greter
- Institute of Experimental Immunology, University of Zürich, 8057 Zurich, Switzerland
| | - Gennady G Yegutkin
- InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland; MediCity Research Laboratory, University of Turku, 20520 Turku, Finland
| | - Marko Salmi
- Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland; MediCity Research Laboratory, University of Turku, 20520 Turku, Finland
| | - Heidi Gerke
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland
| | - Pia Rantakari
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Institute of Biomedicine, University of Turku, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku, 20520 Turku, Finland.
| |
Collapse
|
13
|
Santamaria de Souza N, Cherrak Y, Andersen TB, Vetsch M, Barthel M, Kroon S, Bakkeren E, Schubert C, Christen P, Kiefer P, Vorholt JA, Nguyen BD, Hardt WD. Context-dependent change in the fitness effect of (in)organic phosphate antiporter glpT during Salmonella Typhimurium infection. Nat Commun 2025; 16:1912. [PMID: 39994176 PMCID: PMC11850910 DOI: 10.1038/s41467-025-56851-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 02/04/2025] [Indexed: 02/26/2025] Open
Abstract
Salmonella enterica is a frequent cause of foodborne diseases, which is attributed to its adaptability. Even within a single host, expressing a gene can be beneficial in certain infection stages but neutral or even detrimental in others as previously shown for flagellins. Mutants deficient for the conserved glycerol-3-phosphate and phosphate antiporter glpT have been shown to be positively selected in nature, clinical, and laboratory settings. This suggests that different selective pressures select for the presence or absence of GlpT in a context dependent fashion, a phenomenon known as antagonistic pleiotropy. Using mutant libraries and reporters, we investigated the fitness of glpT-deficient mutants during murine orogastric infection. While glpT-deficient mutants thrive during initial growth in the gut lumen, where GlpT's capacity to import phosphate is disadvantageous, they are counter-selected by macrophages. The dichotomy showcases the need to study the spatial and temporal heterogeneity of enteric pathogens' fitness across distinct lifestyles and niches. Insights into the differential adaptation during infection may reveal opportunities for therapeutic interventions.
Collapse
Affiliation(s)
| | - Yassine Cherrak
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Thea Bill Andersen
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Michel Vetsch
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Manja Barthel
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Sanne Kroon
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Erik Bakkeren
- Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
| | - Christopher Schubert
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Philipp Christen
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Patrick Kiefer
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Julia A Vorholt
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Bidong D Nguyen
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland
| | - Wolf-Dietrich Hardt
- Department of Biology, Institute of Microbiology, ETH Zürich, Zürich, Switzerland.
| |
Collapse
|
14
|
Lin L, Huang T, Li L, Lin Y, Chen F, Zheng Z, Zhou J, Wang Y, You W, Duan Y, An Y, He S, Ye W. Single-cell profiling reveals a reduced epithelial defense system, decreased immune responses and the immune regulatory roles of different fibroblast subpopulations in chronic atrophic gastritis. J Transl Med 2025; 23:159. [PMID: 39905493 PMCID: PMC11796052 DOI: 10.1186/s12967-025-06150-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 01/18/2025] [Indexed: 02/06/2025] Open
Abstract
PURPOSE To identify key cellular changes and molecular events in atrophic mucosa, we aimed to elucidate the molecular mechanisms driving the occurrence of chronic atrophic gastritis (CAG). METHODS We used single-cell RNA sequencing (scRNA-seq) to characterize changes in the epithelial state and tissue microenvironment associated with CAG. The molecular changes were identified by comparing differentially expressed genes (DEGs) between the two mucosa states. Gene Ontology (GO) pathway enrichment analysis was used to explore the potential functional changes in each cell subtype in atrophic mucosa. Gene set score analysis was conducted to compare the functional roles of different fibroblast subtypes and functional changes in cell subtypes between the CAG and control groups. Metabolic analysis was performed to compare the metabolic activity of C1Q+ macrophages under different conditions. NichNet analysis was used to analyze the regulatory relationships between CCL11+APOE+ fibroblasts and C1Q+ macrophages and between CCL11+APOE+ fibroblasts and CD8+ effector T cells. Transcription factor (TF) analysis was performed to determine the transcription status of different T-cell subtypes in atrophic and normal mucosa. RESULTS We generated a single-cell transcriptomic atlas from 3 CAG biopsy samples and paired adjacent normal tissues. Our analysis revealed that chief cells and parietal cells exhibited a loss of detoxification ability and that surface mucous cells displayed a reduced antimicrobial defense ability in CAG lesions. The mucous neck cells in CAG lesions showed upregulation of genes related to cell cycle transition, which may lead to aberrant DNA replication. Additionally, cells with the T exhaustion phenotype infiltrated under CAG condition. C1Q+ macrophages exhibited reduced phagocytosis, downregulated expression of pattern recognition receptors and decreased metabolic activity. NichNet analysis revealed that a subpopulation of CXCL11+APOE+ fibroblasts regulated the inflammatory response in the pathogenesis of atrophic gastritis. APSN+CXCL11+APOE+ fibroblasts were found to be associated with gastric cancer (GC) development. CONCLUSIONS The main goal of this study was to comprehensively elucidate the cellular changes in CAG lesions. We observed an immune decline in the mucosal microenvironment during the development of CAG, including a reduced immune response of C1Q+ macrophages, reduced cytotoxicity of T cells, and increased infiltration of exhausted T cells. Specifically, we demonstrated that different epithelial subtypes aberrantly express genes related to susceptibility to external bacterial infection and aberrant cell cycle progression. Our study provides new insights into the functions of epithelial changes and immune alterations during the development of CAG.
Collapse
Affiliation(s)
- Lin Lin
- Institute of Population Medicine, School of Public Health, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, China
| | - Tingxuan Huang
- Department of Gastroenterology, Fujian Medical University Union Hospital, Fuzhou, 350001, China
- Fujian Clinical Research Center for Digestive System Tumors and Upper Gastrointestinal Diseases, Fuzhou, 350001, China
| | - Lizhi Li
- Department of Pediatric Surgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
| | - Yang Lin
- Department of Pediatric Surgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
| | - Feng Chen
- Department of Pediatric Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Ziyi Zheng
- Department of Pediatric Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Jie Zhou
- Department of Pediatric Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
| | - Yizhe Wang
- Institute of Population Medicine, School of Public Health, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, China
| | - Weihao You
- Institute of Population Medicine, School of Public Health, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, China
| | - Yujie Duan
- Institute of Population Medicine, School of Public Health, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, China
| | - Yawen An
- Institute of Population Medicine, School of Public Health, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, China
| | - Shiwei He
- Institute of Population Medicine, School of Public Health, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, China.
| | - Weimin Ye
- Institute of Population Medicine, School of Public Health, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, China.
- Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Fujian Medical University, Fuzhou, 350122, China.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, 17177, Sweden.
| |
Collapse
|
15
|
Waibl Polania J, Hoyt-Miggelbrink A, Tomaszewski WH, Wachsmuth LP, Lorrey SJ, Wilkinson DS, Lerner E, Woroniecka K, Finlay JB, Ayasoufi K, Fecci PE. Antigen presentation by tumor-associated macrophages drives T cells from a progenitor exhaustion state to terminal exhaustion. Immunity 2025; 58:232-246.e6. [PMID: 39724910 DOI: 10.1016/j.immuni.2024.11.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 08/26/2024] [Accepted: 11/27/2024] [Indexed: 12/28/2024]
Abstract
Whereas terminally exhausted T (Tex_term) cells retain anti-tumor cytotoxic functions, the frequencies of stem-like progenitor-exhausted T (Tex_prog) cells better reflect immunotherapeutic responsivity. Here, we examined the intratumoral cellular interactions that govern the transition to terminal T cell exhaustion. We defined a metric reflecting the intratumoral progenitor exhaustion-to-terminal exhaustion ratio (PETER), which decreased with tumor progression in solid cancers. Single-cell analyses of Tex_prog cells and Tex_term cells in glioblastoma (GBM), a setting of severe T cell exhaustion, revealed disproportionate loss of Tex_prog cells over time. Exhaustion concentrated within tumor-specific T cell subsets, with cognate antigen exposure requisite for acquisition of the Tex_term phenotype. Tumor-associated macrophages (TAMs)-not tumor cells-were the primary source of antigenic exposure governing the Tex_prog to Tex_term transition. TAM depletion increased frequencies of Tex_prog cells in multiple tumor models, increased PETER, and promoted responsiveness to αPD1 immunotherapy. Thus, targeting TAM-T cell interactions may further license checkpoint blockade responses.
Collapse
Affiliation(s)
| | | | | | - Lucas P Wachsmuth
- Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA; Duke Medical Scientist Training Program, Duke University School of Medicine, Durham, NC 27710, USA
| | - Selena J Lorrey
- Department of Immunology, Duke University, Durham, NC 27710, USA
| | - Daniel S Wilkinson
- Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - Emily Lerner
- Duke Medical Scientist Training Program, Duke University School of Medicine, Durham, NC 27710, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27710, USA
| | - Karolina Woroniecka
- Department of Pathology, Duke University School of Medicine, Durham, NC 27710, USA
| | - John B Finlay
- Duke Medical Scientist Training Program, Duke University School of Medicine, Durham, NC 27710, USA
| | - Katayoun Ayasoufi
- Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - Peter E Fecci
- Department of Neurosurgery, Duke University School of Medicine, Durham, NC 27710, USA.
| |
Collapse
|
16
|
Carter-Cusack D, Huang S, Keshvari S, Patkar O, Sehgal A, Allavena R, Byrne RAJ, Morgan BP, Bush SJ, Summers KM, Irvine KM, Hume DA. Wild-type bone marrow cells repopulate tissue resident macrophages and reverse the impacts of homozygous CSF1R mutation. PLoS Genet 2025; 21:e1011525. [PMID: 39869647 PMCID: PMC11785368 DOI: 10.1371/journal.pgen.1011525] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/31/2025] [Accepted: 12/04/2024] [Indexed: 01/29/2025] Open
Abstract
Adaptation to existence outside the womb is a key event in the life of a mammal. The absence of macrophages in rats with a homozygous mutation in the colony-stimulating factor 1 receptor (Csf1r) gene (Csf1rko) severely compromises pre-weaning somatic growth and maturation of organ function. Transfer of wild-type bone marrow cells (BMT) at weaning rescues tissue macrophage populations permitting normal development and long-term survival. To dissect the phenotype and function of macrophages in postnatal development, we generated transcriptomic profiles of all major organs of wild-type and Csf1rko rats at weaning and in selected organs following rescue by BMT. The transcriptomic profiles revealed subtle effects of macrophage deficiency on development of all major organs. Network analysis revealed a common signature of CSF1R-dependent resident tissue macrophages that includes the components of complement C1Q (C1qa/b/c genes). Circulating C1Q was almost undetectable in Csf1rko rats and rapidly restored to normal levels following BMT. Tissue-specific macrophage signatures were also identified, notably including sinus macrophage populations in the lymph nodes. Their loss in Csf1rko rats was confirmed by immunohistochemical localisation of CD209B (SIGNR1). By 6-12 weeks, Csf1rko rats succumb to emphysema-like pathology associated with the selective loss of interstitial macrophages and granulocytosis. This pathology was reversed by BMT. Along with physiological rescue, BMT precisely regenerated the abundance and expression profiles of resident macrophages. The exception was the brain, where BM-derived microglia-like cells had a distinct expression profile compared to resident microglia. In addition, the transferred BM failed to restore blood monocyte or CSF1R-positive bone marrow progenitors. These studies provide a model for the pathology and treatment of CSF1R mutations in humans and the innate immune deficiency associated with prematurity.
Collapse
Affiliation(s)
- Dylan Carter-Cusack
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Stephen Huang
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Sahar Keshvari
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Omkar Patkar
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Anuj Sehgal
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Rachel Allavena
- School of Veterinary Science, The University of Queensland, Gatton, Australia
| | - Robert A. J. Byrne
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - B. Paul Morgan
- UK Dementia Research Institute Cardiff, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Stephen J. Bush
- School of Automation Science and Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China
| | - Kim M. Summers
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - Katharine M. Irvine
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| | - David A. Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, Brisbane, Australia
| |
Collapse
|
17
|
Huang T, Wei L, Zhou H, Liu J. Macrophage Infiltration and ITGB2 Expression in ESCC: A Novel Correlation. Cancer Med 2025; 14:e70604. [PMID: 39825491 PMCID: PMC11742006 DOI: 10.1002/cam4.70604] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 09/22/2024] [Accepted: 01/03/2025] [Indexed: 01/20/2025] Open
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is one of the most prevalent and lethal malignancies worldwide. Despite progress in immunotherapy for cancer treatment, its application and efficacy in ESCC remain limited. Therefore, there is an ongoing need to explore potential molecules and therapeutic strategies related to tumor immunity in ESCC. METHODS In this study, we integrated high-throughput sequencing data, gene chip data, single-cell sequencing data, and various bioinformatics analysis methods along with experimental approaches to identify key genes involved in immune infiltration in ESCC and investigate their relationship with immune cell development, as well as the potential of these key genes in immunotherapy. RESULTS We discovered and validated a positive correlation between macrophage infiltration and ITGB2 expression in ESCC. ITGB2 is overexpressed in ESCC and has potential as a prognostic biomarker for the disease. We present for the first time the finding that the expression of ITGB2 in infiltrating macrophages increases as these macrophages polarize toward a tumor-promoting phenotype in ESCC. Moreover, during the progression of ESCC, ITGB2 expression in infiltrating macrophages is upregulated. The higher the expression of ITGB2, the more feasible it is to target macrophages. Additionally, we found that evaluating immune therapy responses in ESCC patients through ITGB2 expression is a viable approach. Furthermore, we identified three miRNAs associated with abnormal ITGB2 expression, providing insights into the upstream molecular interactions of ITGB2. CONCLUSIONS Macrophage infiltration in ESCC is closely associated with ITGB2, which holds significant potential for immunotherapy applications in ESCC. Based on our findings and prior studies, we propose a novel hypothesis: inducing M1 macrophages in vitro, knocking out ITGB2, and then reinfusing these ITGB2-knockout M1 macrophages into ESCC patients may represent a promising new immunotherapy strategy, providing a new avenue for ESCC immunotherapy.
Collapse
Affiliation(s)
- Tao Huang
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Guangxi Medical UniversityNanningPeople's Republic of China
| | - Longqian Wei
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Guangxi Medical UniversityNanningPeople's Republic of China
| | - Huafu Zhou
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Guangxi Medical UniversityNanningPeople's Republic of China
| | - Jun Liu
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Guangxi Medical UniversityNanningPeople's Republic of China
| |
Collapse
|
18
|
Mo H, Zhang X, Ren L. Analysis of neuroglia and immune cells in the tumor microenvironment of breast cancer brain metastasis. Cancer Biol Ther 2024; 25:2398285. [PMID: 39238191 PMCID: PMC11382727 DOI: 10.1080/15384047.2024.2398285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 08/15/2024] [Accepted: 08/26/2024] [Indexed: 09/07/2024] Open
Abstract
Breast cancer stands as the most prevalent cancer diagnosed worldwide, often leading to brain metastasis, a challenging complication characterized by high mortality rates and a grim prognosis. Understanding the intricate mechanisms governing breast cancer brain metastasis (BCBM) remains an ongoing challenge. The unique microenvironment in the brain fosters an ideal setting for the colonization of breast cancer cells. The tumor microenvironment (TME) in brain metastases plays a pivotal role in the initiation and progression of BCBM, shaping the landscape for targeted therapeutic interventions. Current research primarily concentrates on unraveling the complexities of the TME in BCBM, with a particular emphasis on neuroglia and immune cells, such as microglia, monocyte-derived macrophages (MDMs), astrocytes and T cells. This comprehensive review delves deeply into these elements within the TME of BCBM, shedding light on their interplay, mechanisms, and potential as therapeutic targets to combat BCBM.
Collapse
Affiliation(s)
- Haixin Mo
- Clinical Experimental Center, Jiangmen Engineering Technology Research Center of Clinical Biobank and Translational Research, Jiangmen Central Hospital, Jiangmen, China
| | - Xin Zhang
- Clinical Experimental Center, Jiangmen Engineering Technology Research Center of Clinical Biobank and Translational Research, Jiangmen Central Hospital, Jiangmen, China
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan, China
- Collaborative Innovation Center for Antitumor Active Substance Research and Development, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Liangliang Ren
- Clinical Experimental Center, Jiangmen Engineering Technology Research Center of Clinical Biobank and Translational Research, Jiangmen Central Hospital, Jiangmen, China
| |
Collapse
|
19
|
Mohamed SH, Vanhoffelen E, Shun Fu M, Hei Lau P, Hain S, Seldeslachts L, Cosway E, Anderson G, McCulloch L, Vande Velde G, Drummond RA. CSF1R inhibition by PLX5622 reduces pulmonary fungal infection by depleting MHCII hi interstitial lung macrophages. Mucosal Immunol 2024; 17:1256-1272. [PMID: 39168451 DOI: 10.1016/j.mucimm.2024.08.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 08/08/2024] [Accepted: 08/14/2024] [Indexed: 08/23/2024]
Abstract
PLX5622 is a small molecular inhibitor of the CSF1 receptor (CSF1R) and is widely used to deplete macrophages within the central nervous system (CNS). We investigated the impact of PLX5622 treatment in wild-type C57BL/6 mice and discovered that one-week treatment with PLX5622 was sufficient to deplete interstitial macrophages in the lung and brain-infiltrating Ly6Clow patrolling monocytes, in addition to CNS-resident macrophages. These cell types were previously indicated to act as infection reservoirs for the pathogenic fungus Cryptococcus neoformans. We found that PLX5622-treated mice had significantly reduced fungal lung infection and reduced extrapulmonary dissemination to the CNS but not to the spleen or liver. Fungal lung infection mapped to MHCIIhi interstitial lung macrophages, which underwent significant expansion during infection following monocyte replenishment and not local division. Although PLX5622 depleted CNS infiltrating patrolling monocytes, these cells did not accumulate in the fungal-infected CNS following pulmonary infection. In addition, Nr4a1-deficient mice, which lack patrolling monocytes, had similar control and dissemination of C. neoformans infection to wild-type controls. PLX5622 did not directly affect CD4 T-cell responses, or significantly affect production of antibody in the lung during infection. However, we found that mice lacking lymphocytes had reduced numbers of MHCIIhi interstitial macrophages in the lung, which correlated with reduced infection load. Accordingly, PLX5622 treatment did not alter fungal burdens in the lungs of lymphocyte-deficient mice. Our data demonstrate that PLX5622 may help reduce lung burden of pathogenic fungi that utilise CSF1R-dependent myeloid cells as infection reservoirs, an effect which is dependent on the presence of lymphocytes.
Collapse
Affiliation(s)
- Sally H Mohamed
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Eliane Vanhoffelen
- Department of Imaging and Pathology, Biomedical MRI/MoSAIC, KU Leuven, Leuven, Belgium
| | - Man Shun Fu
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Pui Hei Lau
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Sofia Hain
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Laura Seldeslachts
- Department of Imaging and Pathology, Biomedical MRI/MoSAIC, KU Leuven, Leuven, Belgium
| | - Emilie Cosway
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Graham Anderson
- Institute of Immunology & Immunotherapy, University of Birmingham, UK
| | - Laura McCulloch
- Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK
| | - Greetje Vande Velde
- Department of Imaging and Pathology, Biomedical MRI/MoSAIC, KU Leuven, Leuven, Belgium
| | - Rebecca A Drummond
- Institute of Immunology & Immunotherapy, University of Birmingham, UK; Institute of Microbiology & Infection, University of Birmingham, UK.
| |
Collapse
|
20
|
Murrey MW, Ng IT, Pixley FJ. The role of macrophage migratory behavior in development, homeostasis and tumor invasion. Front Immunol 2024; 15:1480084. [PMID: 39588367 PMCID: PMC11586339 DOI: 10.3389/fimmu.2024.1480084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 10/23/2024] [Indexed: 11/27/2024] Open
Abstract
Tumor-associated macrophages (TAMs) recapitulate the developmental and homeostatic behaviors of tissue resident macrophages (TRMs) to promote tumor growth, invasion and metastasis. TRMs arise in the embryo and colonize developing tissues, initially to guide tissue morphogenesis and then to form complex networks in adult tissues to constantly search for threats to homeostasis. The macrophage growth factor, colony-stimulating factor-1 (CSF-1), which is essential for TRM survival and differentiation, is also responsible for the development of the unique motility machinery of mature macrophages that underpins their ramified morphologies, migratory capacity and ability to degrade matrix. Two CSF-1-activated kinases, hematopoietic cell kinase and the p110δ catalytic isoform of phosphatidylinositol 3-kinase, regulate this machinery and selective inhibitors of these proteins completely block macrophage invasion. Considering tumors co-opt the invasive capacity of TAMs to promote their own invasion, these proteins are attractive targets for drug development to inhibit tumor progression to invasion and metastasis.
Collapse
Affiliation(s)
| | | | - Fiona J. Pixley
- Macrophage Biology and Cancer Laboratory, School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia
| |
Collapse
|
21
|
Gómez-Oro C, Latorre MC, Arribas-Poza P, Ibáñez-Escribano A, Baca-Cornejo KR, Gallego-Valle J, López-Escobar N, Mondéjar-Palencia M, Pion M, López-Fernández LA, Mercader E, Pérez-Milán F, Relloso M. Progesterone promotes CXCl2-dependent vaginal neutrophil killing by activating cervical resident macrophage-neutrophil crosstalk. JCI Insight 2024; 9:e177899. [PMID: 39298265 PMCID: PMC11529979 DOI: 10.1172/jci.insight.177899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 09/05/2024] [Indexed: 09/21/2024] Open
Abstract
Vaginal infections in women of reproductive age represent a clinical dilemma with significant socioeconomic implications. The current understanding of mucosal immunity failure during early pathogenic invasions that allows the pathogen to grow and thrive is far from complete. Neutrophils infiltrate most tissues following circadian patterns as part of normal repair, regulation of microbiota, or immune surveillance and become more numerous after infection. Neutrophils are responsible for maintaining vaginal immunity. Specific to the vagina, neutrophils continuously infiltrate at high levels, although during ovulation, they retreat to avoid sperm damage and permit reproduction. Here we show that, after ovulation, progesterone promotes resident vaginal macrophage-neutrophil crosstalk by upregulating Yolk sac early fetal organs (FOLR2+) macrophage CXCl2 expression, in a TNFA-patrolling monocyte-derived macrophage-mediated (CX3CR1hiMHCIIhi-mediated) manner, to activate the neutrophils' capacity to eliminate sex-transmitted and opportunistic microorganisms. Indeed, progesterone plays an essential role in conciliating the balance between the commensal microbiota, sperm, and the threat of pathogens because progesterone not only promotes a flurry of neutrophils but also increases neutrophilic fury to restore immunity after ovulation to thwart pathogenic invasion after intercourse. Therefore, modest progesterone dysregulations could lead to a suboptimal neutrophilic response, resulting in insufficient mucosal defense and recurrent unresolved infections.
Collapse
Affiliation(s)
- Carla Gómez-Oro
- Laboratorio de InmunoReproducción, Grupo Fisiopatología de la mujer, del embarazo, parto y puerperio, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Maria C. Latorre
- Laboratorio de InmunoReproducción, Grupo Fisiopatología de la mujer, del embarazo, parto y puerperio, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Patricia Arribas-Poza
- Laboratorio de InmunoReproducción, Grupo Fisiopatología de la mujer, del embarazo, parto y puerperio, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Alexandra Ibáñez-Escribano
- Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, Madrid, Spain
| | - Katia R. Baca-Cornejo
- Laboratorio de InmunoReproducción, Grupo Fisiopatología de la mujer, del embarazo, parto y puerperio, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | | | - Natalia López-Escobar
- Laboratorio de InmunoReproducción, Grupo Fisiopatología de la mujer, del embarazo, parto y puerperio, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Mabel Mondéjar-Palencia
- Laboratorio de InmunoReproducción, Grupo Fisiopatología de la mujer, del embarazo, parto y puerperio, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| | - Marjorie Pion
- Laboratorio de InmunoRegulación, IiSGM, Madrid, Spain
| | - Luis A. López-Fernández
- Laboratorio de Farmacogenética, Grupo de Farmacia Hospitalaria y Farmacogenómica, IiSGM, Madrid, Spain
| | - Enrique Mercader
- Laboratorio de InmunoReproducción, Grupo Fisiopatología de la mujer, del embarazo, parto y puerperio, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Unidad Cirugía Endocrino-metabólica, Servicio de Cirugía General y Aparato Digestivo, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Federico Pérez-Milán
- Laboratorio de InmunoReproducción, Grupo Fisiopatología de la mujer, del embarazo, parto y puerperio, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
- Unidad de Reproducción Asistida, Servicio de Obstetricia y Ginecología, Hospital General Universitario Gregorio Marañón, Madrid, Spain
| | - Miguel Relloso
- Laboratorio de InmunoReproducción, Grupo Fisiopatología de la mujer, del embarazo, parto y puerperio, Instituto de Investigación Sanitaria Gregorio Marañón (IiSGM), Madrid, Spain
| |
Collapse
|
22
|
Petit M, Weber-Delacroix E, Lanthiez F, Barthélémy S, Guillou N, Firpion M, Bonduelle O, Hume DA, Combadière C, Boissonnas A. Visualizing the spatial organization of monocytes, interstitial macrophages, and tissue-specific macrophages in situ. Cell Rep 2024; 43:114847. [PMID: 39395172 DOI: 10.1016/j.celrep.2024.114847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 08/03/2024] [Accepted: 09/23/2024] [Indexed: 10/14/2024] Open
Abstract
Tissue-resident mononuclear phagocytes (MPs) are an abundant cell population whose localization in situ reflects their identity. To enable assessment of their heterogeneity, we developed the red/green/blue (RGB)-Mac mouse based upon combinations of Cx3cr1 and Csf1r reporter transgenes, providing a complete visualization of their spatial organization in situ. 3D-multi-photon imaging for spatial mapping and spectral cytometry employing the three markers in combination distinguished tissue-associated monocytes, tissue-specific macrophages, and three subsets of connective-tissue-associated MPs, including CCR2+ monocyte-derived cell, CX3CR1+, and FOLR2+ interstitial subsets, associated with distinct sub-anatomic territories. These populations were selectively reduced by blockade of CSF1, CSF2, CCR2, and CX3CR1 and efficiently reconstitute their spatial distribution after transient myelo-ablation, suggesting an autonomous regulatory environment. Our findings emphasize the organization of the MP compartment at the sub-anatomic level under steady-state conditions, thereby providing a holistic understanding of their relative heterogeneity across different tissues.
Collapse
Affiliation(s)
- Maxime Petit
- Sorbonne Université ́, Inserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Eléonore Weber-Delacroix
- Sorbonne Université ́, Inserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - François Lanthiez
- Sorbonne Université ́, Inserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Sandrine Barthélémy
- Sorbonne Université ́, Inserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Noëlline Guillou
- Sorbonne Université ́, Inserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Marina Firpion
- Sorbonne Université ́, Inserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Olivia Bonduelle
- Sorbonne Université ́, Inserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - David A Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Christophe Combadière
- Sorbonne Université ́, Inserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France
| | - Alexandre Boissonnas
- Sorbonne Université ́, Inserm U1135, CNRS ERL 8255, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), Paris, France.
| |
Collapse
|
23
|
Mildner A, Kim KW, Yona S. Unravelling monocyte functions: from the guardians of health to the regulators of disease. DISCOVERY IMMUNOLOGY 2024; 3:kyae014. [PMID: 39430099 PMCID: PMC11486918 DOI: 10.1093/discim/kyae014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2024] [Revised: 08/06/2024] [Accepted: 08/29/2024] [Indexed: 10/22/2024]
Abstract
Monocytes are a key component of the innate immune system. They undergo intricate developmental processes within the bone marrow, leading to diverse monocyte subsets in the circulation. In a state of healthy homeostasis, monocytes are continuously released into the bloodstream, destined to repopulate specific tissue-resident macrophage pools where they fulfil tissue-specific functions. However, under pathological conditions monocytes adopt various phenotypes to resolve inflammation and return to a healthy physiological state. This review explores the nuanced developmental pathways and functional roles that monocytes perform, shedding light on their significance in both physiological and pathological contexts.
Collapse
Affiliation(s)
- Alexander Mildner
- MediCity Research Laboratory, University of Turku, Turku, Finland
- InFLAMES Research Flagship, University of Turku, 20014 Turku, Finland
| | - Ki-Wook Kim
- Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Simon Yona
- Institute of Biomedical and Oral Research, Faculty of Dental Medicine, Hebrew University, Jerusalem, Israel
| |
Collapse
|
24
|
Becker SH, Ronayne CE, Bold TD, Jenkins MK. CD4 + T cells recruit, then engage macrophages in cognate interactions to clear Mycobacterium tuberculosis from the lungs. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.22.609198. [PMID: 39229103 PMCID: PMC11370583 DOI: 10.1101/2024.08.22.609198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
IFN-γ-producing CD4 + T cells are required for protection against lethal Mycobacterium tuberculosis ( Mtb ) infections. However, the ability of CD4 + T cells to suppress Mtb growth cannot be fully explained by IFN-γ or other known T cell products. In this study, we show that CD4 + T cell-derived IFN-γ promoted the recruitment of monocyte-derived macrophages (MDMs) to the lungs of Mtb -infected mice. Although the recruited MDMs became quickly and preferentially infected with Mtb , CD4 + T cells rapidly disinfected the MDMs. Clearance of Mtb from MDMs was not explained by IFN-γ, but rather by MHCII-mediated cognate interactions with CD4 + T cells. These interactions promoted MDM expression of glycolysis genes essential for Mtb control. Thus, by recruiting MDMs, CD4 + T cells initiate a cycle of bacterial phagocytosis, Mtb antigen presentation and disinfection in an attempt to clear the bacteria from the lungs.
Collapse
|
25
|
Lu H, Suo Z, Lin J, Cong Y, Liu Z. Monocyte-macrophages modulate intestinal homeostasis in inflammatory bowel disease. Biomark Res 2024; 12:76. [PMID: 39095853 PMCID: PMC11295551 DOI: 10.1186/s40364-024-00612-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Accepted: 07/04/2024] [Indexed: 08/04/2024] Open
Abstract
BACKGROUND Monocytes and macrophages play an indispensable role in maintaining intestinal homeostasis and modulating mucosal immune responses in inflammatory bowel disease (IBD). Although numerous studies have described macrophage properties in IBD, the underlying mechanisms whereby the monocyte-macrophage lineage modulates intestinal homeostasis during gut inflammation remain elusive. MAIN BODY In this review, we decipher the cellular and molecular mechanisms governing the generation of intestinal mucosal macrophages and fill the knowledge gap in understanding the origin, maturation, classification, and functions of mucosal macrophages in intestinal niches, particularly the phagocytosis and bactericidal effects involved in the elimination of cell debris and pathogens. We delineate macrophage-mediated immunoregulation in the context of producing pro-inflammatory and anti-inflammatory cytokines, chemokines, toxic mediators, and macrophage extracellular traps (METs), and participating in the modulation of epithelial cell proliferation, angiogenesis, and fibrosis in the intestine and its accessory tissues. Moreover, we emphasize that the maturation of intestinal macrophages is arrested at immature stage during IBD, and the deficiency of MCPIP1 involves in the process via ATF3-AP1S2 signature. In addition, we confirmed the origin potential of IL-1B+ macrophages and defined C1QB+ macrophages as mature macrophages. The interaction crosstalk between the intestine and the mesentery has been described in this review, and the expression of mesentery-derived SAA2 is upregulated during IBD, which contributes to immunoregulation of macrophage. Moreover, we also highlight IBD-related susceptibility genes (e.g., RUNX3, IL21R, GTF2I, and LILRB3) associated with the maturation and functions of macrophage, which provide promising therapeutic opportunities for treating human IBD. CONCLUSION In summary, this review provides a comprehensive, comprehensive, in-depth and novel description of the characteristics and functions of macrophages in IBD, and highlights the important role of macrophages in the molecular and cellular process during IBD.
Collapse
Affiliation(s)
- Huiying Lu
- Department of Gastroenterology, Huaihe Hospital of Henan University, Henan Province, Kaifeng, 475000, China
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China
| | - Zhimin Suo
- Department of Gastroenterology, Huaihe Hospital of Henan University, Henan Province, Kaifeng, 475000, China
| | - Jian Lin
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China
| | - Yingzi Cong
- Division of Gastroenterology and Hepatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
- Center for Human Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA
| | - Zhanju Liu
- Center for Inflammatory Bowel Disease Research and Department of Gastroenterology, Shanghai Tenth People's Hospital of Tongji University, No. 301 Yanchang Road, Shanghai, 200072, China.
| |
Collapse
|
26
|
Ma Y, Nenkov M, Chen Y, Gaßler N. The Role of Adipocytes Recruited as Part of Tumor Microenvironment in Promoting Colorectal Cancer Metastases. Int J Mol Sci 2024; 25:8352. [PMID: 39125923 PMCID: PMC11313311 DOI: 10.3390/ijms25158352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 07/15/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
Adipose tissue dysfunction, which is associated with an increased risk of colorectal cancer (CRC), is a significant factor in the pathophysiology of obesity. Obesity-related inflammation and extracellular matrix (ECM) remodeling promote colorectal cancer metastasis (CRCM) by shaping the tumor microenvironment (TME). When CRC occurs, the metabolic symbiosis of tumor cells recruits adjacent adipocytes into the TME to supply energy. Meanwhile, abundant immune cells, from adipose tissue and blood, are recruited into the TME, which is stimulated by pro-inflammatory factors and triggers a chronic local pro-inflammatory TME. Dysregulated ECM proteins and cell surface adhesion molecules enhance ECM remodeling and further increase contractibility between tumor and stromal cells, which promotes epithelial-mesenchymal transition (EMT). EMT increases tumor migration and invasion into surrounding tissues or vessels and accelerates CRCM. Colorectal symbiotic microbiota also plays an important role in the promotion of CRCM. In this review, we provide adipose tissue and its contributions to CRC, with a special emphasis on the role of adipocytes, macrophages, neutrophils, T cells, ECM, and symbiotic gut microbiota in the progression of CRC and their contributions to the CRC microenvironment. We highlight the interactions between adipocytes and tumor cells, and potential therapeutic approaches to target these interactions.
Collapse
Affiliation(s)
| | | | | | - Nikolaus Gaßler
- Section Pathology of the Institute of Forensic Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747 Jena, Germany (M.N.)
| |
Collapse
|
27
|
Chen Y, Wang J, An C, Bao S, Zhang C. The role and research progress of macrophages after heart transplantation. Heliyon 2024; 10:e33844. [PMID: 39027574 PMCID: PMC11255595 DOI: 10.1016/j.heliyon.2024.e33844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/20/2024] Open
Abstract
Since the 60s of the 20th century, heart transplantation has been the best treatment for patients with end-stage heart failure. Due to the increasing number of patients, how to expand the number of donor organs and enhance immune compatibility has become an urgent problem to be solved at this stage. Although current immunosuppression is effective, its side effects are also quite obvious, such as opportunistic infections and malignant tumors. In this review, we focus on the important role in macrophages after heart transplantation and their potential targets for achieving allogeneic graft tolerance, in order to improve effective graft survival and reduce infection and the occurrence of malignant tumors.
Collapse
Affiliation(s)
- Yao Chen
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - JianPeng Wang
- School of First Clinical Medical College, Anhui Medical University, Hefei, China
| | - Cheng An
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - ShanQing Bao
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| | - ChengXin Zhang
- Department of Cardiovascular Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China
| |
Collapse
|
28
|
Bennett ZT, Huang G, Dellinger MT, Sumer BD, Gao J. Stepwise Ultra-pH-Sensitive Micelles Overcome a p Ka Barrier for Systemic Lymph Node Delivery. ACS NANO 2024; 18:16632-16647. [PMID: 38900677 DOI: 10.1021/acsnano.4c00876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/22/2024]
Abstract
While local nanoparticle delivery to lymph nodes is well studied, there are few design criteria for intravenous delivery to the entire lymph node repertoire. In this study, we investigated the effect of NP pH transition on lymph node targeting by employing a series of ultra-pH-sensitive (UPS) polymeric micelles. The UPS library responds to pH thresholds (pKa 6.9, 6.2, and 5.3) over a range of physiological pH. We observed a dependence of intravenous lymph node targeting on micelle pH transition. UPS6.9 (subscript indicates pKa) shows poor lymph node delivery, while UPS5.3 delivers efficiently to lymph node sets. We investigated targeting mechanisms of UPS5.3, observing an accumulation among lymph node lymphatics and a dependence on lymph node-resident macrophages. To overcome the pH-threshold barrier, which limits UPS6.9, we rationally designed a nanoparticle coassembly of UPS6.9 with UPS5.3, called HyUPS. The HyUPS micelle retains the constitutive pH transitions of each polymer, showing stepwise responses to discrete pH thresholds. We demonstrate that HyUPS improves UPS6.9 delivery to lymph nodes, extending this platform for disease detection of lymph node metastasis.
Collapse
Affiliation(s)
- Zachary T Bennett
- Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Department of Biomedical Engineering, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Gang Huang
- Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Michael T Dellinger
- Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Baran D Sumer
- Department of Otolaryngology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| | - Jinming Gao
- Department of Pharmacology, Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Department of Biomedical Engineering, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Department of Otolaryngology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
- Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, United States
| |
Collapse
|
29
|
Brennan FH, Swarts EA, Kigerl KA, Mifflin KA, Guan Z, Noble BT, Wang Y, Witcher KG, Godbout JP, Popovich PG. Microglia promote maladaptive plasticity in autonomic circuitry after spinal cord injury in mice. Sci Transl Med 2024; 16:eadi3259. [PMID: 38865485 DOI: 10.1126/scitranslmed.adi3259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 05/16/2024] [Indexed: 06/14/2024]
Abstract
Robust structural remodeling and synaptic plasticity occurs within spinal autonomic circuitry after severe high-level spinal cord injury (SCI). As a result, normally innocuous visceral or somatic stimuli elicit uncontrolled activation of spinal sympathetic reflexes that contribute to systemic disease and organ-specific pathology. How hyperexcitable sympathetic circuitry forms is unknown, but local cues from neighboring glia likely help mold these maladaptive neuronal networks. Here, we used a mouse model of SCI to show that microglia surrounded active glutamatergic interneurons and subsequently coordinated multi-segmental excitatory synaptogenesis and expansion of sympathetic networks that control immune, neuroendocrine, and cardiovascular functions. Depleting microglia during critical periods of circuit remodeling after SCI prevented maladaptive synaptic and structural plasticity in autonomic networks, decreased the frequency and severity of autonomic dysreflexia, and prevented SCI-induced immunosuppression. Forced turnover of microglia in microglia-depleted mice restored structural and functional indices of pathological dysautonomia, providing further evidence that microglia are key effectors of autonomic plasticity. Additional data show that microglia-dependent autonomic plasticity required expression of triggering receptor expressed on myeloid cells 2 (Trem2) and α2δ-1-dependent synaptogenesis. These data suggest that microglia are primary effectors of autonomic neuroplasticity and dysautonomia after SCI in mice. Manipulating microglia may be a strategy to limit autonomic complications after SCI or other forms of neurologic disease.
Collapse
Affiliation(s)
- Faith H Brennan
- Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Belford Center for Spinal Cord Injury, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Emily A Swarts
- Department of Biomedical and Molecular Sciences and Center for Neuroscience Studies, Queen's University, Kingston, ON K7L 3N6, Canada
| | - Kristina A Kigerl
- Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Belford Center for Spinal Cord Injury, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Katherine A Mifflin
- Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Belford Center for Spinal Cord Injury, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Zhen Guan
- Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Belford Center for Spinal Cord Injury, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Benjamin T Noble
- Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Belford Center for Spinal Cord Injury, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Yan Wang
- Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Belford Center for Spinal Cord Injury, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Kristina G Witcher
- Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Institute for Behavioral Medicine Research, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Jonathan P Godbout
- Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Institute for Behavioral Medicine Research, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Phillip G Popovich
- Department of Neuroscience, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Belford Center for Spinal Cord Injury, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
- Institute for Behavioral Medicine Research, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| |
Collapse
|
30
|
Lee HJ, Choi YR, Ko JH, Ryu JS, Oh JY. Defining mesenchymal stem/stromal cell-induced myeloid-derived suppressor cells using single-cell transcriptomics. Mol Ther 2024; 32:1970-1983. [PMID: 38627968 PMCID: PMC11184332 DOI: 10.1016/j.ymthe.2024.04.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 02/27/2024] [Accepted: 04/12/2024] [Indexed: 04/29/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) modulate the immune response through interactions with innate immune cells. We previously demonstrated that MSCs alleviate ocular autoimmune inflammation by directing bone marrow cell differentiation from pro-inflammatory CD11bhiLy6ChiLy6Glo cells into immunosuppressive CD11bmidLy6CmidLy6Glo cells. Herein, we analyzed MSC-induced CD11bmidLy6Cmid cells using single-cell RNA sequencing and compared them with CD11bhiLy6Chi cells. Our investigation revealed seven distinct immune cell types including myeloid-derived suppressor cells (MDSCs) in the CD11bmidLy6Cmid cells, while CD11bhiLy6Chi cells included mostly monocytes/macrophages with a small cluster of neutrophils. These MSC-induced MDSCs highly expressed Retnlg, Cxcl3, Cxcl2, Mmp8, Cd14, and Csf1r as well as Arg1. Comparative analyses of CSF-1RhiCD11bmidLy6Cmid and CSF-1RloCD11bmidLy6Cmid cells demonstrated that the former had a homogeneous monocyte morphology and produced elevated levels of interleukin-10. Functionally, these CSF-1RhiCD11bmidLy6Cmid cells, compared with the CSF-1RloCD11bmidLy6Cmid cells, inhibited CD4+ T cell proliferation and promoted CD4+CD25+Foxp3+ Treg expansion in culture and in a mouse model of experimental autoimmune uveoretinitis. Resistin-like molecule (RELM)-γ encoded by Retnlg, one of the highly upregulated genes in MSC-induced MDSCs, had no direct effects on T cell proliferation, Treg expansion, or splenocyte activation. Together, our study revealed a distinct transcriptional profile of MSC-induced MDSCs and identified CSF-1R as a key cell-surface marker for detection and therapeutic enrichment of MDSCs.
Collapse
Affiliation(s)
- Hyun Ju Lee
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
| | - Yoo Rim Choi
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
| | - Jung Hwa Ko
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
| | - Jin Suk Ryu
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea
| | - Joo Youn Oh
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea; Department of Ophthalmology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea.
| |
Collapse
|
31
|
Vizcaino Castro A, Daemen T, Oyarce C. Strategies to reprogram anti-inflammatory macrophages towards pro-inflammatory macrophages to support cancer immunotherapies. Immunol Lett 2024; 267:106864. [PMID: 38705481 DOI: 10.1016/j.imlet.2024.106864] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 04/25/2024] [Accepted: 04/30/2024] [Indexed: 05/07/2024]
Abstract
Tumor-associated myeloid cells, including macrophages and myeloid-derived suppressor cells, can be highly prevalent in solid tumors and play a significant role in the development of the tumor. Therefore, myeloid cells are being considered potential targets for cancer immunotherapies. In this review, we focused on strategies aimed at targeting tumor-associated macrophages (TAMs). Most strategies were studied preclinically but we also included a limited number of clinical studies based on these strategies. We describe possible underlying mechanisms and discuss future challenges and prospects.
Collapse
Affiliation(s)
- Ana Vizcaino Castro
- Laboratory of Tumor Virology and Cancer Immunotherapy, Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Toos Daemen
- Laboratory of Tumor Virology and Cancer Immunotherapy, Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Cesar Oyarce
- Laboratory of Tumor Virology and Cancer Immunotherapy, Department of Medical Microbiology and Infection Prevention, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| |
Collapse
|
32
|
Mandula JK, Sierra-Mondragon RA, Jimenez RV, Chang D, Mohamed E, Chang S, Vazquez-Martinez JA, Cao Y, Anadon CM, Lee SB, Das S, Rocha-Munguba L, Pham VM, Li R, Tarhini AA, Furqan M, Dalton W, Churchman M, Moran-Segura CM, Nguyen J, Perez B, Kojetin DJ, Obermayer A, Yu X, Chen A, Shaw TI, Conejo-Garcia JR, Rodriguez PC. Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages. Immunity 2024; 57:1124-1140.e9. [PMID: 38636522 PMCID: PMC11096038 DOI: 10.1016/j.immuni.2024.03.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 02/13/2024] [Accepted: 03/26/2024] [Indexed: 04/20/2024]
Abstract
Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2-/- lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.
Collapse
Affiliation(s)
- Jay K Mandula
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | | | - Rachel V Jimenez
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Darwin Chang
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Eslam Mohamed
- California Northstate University, Elk Grove, CA 95757, USA
| | - Shiun Chang
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | | | - Yu Cao
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Carmen M Anadon
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27708, USA
| | - Sae Bom Lee
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Satyajit Das
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Léo Rocha-Munguba
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Vincent M Pham
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Roger Li
- Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Ahmad A Tarhini
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; Department of Cutaneous Oncology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Muhammad Furqan
- Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA 52242, USA
| | | | | | - Carlos M Moran-Segura
- Advanced Analytical and Digital Laboratory, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Jonathan Nguyen
- Advanced Analytical and Digital Laboratory, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Bradford Perez
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Douglas J Kojetin
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Alyssa Obermayer
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Xiaoqing Yu
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Ann Chen
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Timothy I Shaw
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA; Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA
| | - Jose R Conejo-Garcia
- Department of Integrative Immunobiology, Duke University School of Medicine, Durham, NC 27708, USA
| | - Paulo C Rodriguez
- Department of Immunology, H. Lee Moffitt Cancer Center, Tampa, FL 33612, USA.
| |
Collapse
|
33
|
Sharma N, Fan X, Atolagbe OT, Ge Z, Dao KN, Sharma P, Allison JP. ICOS costimulation in combination with CTLA-4 blockade remodels tumor-associated macrophages toward an antitumor phenotype. J Exp Med 2024; 221:e20231263. [PMID: 38517331 PMCID: PMC10959121 DOI: 10.1084/jem.20231263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 01/19/2024] [Accepted: 02/27/2024] [Indexed: 03/23/2024] Open
Abstract
We have previously demonstrated synergy between ICOS costimulation (IVAX; ICOSL-transduced B16-F10 cellular vaccine) and CTLA-4 blockade in antitumor therapy. In this study, we employed CyTOF and single-cell RNA sequencing and observed significant remodeling of the lymphoid and myeloid compartments in combination therapy. Compared with anti-CTLA-4 monotherapy, the combination therapy enriched Th1 CD4 T cells, effector CD8 T cells, and M1-like antitumor proinflammatory macrophages. These macrophages were critical to the therapeutic efficacy of anti-CTLA-4 combined with IVAX or anti-PD-1. Macrophage depletion with clodronate reduced the tumor-infiltrating effector CD4 and CD8 T cells, impairing their antitumor functions. Furthermore, the recruitment and polarization of M1-like macrophages required IFN-γ. Therefore, in this study, we show that there is a positive feedback loop between intratumoral effector T cells and tumor-associated macrophages (TAMs), in which the IFN-γ produced by the T cells polarizes the TAMs into M1-like phenotype, and the TAMs, in turn, reshape the tumor microenvironment to facilitate T cell infiltration, immune function, and tumor rejection.
Collapse
Affiliation(s)
- Naveen Sharma
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiaozhou Fan
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Zhongqi Ge
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kelly N. Dao
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Padmanee Sharma
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Immunotherapy Platform, James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - James P. Allison
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- James P. Allison Institute, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| |
Collapse
|
34
|
Adams RC, Carter-Cusack D, Llanes GT, Hunter CR, Vinnakota JM, Ruitenberg MJ, Vukovic J, Bertolino P, Chand KK, Wixey JA, Nayler SP, Hill GR, Furlan SN, Zeiser R, MacDonald KPA. CSF1R inhibition promotes neuroinflammation and behavioral deficits during graft-versus-host disease in mice. Blood 2024; 143:912-929. [PMID: 38048572 DOI: 10.1182/blood.2023022040] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 10/31/2023] [Accepted: 11/13/2023] [Indexed: 12/06/2023] Open
Abstract
ABSTRACT Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognized, in which brain-infiltrating donor major histocompatibility complex (MHC) class II+ bone marrow-derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesized that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early after transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients, in which CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signaling after transplant failed to reverse GVHD-induced behavioral changes. Moreover, we observed aberrant behavior in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr-/- grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS.
Collapse
Affiliation(s)
- Rachael C Adams
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Department of Medicine I, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dylan Carter-Cusack
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Genesis T Llanes
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Christopher R Hunter
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Janaki Manoja Vinnakota
- Department of Medicine I, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Faculty of Biology, Albert-Ludwigs University, Freiburg, Germany
| | - Marc J Ruitenberg
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Jana Vukovic
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Patrick Bertolino
- Centenary Institute and University of Sydney, AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - Kirat K Chand
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Julie A Wixey
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Perinatal Research Centre, Royal Brisbane and Women's Hospital, Herston, Brisbane, QLD, Australia
| | - Samuel P Nayler
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Geoffrey R Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
- Division of Oncology, Department of Medicine, University of Washington, Seattle, WA
| | - Scott N Furlan
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Robert Zeiser
- Department of Medicine I, Medical Centre, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- German Cancer Consortium, Partner Site Freiburg, Freiburg, Germany, and German Cancer Research Centre, Heidelberg, Germany
| | - Kelli P A MacDonald
- Infection and Inflammation Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| |
Collapse
|
35
|
O'Brien CL, Summers KM, Martin NM, Carter-Cusack D, Yang Y, Barua R, Dixit OVA, Hume DA, Pavli P. The relationship between extreme inter-individual variation in macrophage gene expression and genetic susceptibility to inflammatory bowel disease. Hum Genet 2024; 143:233-261. [PMID: 38421405 PMCID: PMC11043138 DOI: 10.1007/s00439-024-02642-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 01/14/2024] [Indexed: 03/02/2024]
Abstract
The differentiation of resident intestinal macrophages from blood monocytes depends upon signals from the macrophage colony-stimulating factor receptor (CSF1R). Analysis of genome-wide association studies (GWAS) indicates that dysregulation of macrophage differentiation and response to microorganisms contributes to susceptibility to chronic inflammatory bowel disease (IBD). Here, we analyzed transcriptomic variation in monocyte-derived macrophages (MDM) from affected and unaffected sib pairs/trios from 22 IBD families and 6 healthy controls. Transcriptional network analysis of the data revealed no overall or inter-sib distinction between affected and unaffected individuals in basal gene expression or the temporal response to lipopolysaccharide (LPS). However, the basal or LPS-inducible expression of individual genes varied independently by as much as 100-fold between subjects. Extreme independent variation in the expression of pairs of HLA-associated transcripts (HLA-B/C, HLA-A/F and HLA-DRB1/DRB5) in macrophages was associated with HLA genotype. Correlation analysis indicated the downstream impacts of variation in the immediate early response to LPS. For example, variation in early expression of IL1B was significantly associated with local SNV genotype and with subsequent peak expression of target genes including IL23A, CXCL1, CXCL3, CXCL8 and NLRP3. Similarly, variation in early IFNB1 expression was correlated with subsequent expression of IFN target genes. Our results support the view that gene-specific dysregulation in macrophage adaptation to the intestinal milieu is associated with genetic susceptibility to IBD.
Collapse
Affiliation(s)
- Claire L O'Brien
- Centre for Research in Therapeutics Solutions, Faculty of Science and Technology, University of Canberra, Canberra, ACT, Australia
- Inflammatory Bowel Disease Research Group, Canberra Hospital, Canberra, ACT, Australia
| | - Kim M Summers
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Natalia M Martin
- Inflammatory Bowel Disease Research Group, Canberra Hospital, Canberra, ACT, Australia
| | - Dylan Carter-Cusack
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Yuanhao Yang
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, QLD, Australia
| | - Rasel Barua
- Inflammatory Bowel Disease Research Group, Canberra Hospital, Canberra, ACT, Australia
| | - Ojas V A Dixit
- Centre for Research in Therapeutics Solutions, Faculty of Science and Technology, University of Canberra, Canberra, ACT, Australia
| | - David A Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, QLD, Australia.
| | - Paul Pavli
- Inflammatory Bowel Disease Research Group, Canberra Hospital, Canberra, ACT, Australia.
- School of Medicine and Psychology, College of Health and Medicine, Australian National University, Canberra, ACT, Australia.
| |
Collapse
|
36
|
Kou T, Kang L, Zhang B, Li J, Zhao B, Zeng W, Hu X. RBP-J regulates homeostasis and function of circulating Ly6C lo monocytes. eLife 2024; 12:RP88135. [PMID: 38407952 PMCID: PMC10942619 DOI: 10.7554/elife.88135] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/27/2024] Open
Abstract
Notch-RBP-J signaling plays an essential role in the maintenance of myeloid homeostasis. However, its role in monocyte cell fate decisions is not fully understood. Here, we showed that conditional deletion of transcription factor RBP-J in myeloid cells resulted in marked accumulation of blood Ly6Clo monocytes that highly expressed chemokine receptor CCR2. Bone marrow transplantation and parabiosis experiments revealed a cell-intrinsic requirement of RBP-J for controlling blood Ly6CloCCR2hi monocytes. RBP-J-deficient Ly6Clo monocytes exhibited enhanced capacity competing with wildtype counterparts in blood circulation. In accordance with alterations of circulating monocytes, RBP-J deficiency led to markedly increased population of lung tissues with Ly6Clo monocytes and CD16.2+ interstitial macrophages. Furthermore, RBP-J deficiency-associated phenotypes could be genetically corrected by further deleting Ccr2 in myeloid cells. These results demonstrate that RBP-J functions as a crucial regulator of blood Ly6Clo monocytes and thus derived lung-resident myeloid populations, at least in part through regulation of CCR2.
Collapse
Affiliation(s)
- Tiantian Kou
- Institute for Immunology and School of Medicine, Tsinghua UniversityBeijingChina
- Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityBeijingChina
- Beijing Key Laboratory for Immunological Research on Chronic DiseasesBeijingChina
| | - Lan Kang
- Institute for Immunology and School of Medicine, Tsinghua UniversityBeijingChina
- Beijing Key Laboratory for Immunological Research on Chronic DiseasesBeijingChina
| | - Bin Zhang
- Institute for Immunology and School of Medicine, Tsinghua UniversityBeijingChina
- Beijing Key Laboratory for Immunological Research on Chronic DiseasesBeijingChina
| | - Jiaqi Li
- Institute for Immunology and School of Medicine, Tsinghua UniversityBeijingChina
| | - Baohong Zhao
- Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special SurgeryNew YorkUnited States
- Department of Medicine, Weill Cornell Medical CollegeNew YorkUnited States
| | - Wenwen Zeng
- Institute for Immunology and School of Medicine, Tsinghua UniversityBeijingChina
- Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityBeijingChina
- Beijing Key Laboratory for Immunological Research on Chronic DiseasesBeijingChina
| | - Xiaoyu Hu
- Institute for Immunology and School of Medicine, Tsinghua UniversityBeijingChina
- Tsinghua-Peking Center for Life Sciences, Tsinghua UniversityBeijingChina
- Beijing Key Laboratory for Immunological Research on Chronic DiseasesBeijingChina
| |
Collapse
|
37
|
Martin AT, Giri S, Safronova A, Eliseeva SI, Kwok SF, Yarovinsky F. Parasite-induced IFN-γ regulates host defense via CD115 and mTOR-dependent mechanism of tissue-resident macrophage death. PLoS Pathog 2024; 20:e1011502. [PMID: 38377133 PMCID: PMC10906828 DOI: 10.1371/journal.ppat.1011502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 03/01/2024] [Accepted: 01/22/2024] [Indexed: 02/22/2024] Open
Abstract
Host resistance to a common protozoan parasite Toxoplasma gondii relies on a coordinated immune response involving multiple cell types, including macrophages. Embryonically seeded tissue-resident macrophages (TRMs) play a critical role in maintaining tissue homeostasis, but their role in parasite clearance is poorly understood. In this study, we uncovered a crucial aspect of host defense against T. gondii mediated by TRMs. Through the use of neutralizing antibodies and conditional IFN-γ receptor-deficient mice, we demonstrated that IFN-γ directly mediated the elimination of TRMs. Mechanistically, IFN-γ stimulation in vivo rendered macrophages unresponsive to macrophage colony-stimulating factor (M-CSF) and inactivated mTOR signaling by causing the shedding of CD115 (CSFR1), the receptor for M-CSF. Further experiments revealed the essential role of macrophage IFN-γ responsiveness in host resistance to T. gondii. The elimination of peritoneal TRMs emerged as an additional host defense mechanism aimed at limiting the parasite's reservoir. The identified mechanism, involving IFN-γ-induced suppression of CD115-dependent mTOR signaling in macrophages, provides insights into the adaptation of macrophage subsets during infection and highlights a crucial aspect of host defense against intracellular pathogens.
Collapse
Affiliation(s)
- Andrew T. Martin
- Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Shilpi Giri
- Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Alexandra Safronova
- Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Sophia I. Eliseeva
- Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Samantha F. Kwok
- Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America
| | - Felix Yarovinsky
- Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, United States of America
| |
Collapse
|
38
|
Banuelos A, Zhang A, Berouti H, Baez M, Yılmaz L, Georgeos N, Marjon KD, Miyanishi M, Weissman IL. CXCR2 inhibition in G-MDSCs enhances CD47 blockade for melanoma tumor cell clearance. Proc Natl Acad Sci U S A 2024; 121:e2318534121. [PMID: 38261615 PMCID: PMC10835053 DOI: 10.1073/pnas.2318534121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Accepted: 12/16/2023] [Indexed: 01/25/2024] Open
Abstract
The use of colony-stimulating factor-1 receptor (CSF1R) inhibitors has been widely explored as a strategy for cancer immunotherapy due to their robust depletion of tumor-associated macrophages (TAMs). While CSF1R blockade effectively eliminates TAMs from the solid tumor microenvironment, its clinical efficacy is limited. Here, we use an inducible CSF1R knockout model to investigate the persistence of tumor progression in the absence of TAMs. We find increased frequencies of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the bone marrow, throughout circulation, and in the tumor following CSF1R deletion and loss of TAMs. We find that G-MDSCs are capable of suppressing macrophage phagocytosis, and the elimination of G-MDSCs through CXCR2 inhibition increases macrophage capacity for tumor cell clearance. Further, we find that combination therapy of CXCR2 inhibition and CD47 blockade synergize to elicit a significant anti-tumor response. These findings reveal G-MDSCs as key drivers of tumor immunosuppression and demonstrate their inhibition as a potent strategy to increase macrophage phagocytosis and enhance the anti-tumor efficacy of CD47 blockade in B16-F10 melanoma.
Collapse
Affiliation(s)
- Allison Banuelos
- Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA94305
| | - Allison Zhang
- Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA94305
| | - Hala Berouti
- Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA94305
| | - Michelle Baez
- Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA94305
| | - Leyla Yılmaz
- Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA94305
| | - Nardin Georgeos
- Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA94305
| | - Kristopher D. Marjon
- Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA94305
| | - Masanori Miyanishi
- Hematopoietic Stem Cell Biology and Medical Innovation (HSCBMI), Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe650-0047, Japan
| | - Irving L. Weissman
- Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA94305
- Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University, Stanford, CA94305
- Department of Pathology, Stanford University, Stanford, CA94305
| |
Collapse
|
39
|
Laudenberg N, Kinuthia UM, Langmann T. Microglia depletion/repopulation does not affect light-induced retinal degeneration in mice. Front Immunol 2024; 14:1345382. [PMID: 38288111 PMCID: PMC10822957 DOI: 10.3389/fimmu.2023.1345382] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 12/28/2023] [Indexed: 01/31/2024] Open
Abstract
Reactive microglia are a hallmark of age-related retinal degenerative diseases including age-related macular degeneration (AMD). These cells are capable of secreting neurotoxic substances that may aggravate inflammation that leads to loss of photoreceptors and impaired vision. Despite their role in driving detrimental inflammation, microglia also play supporting roles in the retina as they are a crucial cellular component of the regulatory innate immune system. In this study, we used the colony stimulating factor 1 receptor (CSF1R)-antagonist PLX3397 to investigate the effects of microglia depletion and repopulation in a mouse model of acute retinal degeneration that mimics some aspects of dry AMD. Our main goal was to investigate whether microglia depletion and repopulation affects the outcome of light-induced retinal degeneration. We found that microglia depletion effectively decreased the expression of several key pro-inflammatory factors but was unable to influence the extent of retinal degeneration as determined by optical coherence tomography (OCT) and histology. Interestingly, we found prominent cell debris accumulation in the outer retina under conditions of microglia depletion, presumably due to the lack of efficient phagocytosis that could not be compensated by the retinal pigment epithelium. Moreover, our in vivo experiments showed that renewal of retinal microglia by repopulation did also not prevent rapid microglia activation or preserve photoreceptor death under conditions of light damage. We conclude that microglia ablation strongly reduces the expression of pro-inflammatory factors but cannot prevent photoreceptor loss in the light-damage paradigm of retinal degeneration.
Collapse
Affiliation(s)
- Nils Laudenberg
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Urbanus Muthai Kinuthia
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| | - Thomas Langmann
- Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
| |
Collapse
|
40
|
Shaikh SN, Willis EF, Dierich M, Xu Y, Stuart SJS, Gobe GC, Bashaw AA, Rawashdeh O, Kim SJ, Vukovic J. CSF-1R inhibitor PLX3397 attenuates peripheral and brain chronic GVHD and improves functional outcomes in mice. J Neuroinflammation 2023; 20:300. [PMID: 38102698 PMCID: PMC10725001 DOI: 10.1186/s12974-023-02984-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 12/03/2023] [Indexed: 12/17/2023] Open
Abstract
Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood-brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition.
Collapse
Affiliation(s)
- Samreen N Shaikh
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Emily F Willis
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Max Dierich
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Yi Xu
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Samuel J S Stuart
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Glenda C Gobe
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Abate A Bashaw
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Oliver Rawashdeh
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Seung Jae Kim
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Jana Vukovic
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
| |
Collapse
|
41
|
Zhou J, Lyu N, Wang Q, Yang M, Kimchi ET, Cheng K, Joshi T, Tukuli AR, Staveley-O'Carroll KF, Li G. A novel role of TGFBI in macrophage polarization and macrophage-induced pancreatic cancer growth and therapeutic resistance. Cancer Lett 2023; 578:216457. [PMID: 37865162 DOI: 10.1016/j.canlet.2023.216457] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/28/2023] [Accepted: 10/17/2023] [Indexed: 10/23/2023]
Abstract
Tumor-associated macrophages (TAMs), as a major and essential component of tumor microenvironment (TME), play a critical role in orchestrating pancreatic cancer (PaC) tumorigenesis from initiation to angiogenesis, growth, and systemic dissemination, as well as immunosuppression and resistance to chemotherapy and immunotherapy; however, the critical intrinsic factors responsible for TAMs reprograming and function remain to be identified. By performing single-cell RNA sequencing, transforming growth factor-beta-induced protein (TGFBI) was identified as TAM-producing factor in murine PaC tumors. TAMs express TGFBI in human PaC and TGFBI expression is positively related with human PaC growth. By inducing TGFBI loss-of-function in macrophage (MΦs) in vitro with siRNA and in vivo with Cre-Lox strategy in our developed TGFBI-floxed mice, we demonstrated disruption of TGFBI not only inhibited MΦ polarization to M2 phenotype and MΦ-mediated stimulation on PaC growth, but also significantly improved anti-tumor immunity, sensitizing PaC to chemotherapy in association with regulation of fibronectin 1, Cxcl10, and Ccl5. Our studies suggest that targeting TGFBI in MΦ can develop an effective therapeutic intervention for highly lethal PaC.
Collapse
Affiliation(s)
- Jing Zhou
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA; NextGen Precision Health Institute, University of Missouri-Columbia, Columbia, MO, 65212, USA
| | - Nan Lyu
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA; Pancreas Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
| | - Qiongling Wang
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA
| | - Ming Yang
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA; NextGen Precision Health Institute, University of Missouri-Columbia, Columbia, MO, 65212, USA
| | - Eric T Kimchi
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA; NextGen Precision Health Institute, University of Missouri-Columbia, Columbia, MO, 65212, USA; Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, 65212, USA
| | - Kun Cheng
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, 64108, USA
| | - Trupti Joshi
- Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO, 65212, USA; Department of Electrical Engineering and Computer Science, University of Missouri, Columbia, MO, 65212, USA; Department of Health Management and Informatics and MU Institute of Data Science and Informatics, University of Missouri-Columbia, Columbia, MO, 65212, USA
| | - Adama R Tukuli
- Christopher S. Bond Life Science Center, University of Missouri, Columbia, MO, 65212, USA
| | - Kevin F Staveley-O'Carroll
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA; NextGen Precision Health Institute, University of Missouri-Columbia, Columbia, MO, 65212, USA; Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, 65212, USA.
| | - Guangfu Li
- Department of Surgery, University of Missouri-Columbia, Columbia, MO, 65212, USA; NextGen Precision Health Institute, University of Missouri-Columbia, Columbia, MO, 65212, USA; Ellis Fischel Cancer Center, University of Missouri-Columbia, Columbia, MO, 65212, USA; Department of Molecular Microbiology & Immunology, University of Missouri-Columbia, Columbia, MO, 65212, USA.
| |
Collapse
|
42
|
Bosch AJT, Keller L, Steiger L, Rohm TV, Wiedemann SJ, Low AJY, Stawiski M, Rachid L, Roux J, Konrad D, Wueest S, Tugues S, Greter M, Böni-Schnetzler M, Meier DT, Cavelti-Weder C. CSF1R inhibition with PLX5622 affects multiple immune cell compartments and induces tissue-specific metabolic effects in lean mice. Diabetologia 2023; 66:2292-2306. [PMID: 37792013 PMCID: PMC10627931 DOI: 10.1007/s00125-023-06007-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Accepted: 07/07/2023] [Indexed: 10/05/2023]
Abstract
AIMS/HYPOTHESIS Colony stimulating factor 1 (CSF1) promotes the proliferation, differentiation and survival of macrophages, which have been implicated in both beneficial and detrimental effects on glucose metabolism. However, the physiological role of CSF1 signalling in glucose homeostasis and the potential therapeutic implications of modulating this pathway are not known. We aimed to study the composition of tissue macrophages (and other immune cells) following CSF1 receptor (CSF1R) inhibition and elucidate the metabolic consequences of CSF1R inhibition. METHODS We assessed immune cell populations in various organs by flow cytometry, and tissue-specific metabolic effects by hyperinsulinaemic-euglycaemic clamps and insulin secretion assays in mice fed a chow diet containing PLX5622 (a CSF1R inhibitor) or a control diet. RESULTS CSF1R inhibition depleted macrophages in multiple tissues while simultaneously increasing eosinophils and group 2 innate lymphoid cells. These immunological changes were consistent across different organs and were sex independent and reversible after cessation of the PLX5622. CSF1R inhibition improved hepatic insulin sensitivity but concomitantly impaired insulin secretion. In healthy islets, we found a high frequency of IL-1β+ islet macrophages. Their depletion by CSF1R inhibition led to downregulation of macrophage-related pathways and mediators of cytokine activity, including Nlrp3, suggesting IL-1β as a candidate insulin secretagogue. Partial restoration of physiological insulin secretion was achieved by injecting recombinant IL-1β prior to glucose stimulation in mice lacking macrophages. CONCLUSIONS/INTERPRETATION Macrophages and macrophage-derived factors, such as IL-1β, play an important role in physiological insulin secretion. A better understanding of the tissue-specific effects of CSF1R inhibition on immune cells and glucose homeostasis is crucial for the development of targeted immune-modulatory treatments in metabolic disease. DATA AVAILABILITY The RNA-Seq dataset is available in the Gene Expression Omnibus (GEO) under the accession number GSE189434 ( http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE189434 ).
Collapse
Affiliation(s)
- Angela J T Bosch
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Lena Keller
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Laura Steiger
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Theresa V Rohm
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | | | - Andy J Y Low
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Marc Stawiski
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Leila Rachid
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Julien Roux
- Department of Biomedicine, University of Basel, Basel, Switzerland
- Swiss Institute of Bioinformatics, Basel, Switzerland
| | - Daniel Konrad
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, Zurich, Switzerland
- Children's Research Centre, University Children's Hospital, University of Zurich, Zurich, Switzerland
| | - Stephan Wueest
- Division of Pediatric Endocrinology and Diabetology, University Children's Hospital, University of Zurich, Zurich, Switzerland
- Children's Research Centre, University Children's Hospital, University of Zurich, Zurich, Switzerland
| | - Sonia Tugues
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | - Melanie Greter
- Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland
| | | | - Daniel T Meier
- Department of Biomedicine, University of Basel, Basel, Switzerland
| | - Claudia Cavelti-Weder
- Department of Biomedicine, University of Basel, Basel, Switzerland.
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), University of Zurich (UZH), Zurich, Switzerland.
| |
Collapse
|
43
|
Waddell LA, Wu Z, Sauter KA, Hope JC, Hume DA. A novel monoclonal antibody against porcine macrophage colony-stimulating factor (CSF1) detects expression on the cell surface of macrophages. Vet Immunol Immunopathol 2023; 266:110681. [PMID: 37992576 DOI: 10.1016/j.vetimm.2023.110681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 11/06/2023] [Accepted: 11/10/2023] [Indexed: 11/24/2023]
Abstract
Macrophage colony-stimulating factor (CSF1) controls the proliferation and differentiation of cells of the mononuclear phagocyte system through binding to the receptor CSF1R. The expression and function of CSF1 has been well-studied in rodents and humans, but knowledge is lacking in other veterinary species. The development of a novel mouse anti-porcine CSF1 monoclonal antibody (mAb) facilitates the characterisation of this growth factor in pigs. Cell surface expression of CSF1 was confirmed on differentiated macrophage populations derived from blood and bone marrow monocytes, and on lung resident macrophages, the first species for this to be confirmed. However, monocytes isolated from blood and bone marrow lacked CSF1 expression. This species-specific mAb delivers the opportunity to further understanding of porcine myeloid cell biology. This is not only vital for the role of pigs as a model for human health, but also as a veterinary species of significant economic and agricultural importance.
Collapse
Affiliation(s)
- Lindsey A Waddell
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
| | - Zhiguang Wu
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
| | - Kristin A Sauter
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK
| | - Jayne C Hope
- The Roslin Institute and R(D)SVS, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
| | - David A Hume
- Mater Research Institute-University of Queensland, 37 Kent St, Woolloongabba, Qld 4104, Australia
| |
Collapse
|
44
|
Claeys W, Verhaege D, Van Imschoot G, Van Wonterghem E, Van Acker L, Amelinck L, De Ponti FF, Scott C, Geerts A, Van Steenkiste C, Van Hoecke L, Vandenbroucke RE. Limitations of PLX3397 as a microglial investigational tool: peripheral and off-target effects dictate the response to inflammation. Front Immunol 2023; 14:1283711. [PMID: 38077359 PMCID: PMC10703484 DOI: 10.3389/fimmu.2023.1283711] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Accepted: 10/23/2023] [Indexed: 12/18/2023] Open
Abstract
Microglia, the resident macrophages of the central nervous system (CNS), play a critical role in CNS homeostasis and neuroinflammation. Pexidartinib (PLX3397), a colony-stimulating factor 1 (CSF1) receptor inhibitor, is widely used to deplete microglia, offering flexible options for both long-term depletion and highly versatile depletion-repopulation cycles. However, the potential impact of PLX3397 on peripheral (immune) cells remains controversial. Until now, the microglia-specificity of this type of compounds has not been thoroughly evaluated, particularly in the context of peripherally derived neuroinflammation. Our study addresses this gap by examining the effects of PLX3397 on immune cells in the brain, liver, circulation and bone marrow, both in homeostasis and systemic inflammation models. Intriguingly, we demonstrate that PLX3397 treatment not only influences the levels of tissue-resident macrophages, but also affects circulating and bone marrow immune cells beyond the mononuclear phagocyte system (MPS). These alterations in peripheral immune cells disrupt the response to systemic inflammation, consequently impacting the phenotype irrespective of microglial depletion. Furthermore, we observed that a lower dose of PLX3397, which does not deplete microglia, demonstrates similar (non-)MPS effects, both in the periphery and the brain, but fails to fully replicate the peripheral alterations seen in the higher doses, questioning lower doses as a 'peripheral control' strategy. Overall, our data highlight the need for caution when interpreting studies employing this compound, as it may not be suitable for specific investigation of microglial function in the presence of systemic inflammation.
Collapse
Affiliation(s)
- Wouter Claeys
- Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
- Barriers in Inflammation, VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Daan Verhaege
- Barriers in Inflammation, VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Griet Van Imschoot
- Barriers in Inflammation, VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Elien Van Wonterghem
- Barriers in Inflammation, VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Lore Van Acker
- Barriers in Inflammation, VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Laura Amelinck
- Barriers in Inflammation, VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Federico F. De Ponti
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB–UGent Center for Inflammation Research, Ghent, Belgium
| | - Charlotte Scott
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB–UGent Center for Inflammation Research, Ghent, Belgium
| | - Anja Geerts
- Department of Internal Medicine and Paediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium
- Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium
- Department of Gastroenterology and Hepatology, Ghent University Hospital, Ghent, Belgium
| | - Christophe Van Steenkiste
- Antwerp University, Department of Gastroenterology and Hepatology, Antwerp, Belgium
- Department of Gastroenterology and Hepatology, Maria Middelares Hospital, Ghent, Belgium
| | - Lien Van Hoecke
- Barriers in Inflammation, VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Roosmarijn E. Vandenbroucke
- Barriers in Inflammation, VIB-UGent Center for Inflammation Research, VIB, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| |
Collapse
|
45
|
Basak U, Sarkar T, Mukherjee S, Chakraborty S, Dutta A, Dutta S, Nayak D, Kaushik S, Das T, Sa G. Tumor-associated macrophages: an effective player of the tumor microenvironment. Front Immunol 2023; 14:1295257. [PMID: 38035101 PMCID: PMC10687432 DOI: 10.3389/fimmu.2023.1295257] [Citation(s) in RCA: 90] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2023] [Accepted: 10/23/2023] [Indexed: 12/02/2023] Open
Abstract
Cancer progression is primarily caused by interactions between transformed cells and the components of the tumor microenvironment (TME). TAMs (tumor-associated macrophages) make up the majority of the invading immune components, which are further categorized as anti-tumor M1 and pro-tumor M2 subtypes. While M1 is known to have anti-cancer properties, M2 is recognized to extend a protective role to the tumor. As a result, the tumor manipulates the TME in such a way that it induces macrophage infiltration and M1 to M2 switching bias to secure its survival. This M2-TAM bias in the TME promotes cancer cell proliferation, neoangiogenesis, lymphangiogenesis, epithelial-to-mesenchymal transition, matrix remodeling for metastatic support, and TME manipulation to an immunosuppressive state. TAMs additionally promote the emergence of cancer stem cells (CSCs), which are known for their ability to originate, metastasize, and relapse into tumors. CSCs also help M2-TAM by revealing immune escape and survival strategies during the initiation and relapse phases. This review describes the reasons for immunotherapy failure and, thereby, devises better strategies to impair the tumor-TAM crosstalk. This study will shed light on the understudied TAM-mediated tumor progression and address the much-needed holistic approach to anti-cancer therapy, which encompasses targeting cancer cells, CSCs, and TAMs all at the same time.
Collapse
Affiliation(s)
- Udit Basak
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Tania Sarkar
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Sumon Mukherjee
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | | | - Apratim Dutta
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Saikat Dutta
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Debadatta Nayak
- Central Council for Research in Homeopathy (CCRH), New Delhi, India
| | - Subhash Kaushik
- Central Council for Research in Homeopathy (CCRH), New Delhi, India
| | - Tanya Das
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| | - Gaurisankar Sa
- Division of Molecular Medicine, Bose Institute, Kolkata, India
| |
Collapse
|
46
|
Kandalla PK, Subburayalu J, Cocita C, de Laval B, Tomasello E, Iacono J, Nitsche J, Canali MM, Cathou W, Bessou G, Mossadegh‐Keller N, Huber C, Mouchiroud G, Bourette RP, Grasset M, Bornhäuser M, Sarrazin S, Dalod M, Sieweke MH. M-CSF directs myeloid and NK cell differentiation to protect from CMV after hematopoietic cell transplantation. EMBO Mol Med 2023; 15:e17694. [PMID: 37635627 PMCID: PMC10630876 DOI: 10.15252/emmm.202317694] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 07/25/2023] [Accepted: 07/25/2023] [Indexed: 08/29/2023] Open
Abstract
Therapies reconstituting autologous antiviral immunocompetence may represent an important prophylaxis and treatment for immunosuppressed individuals. Following hematopoietic cell transplantation (HCT), patients are susceptible to Herpesviridae including cytomegalovirus (CMV). We show in a murine model of HCT that macrophage colony-stimulating factor (M-CSF) promoted rapid antiviral activity and protection from viremia caused by murine CMV. M-CSF given at transplantation stimulated sequential myeloid and natural killer (NK) cell differentiation culminating in increased NK cell numbers, production of granzyme B and interferon-γ. This depended upon M-CSF-induced myelopoiesis leading to IL15Rα-mediated presentation of IL-15 on monocytes, augmented by type I interferons from plasmacytoid dendritic cells. Demonstrating relevance to human HCT, M-CSF induced myelomonocytic IL15Rα expression and numbers of functional NK cells in G-CSF-mobilized hematopoietic stem and progenitor cells. Together, M-CSF-induced myelopoiesis triggered an integrated differentiation of myeloid and NK cells to protect HCT recipients from CMV. Thus, our results identify a rationale for the therapeutic use of M-CSF to rapidly reconstitute antiviral activity in immunocompromised individuals, which may provide a general paradigm to boost innate antiviral immunocompetence using host-directed therapies.
Collapse
Affiliation(s)
- Prashanth K Kandalla
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| | - Julien Subburayalu
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
- Department of Internal Medicine IUniversity Hospital Carl Gustav Carus DresdenDresdenGermany
| | - Clément Cocita
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
- Aix‐Marseille University, CNRS, INSERMCIML, Turing Center for Living SystemsMarseilleFrance
| | | | - Elena Tomasello
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
- Aix‐Marseille University, CNRS, INSERMCIML, Turing Center for Living SystemsMarseilleFrance
| | - Johanna Iacono
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| | - Jessica Nitsche
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
| | - Maria M Canali
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| | | | - Gilles Bessou
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
- Aix‐Marseille University, CNRS, INSERMCIML, Turing Center for Living SystemsMarseilleFrance
| | | | - Caroline Huber
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| | | | - Roland P Bourette
- CNRS, INSERM, CHU Lille, University LilleUMR9020‐U1277 ‐ CANTHER – Cancer Heterogeneity Plasticity and Resistance to TherapiesLilleFrance
| | | | - Martin Bornhäuser
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
- Department of Internal Medicine IUniversity Hospital Carl Gustav Carus DresdenDresdenGermany
- National Center for Tumor Diseases (NCT), DresdenDresdenGermany
| | - Sandrine Sarrazin
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| | - Marc Dalod
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
- Aix‐Marseille University, CNRS, INSERMCIML, Turing Center for Living SystemsMarseilleFrance
| | - Michael H Sieweke
- Center for Regenerative Therapies Dresden (CRTD)Technical University DresdenDresdenGermany
- Aix Marseille University, CNRS, INSERMCIMLMarseilleFrance
| |
Collapse
|
47
|
Yang Y, Mou B, Zhang QR, Zhao HX, Zhang JY, Yun X, Xiong MT, Liu Y, Liu YU, Pan H, Ma CL, Li BM, Peng J. Microglia are involved in regulating histamine-dependent and non-dependent itch transmissions with distinguished signal pathways. Glia 2023; 71:2541-2558. [PMID: 37392090 DOI: 10.1002/glia.24438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 07/02/2023]
Abstract
Although itch and pain have many similarities, they are completely different in perceptual experience and behavioral response. In recent years, we have a deep understanding of the neural pathways of itch sensation transmission. However, there are few reports on the role of non-neuronal cells in itch. Microglia are known to play a key role in chronic neuropathic pain and acute inflammatory pain. It is still unknown whether microglia are also involved in regulating the transmission of itch sensation. In the present study, we used several kinds of transgenic mice to specifically deplete CX3CR1+ microglia and peripheral macrophages together (whole depletion), or selectively deplete microglia alone (central depletion). We observed that the acute itch responses to histamine, compound 48/80 and chloroquine were all significantly reduced in mice with either whole or central depletion. Spinal c-fos mRNA assay and further studies revealed that histamine and compound 48/80, but not chloroquine elicited primary itch signal transmission from DRG to spinal Npr1- and somatostatin-positive neurons relied on microglial CX3CL1-CX3CR1 pathway. Our results suggested that microglia were involved in multiple types of acute chemical itch transmission, while the underlying mechanisms for histamine-dependent and non-dependent itch transmission were different that the former required the CX3CL1-CX3CR1 signal pathway.
Collapse
Affiliation(s)
- Yuxiu Yang
- School of Basic Medical Sciences, Nanchang University, Nanchang, China
- Institute of Life Science, Nanchang University, Nanchang, China
| | - Bin Mou
- School of Basic Medical Sciences, Nanchang University, Nanchang, China
- Institute of Life Science, Nanchang University, Nanchang, China
| | - Qi-Ruo Zhang
- Institute of Life Science, Nanchang University, Nanchang, China
| | - Hong-Xue Zhao
- School of Basic Medical Sciences, Nanchang University, Nanchang, China
- Institute of Life Science, Nanchang University, Nanchang, China
| | - Jian-Yun Zhang
- Institute of Life Science, Nanchang University, Nanchang, China
| | - Xiao Yun
- Institute of Life Science, Nanchang University, Nanchang, China
| | - Ming-Tao Xiong
- Institute of Life Science, Nanchang University, Nanchang, China
| | - Ying Liu
- Institute of Life Science, Nanchang University, Nanchang, China
| | - Yong U Liu
- Laboratory for Neuroimmunology in Health and Disease, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Haili Pan
- Institute of Life Science, Nanchang University, Nanchang, China
| | - Chao-Lin Ma
- Institute of Life Science, Nanchang University, Nanchang, China
| | - Bao-Ming Li
- Institute of Life Science, Nanchang University, Nanchang, China
- Department of Physiology and Institute of Brain Science, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, China
| | - Jiyun Peng
- School of Basic Medical Sciences, Nanchang University, Nanchang, China
- Institute of Life Science, Nanchang University, Nanchang, China
| |
Collapse
|
48
|
Kim HY, Shim JH, Heo CY. A Rare Skeletal Disorder, Fibrous Dysplasia: A Review of Its Pathogenesis and Therapeutic Prospects. Int J Mol Sci 2023; 24:15591. [PMID: 37958575 PMCID: PMC10650015 DOI: 10.3390/ijms242115591] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Fibrous dysplasia (FD) is a rare, non-hereditary skeletal disorder characterized by its chronic course of non-neoplastic fibrous tissue buildup in place of healthy bone. A myriad of factors have been associated with its onset and progression. Perturbation of cell-cell signaling networks and response outputs leading to disrupted building blocks, incoherent multi-level organization, and loss of rigid structural motifs in mineralized tissues are factors that have been identified to participate in FD induction. In more recent years, novel insights into the unique biology of FD are transforming our understandings of its pathology, natural discourse of the disease, and treatment prospects. Herein, we built upon existing knowledge with recent findings to review clinical, etiologic, and histological features of FD and discussed known and potential mechanisms underlying FD manifestations. Subsequently, we ended on a note of optimism by highlighting emerging therapeutic approaches aimed at either halting or ameliorating disease progression.
Collapse
Affiliation(s)
- Ha-Young Kim
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul 08826, Republic of Korea;
- Department of Plastic and Reconstructive Surgery, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
| | - Jung-Hee Shim
- Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea;
- Department of Research Administration Team, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
| | - Chan-Yeong Heo
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul 08826, Republic of Korea;
- Department of Plastic and Reconstructive Surgery, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
- Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea;
| |
Collapse
|
49
|
Endo A, Imai J, Izumi T, Kawana Y, Sugawara H, Kohata M, Seike J, Kubo H, Komamura H, Sato T, Asai Y, Hosaka S, Kodama S, Takahashi K, Kaneko K, Katagiri H. Phagocytosis by macrophages promotes pancreatic β cell mass reduction after parturition in mice. Dev Cell 2023; 58:1819-1829.e5. [PMID: 37716356 DOI: 10.1016/j.devcel.2023.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 03/07/2023] [Accepted: 08/01/2023] [Indexed: 09/18/2023]
Abstract
Elucidating the mechanism(s) modulating appropriate tissue size is a critical biological issue. Pancreatic β cells increase during pregnancy via cellular proliferation, but how β cells promptly decrease to the original amount after parturition remains unclear. Herein, we demonstrate the role and mechanism of macrophage accumulation in this process. In the final stage of pregnancy, HTR1D signaling upregulates murine β cell CXCL10, thereby promoting macrophage accumulation in pancreatic islets via the CXCL10-CXCR3 axis. Blocking this mechanism by administering an HTR1D antagonist or the CXCR3 antibody and depleting islet macrophages inhibited postpartum β cell mass reduction. β cells engulfed by macrophages increased in postpartum islets, but Annexin V administration suppressed this engulfment and the postpartum β cell mass reduction, indicating the accumulated macrophages to phagocytose β cells. This mechanism contributes to both maintenance of appropriate β cell mass and glucose homeostasis promptly adapting to reduced systemic insulin demand after parturition.
Collapse
Affiliation(s)
- Akira Endo
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Junta Imai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan.
| | - Tomohito Izumi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yohei Kawana
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Hiroto Sugawara
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Masato Kohata
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Junro Seike
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Haremaru Kubo
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Hiroshi Komamura
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Toshihiro Sato
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Yoichiro Asai
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Shinichiro Hosaka
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Shinjiro Kodama
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Kei Takahashi
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Keizo Kaneko
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Hideki Katagiri
- Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| |
Collapse
|
50
|
Ma C, McCallen J, McVey JC, Trehan R, Bauer K, Zhang Q, Ruf B, Wang S, Lai CW, Trinchieri G, Berzofsky JA, Korangy F, Greten TF. CSF-1R+ Macrophages Control the Gut Microbiome-Enhanced Liver Invariant NKT Function through IL-18. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1099-1107. [PMID: 37624046 PMCID: PMC10529904 DOI: 10.4049/jimmunol.2200854] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 07/31/2023] [Indexed: 08/26/2023]
Abstract
The gut microbiome is an important modulator of the host immune system. In this study, we found that altering the gut microbiome by oral vancomycin increases liver invariant NKT (iNKT) cell function. Enhanced iNKT cytokine production and activation marker expression were observed in vancomycin-treated mice following both Ag-specific and Ag-independent in vivo iNKT stimulations, with a more prominent effect in the liver than in the spleen. Fecal transplantation studies demonstrated that the iNKT functional regulation is mediated by altering the gut microbiome but uncoupled from the modulation of iNKT cell population size. Interestingly, when stimulated in vitro, iNKT cells from vancomycin-treated mice did not show increased activation, suggesting an indirect regulation. iNKT cells expressed high levels of IL-18 receptor, and vancomycin increased the expression of IL-18 in the liver. Blocking IL-18 by neutralizing Ab or using genetically deficient mice attenuated the enhanced iNKT activation. Liver macrophages were identified as a major source of IL-18. General macrophage depletion by clodronate abolished this iNKT activation. Using anti-CSF-1R depletion or LyzCrexCSF-1RLsL-DTR mice identified CSF-1R+ macrophages as a critical modulator of iNKT function. Vancomycin treatment had no effect on iNKT cell function in vivo in IL-18 knockout macrophage reconstituted mice. Together, our results demonstrate that the gut microbiome controls liver iNKT function via regulating CSF-1R+ macrophages to produce IL-18.
Collapse
Affiliation(s)
- Chi Ma
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Justin McCallen
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - John C. McVey
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, Ohio 44106, USA
| | - Rajiv Trehan
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Kylynda Bauer
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Qianfei Zhang
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Benjamin Ruf
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Sophie Wang
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Chunwei Walter Lai
- Liver and Energy Metabolism Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Giorgio Trinchieri
- Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Jay A. Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Firouzeh Korangy
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
| | - Tim F. Greten
- Thoracic and GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA
- NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, Maryland 20892, USA
| |
Collapse
|