|
1
|
Stables J, Pal R, Bradford BM, Carter-Cusack D, Taylor I, Pridans C, Khan N, Woodruff TM, Irvine KM, Summers KM, Mabbott NA, Hume DA. The effect of a dominant kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy on brain development and neuropathology. Neurobiol Dis 2024; 203:106743. [PMID: 39581554 DOI: 10.1016/j.nbd.2024.106743] [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: 10/14/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 11/26/2024] Open
Abstract
Amino acid substitutions in the kinase domain of the human CSF1R protein are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (Glu631Lys; E631K) in the mouse Csf1r locus. Previous analysis demonstrated that heterozygous mutation (Csf1rE631K/+) had a dominant inhibitory effect on CSF1R signaling in vitro and in vivo but did not recapitulate human disease pathology. We speculated that leukoencephalopathy in humans requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles. Here we examine the Csf1rE631K/+ mutation impact on microglial phenotype, postnatal brain development, age-related changes in gene expression and on prion disease and experimental autoimmune encephalitis (EAE), two pathologies in which microgliosis is a prominent feature. The Csf1rE631K/+ mutation reduced microglial abundance and the expression of microglial-associated transcripts relative to wild-type controls at 12 and 43 weeks of age. There was no selective effect on homeostatic markers e.g. P2ry12, or age-related changes in gene expression in striatum and hippocampus. An epistatic interaction was demonstrated between Csf1rE631K/+ and Cx3cr1EGFP/+ genotypes leading to dysregulated microglial and neuronal gene expression in hippocampus and striatum. Heterozygous Csf1rE631K mutation reduced the microgliosis associated with both diseases. There was no significant impact on disease severity or progression in prion disease. In EAE, inflammation-associated transcripts in the hippocampus and striatum were suppressed in parallel with microglia-specific transcripts. The results support a dominant inhibitory model of CSF1R-related leukoencephalopathy and likely contributions of an environmental trigger and/or genetic background to neuropathology.
Collapse
Affiliation(s)
- Jennifer Stables
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia; Robinson Research Institute, University of Adelaide, Adelaide, SA 5006, Australia
| | - Reiss Pal
- The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK
| | - Barry M Bradford
- The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK
| | - Dylan Carter-Cusack
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia
| | - Isis Taylor
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia
| | - Clare Pridans
- Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Centre for Inflammation Research, Institute for Regeneration and Repair, The University of Edinburgh, Edinburgh BioQuarter, Edinburgh EH16 4UU, UK
| | - Nemat Khan
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia
| | - Katharine M Irvine
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia
| | - Kim M Summers
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia
| | - Neil A Mabbott
- The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian EH25 9RG, UK
| | - David A Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD 4102, Australia.
| |
Collapse
|
|
2
|
Findik H, Uzun F, Kaim M, Birinci M, Çeliker M, Okutucu M, Gökhan Aslan M. The Impact of Systemic Inflammation on Recurrence in Patients with Congenital Nasolacrimal Duct Obstruction. J Clin Med 2024; 13:6834. [PMID: 39597978 PMCID: PMC11594532 DOI: 10.3390/jcm13226834] [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: 10/11/2024] [Revised: 10/28/2024] [Accepted: 11/09/2024] [Indexed: 11/29/2024] Open
Abstract
Background/Objective: Congenital nasolacrimal duct obstruction (CNLDO) is commonly treated by probing, but recurrence remains a clinical issue. This study investigates the potential role of inflammatory biomarkers, such as the neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR), in predicting recurrence after probing in children with CNLDO. Methods: This retrospective cohort study included 172 patients who underwent initial probing for unilateral CNLDO. The patients were then categorized into two groups: those who experienced the complete resolution of symptoms after primary probing, and those who required Ritleng tube intubation due to recurrence following primary probing. Blood samples for calculating inflammatory biomarkers in all subjects were collected during general anesthesia preparation prior to initial probing. NLR, MLR, and PLR values were compared between the groups using the independent samples t-test. The predictive performance of the inflammatory biomarkers for recurrence was assessed using Receiver Operating Characteristic (ROC) curve analysis. Results: A total of 110 patients were included in the probing group, while 62 patients were in the recurrence group. The mean age at the time of the initial probing procedure was 15 ± 4.06 months in the probing group and 15.83 ± 4.02 months in the recurrence group. There was no difference in the duration of the probing procedure between the groups. The mean age at the time of Ritleng tube intubation in the recurrence group was 37.80 ± 13.34 months. The recurrence group exhibited significantly higher values in all analyzed inflammatory markers compared to the probing group, including the NLR (1.12 ± 0.56 vs. 0.86 ± 0.39, p = 0.002), MLR (0.16 ± 0.06 vs. 0.14 ± 0.06, p = 0.005), and PLR (95.13 ± 24.34 vs. 82.23 ± 22.77, p < 0.001). ROC curve analysis indicated that these inflammatory biomarkers demonstrated moderate performance in predicting recurrence. Conclusions: Recurrence following probing in children with CNLDO was associated with complete blood cell count-derived inflammatory biomarkers. The preoperative assessment of these biomarkers may aid in the individualization of disease management and inform the development of new therapeutic strategies.
Collapse
Affiliation(s)
- Hüseyin Findik
- Department of Ophthalmology, School of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Turkey; (F.U.); (M.K.); (M.O.); (M.G.A.)
| | - Feyzahan Uzun
- Department of Ophthalmology, School of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Turkey; (F.U.); (M.K.); (M.O.); (M.G.A.)
| | - Muhammet Kaim
- Department of Ophthalmology, School of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Turkey; (F.U.); (M.K.); (M.O.); (M.G.A.)
| | - Mehmet Birinci
- Department of Otorhinolaryngology, School of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Turkey; (M.B.); (M.Ç.)
| | - Metin Çeliker
- Department of Otorhinolaryngology, School of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Turkey; (M.B.); (M.Ç.)
| | - Murat Okutucu
- Department of Ophthalmology, School of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Turkey; (F.U.); (M.K.); (M.O.); (M.G.A.)
| | - Mehmet Gökhan Aslan
- Department of Ophthalmology, School of Medicine, Recep Tayyip Erdogan University, 53100 Rize, Turkey; (F.U.); (M.K.); (M.O.); (M.G.A.)
| |
Collapse
|
|
3
|
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
|
|
4
|
Chen G, Lin L, Mai Z, Tang Y, Zhang Q, Chen G, Li Z, Zhang J, Wang Y, Yang Y, Yu Z. Carrier-Free Photodynamic Bioregulators Inhibiting Lactic Acid Efflux Combined with Immune Checkpoint Blockade for Triple-Negative Breast Cancer Immunotherapy. ACS NANO 2024. [PMID: 39034461 DOI: 10.1021/acsnano.4c07213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/23/2024]
Abstract
Abnormal tumor metabolism creates a complex tumor immune microenvironment that plays a dominant role in the metastasis of triple-negative breast cancer (TNBC). TNBC is insensitive to immune checkpoint blockade (ICB) therapy because of insufficient cytotoxic T lymphocyte (CTL) infiltration and a hyper-lactic acid-suppressive immune microenvironment caused by abnormal glycolysis. Herein, we propose an amplified strategy based on lactic acid regulation to reprogram the immunosuppressive tumor microenvironment (ITM) and combine it with ICB therapy to achieve enhanced antitumor immunotherapy effects. Specifically, we constructed CASN, a carrier-free photodynamic bioregulator, through the self-assembly of the photosensitizer Chlorin e6 and monocarboxylate transporter 1 (MCT1) inhibitor AZD3965. CASN exhibited a uniform structure, good stability, and drug accumulation at the tumor site. CASN-mediated photodynamic therapy following laser irradiation inhibited primary tumor growth and induced immunogenic cell death. Furthermore, CASN reduced lactic acid-mediated regulatory T cell generation and M2 tumor-associated macrophage polarization by blocking MCT1-mediated lactic acid efflux to attenuate immune suppression, inducing the recruitment and activation of CTLs. Ultimately, CASN-mediated immunopotentiation combined with ICB therapy considerably strengthened tumor immunotherapy and effectively inhibited tumor growth and metastasis of TNBC. This synergistic amplification strategy overcomes the limitations of an acidic ITM and presents a potential clinical treatment option for metastatic tumors.
Collapse
Affiliation(s)
- Guimei Chen
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Ling Lin
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Ziyi Mai
- Department of Pharmacy, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen 518035, China
| | - Yan Tang
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Qiaoling Zhang
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Gui Chen
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Zibo Li
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
- Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Jiasi Zhang
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
| | - Yongxia Wang
- Department of Galactophore, The Tenth Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Dongguan 523058, China
| | - Yuanyuan Yang
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
| | - Zhiqiang Yu
- Department of Laboratory Medicine, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Guangdong 523058, China
| |
Collapse
|
|
5
|
Yoon SO. Pathologic characteristics of histiocytic and dendritic cell neoplasms. Blood Res 2024; 59:18. [PMID: 38713245 PMCID: PMC11076448 DOI: 10.1007/s44313-024-00015-9] [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: 01/19/2024] [Accepted: 04/05/2024] [Indexed: 05/08/2024] Open
Abstract
Histiocytic and dendritic cell neoplasms comprise diverse tumors originating from the mononuclear phagocytic system, which includes monocytes, macrophages, and dendritic cells. The 5th edition of the World Health Organization (WHO) classification updating the categorization of these tumors, reflecting a deeper understanding of their pathogenesis.In this updated classification system, tumors are categorized as Langerhans cell and other dendritic cell neoplasms, histiocyte/macrophage neoplasms, and plasmacytoid dendritic cell neoplasms. Follicular dendritic cell neoplasms are classified as mesenchymal dendritic cell neoplasms within the stroma-derived neoplasms of lymphoid tissues.Each subtype of histiocytic and dendritic cell neoplasms exhibits distinct morphological characteristics. They also show a characteristic immunophenotypic profile marked by various markers such as CD1a, CD207/langerin, S100, CD68, CD163, CD4, CD123, CD21, CD23, CD35, and ALK, and hematolymphoid markers such as CD45 and CD43. In situ hybridization for EBV-encoded small RNA (EBER) identifies a particular subtype. Immunoprofiling plays a critical role in determining the cell of origin and identifying the specific subtype of tumors. There are frequent genomic alterations in these neoplasms, especially in the mitogen-activated protein kinase pathway, including BRAF (notably BRAF V600E), MAP2K1, KRAS, and NRAS mutations, and ALK gene translocation.This review aims to offer a comprehensive and updated overview of histiocytic and dendritic cell neoplasms, focusing on their ontogeny, morphological aspects, immunophenotypic profiles, and molecular genetics. This comprehensive approach is essential for accurately differentiating and classifying neoplasms according to the updated WHO classification.
Collapse
Affiliation(s)
- Sun Och Yoon
- Department of Pathology, Yonsei University College of Medicine, Severance Hospital, 50-1 Yonsei-Ro, Seodaemun-Gu, Seoul, 03722, South Korea.
| |
Collapse
|
|
6
|
Davodabadi F, Sajjadi SF, Sarhadi M, Mirghasemi S, Nadali Hezaveh M, Khosravi S, Kamali Andani M, Cordani M, Basiri M, Ghavami S. Cancer chemotherapy resistance: Mechanisms and recent breakthrough in targeted drug delivery. Eur J Pharmacol 2023; 958:176013. [PMID: 37633322 DOI: 10.1016/j.ejphar.2023.176013] [Citation(s) in RCA: 36] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 08/21/2023] [Accepted: 08/22/2023] [Indexed: 08/28/2023]
Abstract
Conventional chemotherapy, one of the most widely used cancer treatment methods, has serious side effects, and usually results in cancer treatment failure. Drug resistance is one of the primary reasons for this failure. The most significant drawbacks of systemic chemotherapy are rapid clearance from the circulation, the drug's low concentration in the tumor site, and considerable adverse effects outside the tumor. Several ways have been developed to boost neoplasm treatment efficacy and overcome medication resistance. In recent years, targeted drug delivery has become an essential therapeutic application. As more mechanisms of tumor treatment resistance are discovered, nanoparticles (NPs) are designed to target these pathways. Therefore, understanding the limitations and challenges of this technology is critical for nanocarrier evaluation. Nano-drugs have been increasingly employed in medicine, incorporating therapeutic applications for more precise and effective tumor diagnosis, therapy, and targeting. Many benefits of NP-based drug delivery systems in cancer treatment have been proven, including good pharmacokinetics, tumor cell-specific targeting, decreased side effects, and lessened drug resistance. As more mechanisms of tumor treatment resistance are discovered, NPs are designed to target these pathways. At the moment, this innovative technology has the potential to bring fresh insights into cancer therapy. Therefore, understanding the limitations and challenges of this technology is critical for nanocarrier evaluation.
Collapse
Affiliation(s)
- Fatemeh Davodabadi
- Department of Biology, Faculty of Basic Science, Payame Noor University, Tehran, Iran.
| | - Seyedeh Fatemeh Sajjadi
- School of Biological Science, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran.
| | - Mohammad Sarhadi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Shaghayegh Mirghasemi
- Department of Chemistry, Science and Research Branch, Islamic Azad University, Tehran, Iran.
| | - Mahdieh Nadali Hezaveh
- Department of Chemical Engineering, Isfahan University of Technology, Isfahan, 84156-83111, Iran.
| | - Samin Khosravi
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, North Tehran Branch, Islamic Azad University, Tehran, Iran.
| | - Mahdieh Kamali Andani
- Department of Biology, Faculty of Basic Science, Payame Noor University, Tehran, Iran.
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biological Sciences, Complutense University of Madrid, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
| | - Mohsen Basiri
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
| | - Saeid Ghavami
- Academy of Silesia, Faculty of Medicine, Rolna 43, 40-555. Katowice, Poland; Research Institute of Oncology and Hematology, Cancer Care Manitoba-University of Manitoba, Winnipeg, MB R3E 3P5, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; Department of Human Anatomy and Cell Science, University of Manitoba College of Medicine, Winnipeg, MB R3E 3P5, Canada.
| |
Collapse
|
|
7
|
Pereira F, Petroianu A, Geraldo JM, Pereira C. Megavoltage radiotherapy effects on organs of the reticuloendothelial system. Acta Cir Bras 2023; 38:e384123. [PMID: 37878983 PMCID: PMC10592569 DOI: 10.1590/acb384123] [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: 05/28/2023] [Accepted: 07/30/2023] [Indexed: 10/27/2023] Open
Abstract
PURPOSE To study the uptake capacity of cells from the reticuloendothelial system after irradiation with high-energy X-rays. METHODS Eighteen male Wistar rats were distributed in three groups: group A (n = 6): control, unirradiated animals studied alongside animals from group B; group B (n = 6) and group C (n = 6): animals irradiated and studied after 24 and 48 hours, respectively. The rats were anesthetized and placed on a 10 MV linear accelerator. Next, they were irradiated in the abdominal region, with 8 Gy. Twenty-four (groups A and B) and 48 hours later (group C), a colloidal carbon solution (1 mL/kg) was intravenously injected in the tail vein. Fifty minutes later, the spleens and livers were withdrawn and prepared to be studied. Kupffer cells and splenic macrophages containing carbon pigments were counted in an optical microscope. Arithmetic means were calculated for each group and compared among them. RESULTS X-rays were associated with a reduced number of Kupffer cells containing colloidal carbon, proliferation and enlargement of biliary ducts, hypoplasia, and hepatocyte necrosis. In the irradiated spleen, the colloidal carbon uptake was concentrated in the marginal zone around the white pulp, with an inexpressive uptake of pigments by macrophages from white and red pulps. CONCLUSIONS The X-rays in the rat abdomen are associated with a reduction in the Kupffer cells uptake of colloidal carbon, hepatocyte disorders, bile duct proliferation, and splenic uptake of colloidal carbon concentrated in the marginal zone.
Collapse
Affiliation(s)
- Fernando Pereira
- Universidade Federal de Minas Gerais - Departamento de Engenharia Nuclear - Belo Horizonte (MG) - Brazil
| | - Andy Petroianu
- Universidade Federal de Minas Gerais - Departamento de Cirurgia - Belo Horizonte (MG) - Brazil
| | | | - Claubia Pereira
- Universidade Federal de Minas Gerais - Departamento de Engenharia Nuclear - Belo Horizonte (MG) - Brazil
| |
Collapse
|
|
8
|
Li M, Wang M, Wen Y, Zhang H, Zhao G, Gao Q. Signaling pathways in macrophages: molecular mechanisms and therapeutic targets. MedComm (Beijing) 2023; 4:e349. [PMID: 37706196 PMCID: PMC10495745 DOI: 10.1002/mco2.349] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 07/24/2023] [Accepted: 07/27/2023] [Indexed: 09/15/2023] Open
Abstract
Macrophages play diverse roles in development, homeostasis, and immunity. Accordingly, the dysfunction of macrophages is involved in the occurrence and progression of various diseases, such as coronavirus disease 2019 and atherosclerosis. The protective or pathogenic effect that macrophages exert in different conditions largely depends on their functional plasticity, which is regulated via signal transduction such as Janus kinase-signal transducer and activator of transcription, Wnt and Notch pathways, stimulated by environmental cues. Over the past few decades, the molecular mechanisms of signaling pathways in macrophages have been gradually elucidated, providing more alternative therapeutic targets for diseases treatment. Here, we provide an overview of the basic physiology of macrophages and expound the regulatory pathways within them. We also address the crucial role macrophages play in the pathogenesis of diseases, including autoimmune, neurodegenerative, metabolic, infectious diseases, and cancer, with a focus on advances in macrophage-targeted strategies exploring modulation of components and regulators of signaling pathways. Last, we discuss the challenges and possible solutions of macrophage-targeted therapy in clinical applications. We hope that this comprehensive review will provide directions for further research on therapeutic strategies targeting macrophage signaling pathways, which are promising to improve the efficacy of disease treatment.
Collapse
Affiliation(s)
- Ming Li
- Department of Gynecological OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- National Clinical Research Center for Obstetrics and GynecologyCancer Biology Research Center (Key Laboratory of the Ministry of Education)Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Mengjie Wang
- Department of Gynecological OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- National Clinical Research Center for Obstetrics and GynecologyCancer Biology Research Center (Key Laboratory of the Ministry of Education)Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Yuanjia Wen
- Department of Gynecological OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- National Clinical Research Center for Obstetrics and GynecologyCancer Biology Research Center (Key Laboratory of the Ministry of Education)Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Hongfei Zhang
- Department of Gynecological OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- National Clinical Research Center for Obstetrics and GynecologyCancer Biology Research Center (Key Laboratory of the Ministry of Education)Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Guang‐Nian Zhao
- Department of Gynecological OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- National Clinical Research Center for Obstetrics and GynecologyCancer Biology Research Center (Key Laboratory of the Ministry of Education)Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| | - Qinglei Gao
- Department of Gynecological OncologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
- National Clinical Research Center for Obstetrics and GynecologyCancer Biology Research Center (Key Laboratory of the Ministry of Education)Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina
| |
Collapse
|
|
9
|
Lazzarini G, Abramo F, Albanese F, Pirone A, Miragliotta V. Combined immunohistochemical protocols to differentiate macrophages within the mononuclear-phagocyte system. Ann Anat 2023:152107. [PMID: 37207851 DOI: 10.1016/j.aanat.2023.152107] [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: 12/02/2022] [Revised: 04/29/2023] [Accepted: 05/13/2023] [Indexed: 05/21/2023]
Abstract
BACKGROUND The "mononuclear phagocyte system" (MPS) refers to dispersed mononuclear monocytes and macrophages and is used to distinguish them from polymorphonuclear cells. The term "histiocyte" indicates large cells with voluminous granulated cytoplasm, sometimes containing engulfed particles, recognized as fully differentiated end cells of the MPS. Dendritic cells (DC) represent another diversified population whose inclusion in the MPS is still debated. The diverse cells of the MPS cannot all be characterized by single antigen markers or unique functions expressed at all stages of cell differentiation or activation. Nevertheless, in a diagnostic setting, their reliable identification plays a major role when a specific therapy must be established. Understanding the heterogeneity among MPS cell populations is indeed relevant to define different therapeutic approaches that can range from the use of antibiotics to immunomodulatory agents. For this reason, we attempted to establish a protocol to reliably identify the proportion of macrophages within the mononuclear phagocyte system in a tissue and/or in a given inflammatory population. METHODS the Tafuri method was used in different double immunofluorescence protocols using an anti-Iba-1, anti-MAC387, and anti-CD11b-CD68-CD163-CD14-CD16 antibody. RESULTS AND DISCUSSION in normal canine skin the anti-Iba-1 antibody stained an epidermal cell population (i.e. Langerhans cells) and scattered cells within the dermal compartment. MAC387 was unable to stain cells containing Leishmania amastigotes in leishmaniasis-diagnosed samples as the anti-CD11b-CD68-CD163-CD14-CD16 antibody did. By using a combination of staining protocols to differentiate macrophages within the whole histiocytic infiltrate we validated the use of a cocktail of rabbit monoclonal antibodies raised against CD11b, CD68, CD163, CD14, CD16 to stain skin macrophages.
Collapse
Affiliation(s)
- G Lazzarini
- Department of Veterinary Sciences, University of Pisa, Pisa, Italy.
| | - F Abramo
- Department of Veterinary Sciences, University of Pisa, Pisa, Italy
| | - F Albanese
- Veterinary Diagnostic Laboratory MyLav-La Vallonea, Passirana di Rho (MI), Italy
| | - A Pirone
- Department of Veterinary Sciences, University of Pisa, Pisa, Italy
| | - V Miragliotta
- Department of Veterinary Sciences, University of Pisa, Pisa, Italy
| |
Collapse
|
|
10
|
MafB-restricted local monocyte proliferation precedes lung interstitial macrophage differentiation. Nat Immunol 2023; 24:827-840. [PMID: 36928411 PMCID: PMC10154211 DOI: 10.1038/s41590-023-01468-3] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 02/15/2023] [Indexed: 03/18/2023]
Abstract
Resident tissue macrophages (RTMs) are differentiated immune cells that populate distinct niches and exert important tissue-supportive functions. RTM maintenance is thought to rely either on differentiation from monocytes or on RTM self-renewal. Here, we used a mouse model of inducible lung interstitial macrophage (IM) niche depletion and refilling to investigate the development of IMs in vivo. Using time-course single-cell RNA-sequencing analyses, bone marrow chimeras and gene targeting, we found that engrafted Ly6C+ classical monocytes proliferated locally in a Csf1 receptor-dependent manner before differentiating into IMs. The transition from monocyte proliferation toward IM subset specification was controlled by the transcription factor MafB, while c-Maf specifically regulated the identity of the CD206+ IM subset. Our data provide evidence that, in the mononuclear phagocyte system, the ability to proliferate is not merely restricted to myeloid progenitor cells and mature RTMs but is also a tightly regulated capability of monocytes developing into RTMs in vivo.
Collapse
|
|
11
|
Qiao DR, Shan GY, Wang S, Cheng JY, Yan WQ, Li HJ. The mononuclear phagocyte system in hepatocellular carcinoma. World J Gastroenterol 2022; 28:6345-6355. [PMID: 36533105 PMCID: PMC9753057 DOI: 10.3748/wjg.v28.i45.6345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 10/10/2022] [Accepted: 11/17/2022] [Indexed: 12/02/2022] Open
Abstract
The mononuclear phagocyte system (MPS) consists of monocytes, dendritic cells and macrophages, which play vital roles in innate immune defense against cancer. Hepatocellular carcinoma (HCC) is a complex disease that is affected or initiated by many factors, including chronic hepatitis B virus infection, hepatitis C virus infection, metabolic disorders or alcohol consumption. Liver function, tumor stage and the performance status of patients affect HCC clinical outcomes. Studies have shown that targeted treatment of tumor microenvironment disorders may improve the efficacy of HCC treatments. Cytokines derived from the innate immune response can regulate T-cell differentiation, thereby shaping adaptive immunity, which is associated with the prognosis of HCC. Therefore, it is important to elucidate the function of the MPS in the progression of HCC. In this review, we outline the impact of HCC on the MPS. We illustrate how HCC reshapes MPS cell phenotype remodeling and the production of associated cytokines and characterize the function and impairment of the MPS in HCC.
Collapse
Affiliation(s)
- Duan-Rui Qiao
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130021, Jilin Province, China
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Guan-Yue Shan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Shuai Wang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Students Affairs, China-Japan Union Hospital of Jilin University, Changchun 130031, Jilin Province, China
| | - Jun-Ya Cheng
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130021, Jilin Province, China
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Wei-Qun Yan
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130021, Jilin Province, China
| | - Hai-Jun Li
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Institute of Liver Diseases, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| |
Collapse
|
|
12
|
Louwe PA, Forbes SJ, Bénézech C, Pridans C, Jenkins SJ. Cell origin and niche availability dictate the capacity of peritoneal macrophages to colonize the cavity and omentum. Immunology 2022; 166:458-474. [PMID: 35437746 PMCID: PMC7613338 DOI: 10.1111/imm.13483] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 03/15/2022] [Indexed: 12/02/2022] Open
Abstract
The relationship between macrophages of the peritoneal cavity and the adjacent omentum remains poorly understood. Here, we describe two populations of omental macrophages distinguished by CD102 expression and use an adoptive cell transfer approach to investigate whether these arise from peritoneal macrophages, and whether this depends upon inflammatory status, the origin of peritoneal macrophages and availability of the omental niches. We show that whereas established resident peritoneal macrophages largely fail to migrate to the omentum, monocyte-derived resident cells readily migrate and form a substantial component of omental CD102+ macrophages in the months following resolution of peritoneal inflammation. In contrast, both populations had the capacity to migrate to the omentum in the absence of endogenous peritoneal and omental macrophages. However, inflammatory macrophages expanded more effectively and more efficiently repopulated both CD102+ and CD102- omental populations, whereas established resident macrophages partially reconstituted the omental niche via recruitment of monocytes. Hence, cell origin determines the migration of peritoneal macrophages to the omentum and predisposes established resident macrophages to drive infiltration of monocyte-derived cells.
Collapse
Affiliation(s)
- Pieter A. Louwe
- Queens Medical Research Institute, University of Edinburgh Centre for Inflammation Research, Edinburgh, UK
- Laboratory of Myeloid Cell Biology in Tissue Damage and Inflammation, VIB Center for Inflammation Research, Ghent, Belgium
| | - Stuart J. Forbes
- Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, UK
| | - Cécile Bénézech
- Queens Medical Research Institute, University of Edinburgh Centre for Cardiovascular Science, Edinburgh, UK
| | - Clare Pridans
- Queens Medical Research Institute, University of Edinburgh Centre for Inflammation Research, Edinburgh, UK
- Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
| | - Stephen J. Jenkins
- Queens Medical Research Institute, University of Edinburgh Centre for Inflammation Research, Edinburgh, UK
| |
Collapse
|
|
13
|
Szittner Z, Péter B, Kurunczi S, Székács I, Horváth R. Functional blood cell analysis by label-free biosensors and single-cell technologies. Adv Colloid Interface Sci 2022; 308:102727. [DOI: 10.1016/j.cis.2022.102727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/25/2022] [Accepted: 06/27/2022] [Indexed: 11/01/2022]
|
|
14
|
Colony stimulating factor-1 producing endothelial cells and mesenchymal stromal cells maintain monocytes within a perivascular bone marrow niche. Immunity 2022; 55:862-878.e8. [PMID: 35508166 DOI: 10.1016/j.immuni.2022.04.005] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 01/13/2022] [Accepted: 04/08/2022] [Indexed: 12/15/2022]
Abstract
Macrophage colony stimulating factor-1 (CSF-1) plays a critical role in maintaining myeloid lineage cells. However, congenital global deficiency of CSF-1 (Csf1op/op) causes severe musculoskeletal defects that may indirectly affect hematopoiesis. Indeed, we show here that osteolineage-derived Csf1 prevented developmental abnormalities but had no effect on monopoiesis in adulthood. However, ubiquitous deletion of Csf1 conditionally in adulthood decreased monocyte survival, differentiation, and migration, independent of its effects on bone development. Bone histology revealed that monocytes reside near sinusoidal endothelial cells (ECs) and leptin receptor (Lepr)-expressing perivascular mesenchymal stromal cells (MSCs). Targeted deletion of Csf1 from sinusoidal ECs selectively reduced Ly6C- monocytes, whereas combined depletion of Csf1 from ECs and MSCs further decreased Ly6Chi cells. Moreover, EC-derived CSF-1 facilitated recovery of Ly6C- monocytes and protected mice from weight loss following induction of polymicrobial sepsis. Thus, monocytes are supported by distinct cellular sources of CSF-1 within a perivascular BM niche.
Collapse
|
|
15
|
Mills JA, Liu F, Jarrett TR, Fletcher NL, Thurecht KJ. Nanoparticle based medicines: approaches for evading and manipulating the mononuclear phagocyte system and potential for clinical translation. Biomater Sci 2022; 10:3029-3053. [PMID: 35419582 DOI: 10.1039/d2bm00181k] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
For decades, nanomedicines have been reported as a potential means to overcome the limitations of conventional drug delivery systems by reducing side effects, toxicity and the non-ideal pharmacokinetic behaviour typically exhibited by small molecule drugs. However, upon administration many nanoparticles prompt induction of host inflammatory responses due to recognition and uptake by macrophages, eliminating up to 95% of the administered dose. While significant advances in nanoparticle engineering and consequent therapeutic efficacy have been made, it is becoming clear that nanoparticle recognition by the mononuclear phagocyte system (MPS) poses an impassable junction in the current framework of nanoparticle development. Hence, this has negative consequences on the clinical translation of nanotechnology with respect to therapeutic efficacy, systemic toxicity and economic benefit. In order to improve the translation of nanomedicines from bench-to-bedside, there is a requirement to either modify nanomedicines in terms of how they interact with intrinsic processes in the body, or modulate the body to be more accommodating for nanomedicine treatments. Here we provide an overview of the current standard for design elements of nanoparticles, as well as factors to consider when producing nanomedicines that have minimal MPS-nanoparticle interactions; we explore this landscape across the cellular to tissue and organ levels. Further, rather than designing materials to suit the body, a growing research niche involves modulating biological responses to administered nanomaterials. We here discuss how developing strategic methods of MPS 'pre-conditioning' with small molecule or biological drugs, as well as implementing strategic dosing regimens, such as 'decoy' nanoparticles, is essential to increasing nanoparticle therapeutic efficacy. By adopting such a perspective, we hope to highlight the increasing trends in research dedicated to improving nanomedicine translation, and subsequently making a positive clinical impact.
Collapse
Affiliation(s)
- Jessica A Mills
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. .,Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australia
| | - Feifei Liu
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. .,Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australia.,ARC Centre for Innovation in Biomedical Imaging Technology, Australia
| | - Thomas R Jarrett
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. .,Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australia.,ARC Centre for Innovation in Biomedical Imaging Technology, Australia
| | - Nicholas L Fletcher
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. .,Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australia
| | - Kristofer J Thurecht
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD 4072, Australia. .,Centre for Advanced Imaging, The University of Queensland, St Lucia, QLD 4072, Australia.,ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Australia.,ARC Centre for Innovation in Biomedical Imaging Technology, Australia
| |
Collapse
|
|
16
|
The Human Monocyte-A Circulating Sensor of Infection and a Potent and Rapid Inducer of Inflammation. Int J Mol Sci 2022; 23:ijms23073890. [PMID: 35409250 PMCID: PMC8999117 DOI: 10.3390/ijms23073890] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 03/29/2022] [Accepted: 03/30/2022] [Indexed: 02/04/2023] Open
Abstract
Monocytes were previously thought to be the precursors of all tissue macrophages but have recently been found to represent a unique population of cells, distinct from the majority of tissue macrophages. Monocytes and intestinal macrophages seem now to be the only monocyte/macrophage populations that originate primarily from adult bone marrow. To obtain a better view of the biological function of monocytes and how they differ from tissue macrophages, we have performed a quantitative analysis of its transcriptome in vivo and after in vitro stimulation with E. coli LPS. The monocytes rapidly responded to LPS by producing extremely high amounts of mRNA for the classical inflammatory cytokines, IL-1α, IL-1β, IL-6 and TNF-α, but almost undetectable amounts of other cytokines. IL-6 was upregulated 58,000 times, from almost undetectable levels at baseline to become one of the major transcripts already after a few hours of cultivation. The cells also showed very strong upregulation of a number of chemokines, primarily IL-8, Ccl2, Ccl3, Ccl3L3, Ccl20, Cxcl2, Cxcl3 and Cxcl4. IL-8 became the most highly expressed transcript in the monocytes already after four hours of in vitro culture in the presence of LPS. A high baseline level of MHC class II chains and marked upregulation of super oxide dismutase (SOD2), complement factor B, complement factor C3 and coagulation factor 3 (F3; tissue factor) at four hours of in vitro culture were also observed. This indicates a rapid protective response to high production of oxygen radicals, to increase complement activation and possibly also be an inducer of local coagulation. Overall, these findings give strong support for monocytes acting primarily as potent mobile sensors of infection and rapid activators of a strong inflammatory response.
Collapse
|
|
17
|
Zhang X, Moore CM, Harmacek LD, Domenico J, Rangaraj VR, Ideozu JE, Knapp JR, Woods KJ, Jump S, Jia S, Prokop JW, Bowler R, Hessner MJ, Gelfand EW, Levy H. CFTR-mediated monocyte/macrophage dysfunction revealed by cystic fibrosis proband-parent comparisons. JCI Insight 2022; 7:152186. [PMID: 35315363 PMCID: PMC8986072 DOI: 10.1172/jci.insight.152186] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 02/02/2022] [Indexed: 12/23/2022] Open
Abstract
Cystic fibrosis (CF) is an inherited disorder caused by biallelic mutations of the CF transmembrane conductance regulator (CFTR) gene. Converging evidence suggests that CF carriers with only 1 defective CFTR copy are at increased risk for CF-related conditions and pulmonary infections, but the molecular mechanisms underpinning this effect remain unknown. We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) of CF child-parent trios (proband, father, and mother) and healthy control (HC) PBMCs or THP-1 cells incubated with the plasma of these participants. Transcriptomic analyses revealed suppression of cytokine-enriched immune-related genes (IL-1β, CXCL8, CREM), implicating lipopolysaccharide tolerance in innate immune cells (monocytes) of CF probands and their parents. These data suggest that a homozygous as well as a heterozygous CFTR mutation can modulate the immune/inflammatory system. This conclusion is further supported by the finding of lower numbers of circulating monocytes in CF probands and their parents, compared with HCs, and the abundance of mononuclear phagocyte subsets, which correlated with Pseudomonas aeruginosa infection, lung disease severity, and CF progression in the probands. This study provides insight into demonstrated CFTR-related innate immune dysfunction in individuals with CF and carriers of a CFTR mutation that may serve as a target for personalized therapy.
Collapse
Affiliation(s)
- Xi Zhang
- Data Science program, Weinberg College of Arts and Sciences, Northwestern University, Evanston, Illinois, USA.,Division of Pediatric Pulmonary Medicine, Department of Pediatrics, and
| | - Camille M Moore
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
| | - Laura D Harmacek
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
| | - Joanne Domenico
- Division of Pediatric Pulmonary Medicine, Department of Pediatrics, and
| | - Vittobai Rashika Rangaraj
- Division of Pulmonary & Sleep Medicine, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA
| | - Justin E Ideozu
- Genomic Medicine, Genomics Research Center, AbbVie, North Chicago, Illinois, USA
| | - Jennifer R Knapp
- Center for Genes, Environment and Health, National Jewish Health, Denver, Colorado, USA
| | - Katherine J Woods
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Stephanie Jump
- Department of Pediatrics, National Jewish Health, Denver, Colorado, USA
| | - Shuang Jia
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.,Max McGee Center for Juvenile Diabetes, Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA
| | - Jeremy W Prokop
- Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, USA
| | - Russell Bowler
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, and
| | - Martin J Hessner
- Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.,Max McGee Center for Juvenile Diabetes, Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, Wisconsin, USA
| | - Erwin W Gelfand
- Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado, USA.,Division of Immunology, Microbiology and Pediatrics, Department of Pediatrics, University of Colorado School of Medicine, Denver, Colorado, USA
| | - Hara Levy
- Division of Pediatric Pulmonary Medicine, Department of Pediatrics, and
| |
Collapse
|
|
18
|
Paivandy A, Akula S, Lara S, Fu Z, Olsson AK, Kleinau S, Pejler G, Hellman L. Quantitative In-Depth Transcriptome Analysis Implicates Peritoneal Macrophages as Important Players in the Complement and Coagulation Systems. Int J Mol Sci 2022; 23:ijms23031185. [PMID: 35163105 PMCID: PMC8835655 DOI: 10.3390/ijms23031185] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Revised: 01/17/2022] [Accepted: 01/18/2022] [Indexed: 02/05/2023] Open
Abstract
To obtain a more detailed picture of macrophage (MΦ) biology, in the current study, we analyzed the transcriptome of mouse peritoneal MΦs by RNA-seq and PCR-based transcriptomics. The results show that peritoneal MΦs, based on mRNA content, under non-inflammatory conditions produce large amounts of a number of antimicrobial proteins such as lysozyme and several complement components. They were also found to be potent producers of several chemokines, including platelet factor 4 (PF4), Ccl6, Ccl9, Cxcl13, and Ccl24, and to express high levels of both TGF-β1 and TGF-β2. The liver is considered to be the main producer of most complement and coagulation components. However, we can now show that MΦs are also important sources of such compounds including C1qA, C1qB, C1qC, properdin, C4a, factor H, ficolin, and coagulation factor FV. In addition, FX, FVII, and complement factor B were expressed by the MΦs, altogether indicating that MΦs are important local players in both the complement and coagulation systems. For comparison, we analyzed human peripheral blood monocytes. We show that the human monocytes shared many characteristics with the mouse peritoneal MΦs but that there were also many major differences. Similar to the mouse peritoneal MΦs, the most highly expressed transcript in the monocytes was lysozyme, and high levels of both properdin and ficolin were observed. However, with regard to connective tissue components, such as fibronectin, lubricin, syndecan 3, and extracellular matrix protein 1, which were highly expressed by the peritoneal MΦs, the monocytes almost totally lacked transcripts. In contrast, monocytes expressed high levels of MHC Class II, whereas the peritoneal MΦs showed very low levels of these antigen-presenting molecules. Altogether, the present study provides a novel view of the phenotype of the major MΦ subpopulation in the mouse peritoneum and the large peritoneal MΦs and places the transcriptome profile of the peritoneal MΦs in a broader context, including a comparison of the peritoneal MΦ transcriptome with that of human peripheral blood monocytes and the liver.
Collapse
Affiliation(s)
- Aida Paivandy
- Department of Medical Biochemistry and Microbiology, Uppsala University, The Biomedical Center, SE-751 23 Uppsala, Sweden; (A.P.); (A.-K.O.); (G.P.)
| | - Srinivas Akula
- Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, SE-751 24 Uppsala, Sweden; (S.A.); (S.L.); (Z.F.); (S.K.)
| | - Sandra Lara
- Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, SE-751 24 Uppsala, Sweden; (S.A.); (S.L.); (Z.F.); (S.K.)
| | - Zhirong Fu
- Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, SE-751 24 Uppsala, Sweden; (S.A.); (S.L.); (Z.F.); (S.K.)
| | - Anna-Karin Olsson
- Department of Medical Biochemistry and Microbiology, Uppsala University, The Biomedical Center, SE-751 23 Uppsala, Sweden; (A.P.); (A.-K.O.); (G.P.)
| | - Sandra Kleinau
- Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, SE-751 24 Uppsala, Sweden; (S.A.); (S.L.); (Z.F.); (S.K.)
| | - Gunnar Pejler
- Department of Medical Biochemistry and Microbiology, Uppsala University, The Biomedical Center, SE-751 23 Uppsala, Sweden; (A.P.); (A.-K.O.); (G.P.)
| | - Lars Hellman
- Department of Cell and Molecular Biology, Uppsala University, The Biomedical Center, SE-751 24 Uppsala, Sweden; (S.A.); (S.L.); (Z.F.); (S.K.)
- Correspondence: ; Tel.: +46-(0)18-471-4532; Fax: +46-(0)18-471-4862
| |
Collapse
|
|
19
|
Tang XZ, Kreuk LSM, Cho C, Metzger RJ, Allen CDC. Bronchus-associated macrophages efficiently capture and present soluble inhaled antigens and are capable of local Th2 cell activation. eLife 2022; 11:63296. [PMID: 36173678 PMCID: PMC9560158 DOI: 10.7554/elife.63296] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 08/10/2022] [Indexed: 11/13/2022] Open
Abstract
In allergic asthma, allergen inhalation leads to local Th2 cell activation and peribronchial inflammation. However, the mechanisms for local antigen capture and presentation remain unclear. By two-photon microscopy of the mouse lung, we established that soluble antigens in the bronchial airway lumen were efficiently captured and presented by a population of CD11c+ interstitial macrophages with high CX3CR1-GFP and MHC class II expression. We refer to these cells as Bronchus-Associated Macrophages (BAMs) based on their localization underneath the bronchial epithelium. BAMs were enriched in collagen-rich regions near some airway branchpoints, where inhaled antigens are likely to deposit. BAMs engaged in extended interactions with effector Th2 cells and promoted Th2 cytokine production. BAMs were also often in contact with dendritic cells (DCs). After exposure to inflammatory stimuli, DCs migrated to draining lymph nodes, whereas BAMs remained lung resident. We propose that BAMs act as local antigen presenting cells in the lung and also transfer antigen to DCs.
Collapse
Affiliation(s)
- Xin-Zi Tang
- Cardiovascular Research Institute, University of California, San FranciscoSan FranciscoUnited States,Sandler Asthma Basic Research Center, University of California, San FranciscoSan FranciscoUnited States,Biomedical Sciences Graduate Program, University of California, San FranciscoSan FranciscoUnited States
| | - Lieselotte S M Kreuk
- Cardiovascular Research Institute, University of California, San FranciscoSan FranciscoUnited States,Sandler Asthma Basic Research Center, University of California, San FranciscoSan FranciscoUnited States
| | - Cynthia Cho
- Cardiovascular Research Institute, University of California, San FranciscoSan FranciscoUnited States,Sandler Asthma Basic Research Center, University of California, San FranciscoSan FranciscoUnited States
| | - Ross J Metzger
- Department of Anatomy, University of California, San FranciscoSan FranciscoUnited States
| | - Christopher D C Allen
- Cardiovascular Research Institute, University of California, San FranciscoSan FranciscoUnited States,Sandler Asthma Basic Research Center, University of California, San FranciscoSan FranciscoUnited States,Department of Anatomy, University of California, San FranciscoSan FranciscoUnited States
| |
Collapse
|
|
20
|
Sun X, Gao J, Meng X, Lu X, Zhang L, Chen R. Polarized Macrophages in Periodontitis: Characteristics, Function, and Molecular Signaling. Front Immunol 2021; 12:763334. [PMID: 34950140 PMCID: PMC8688840 DOI: 10.3389/fimmu.2021.763334] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/04/2021] [Indexed: 12/23/2022] Open
Abstract
Periodontitis (PD) is a common chronic infectious disease. The local inflammatory response in the host may cause the destruction of supporting periodontal tissue. Macrophages play a variety of roles in PD, including regulatory and phagocytosis. Moreover, under the induction of different factors, macrophages polarize and form different functional phenotypes. Among them, M1-type macrophages with proinflammatory functions and M2-type macrophages with anti-inflammatory functions are the most representative, and both of them can regulate the tendency of the immune system to exert proinflammatory or anti-inflammatory functions. M1 and M2 macrophages are involved in the destructive and reparative stages of PD. Due to the complex microenvironment of PD, the dynamic development of PD, and various local mediators, increasing attention has been given to the study of macrophage polarization in PD. This review summarizes the role of macrophage polarization in the development of PD and its research progress.
Collapse
Affiliation(s)
- Xiaoyu Sun
- *Correspondence: Lei Zhang, ; Xiaoyu Sun,
| | | | | | | | - Lei Zhang
- Key Laboratory of Oral Diseases Research of Anhui Province, Department of Periodontology, Stomatologic Hospital & College, Anhui Medical University, Hefei, China
| | | |
Collapse
|
|
21
|
Jenkins SJ, Allen JE. The expanding world of tissue-resident macrophages. Eur J Immunol 2021; 51:1882-1896. [PMID: 34107057 DOI: 10.1002/eji.202048881] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/02/2021] [Accepted: 06/08/2021] [Indexed: 12/23/2022]
Abstract
The term 'macrophage' encompasses tissue cells that typically share dependence on the same transcriptional regulatory pathways (e.g. the transcription factor PU.1) and growth factors (e.g. CSF1/IL-34). They share a core set of functions that largely arise from a uniquely high phagocytic capacity manifest in their ability to clear dying cells, pathogens and scavenge damaged, toxic or modified host molecules. However, macrophages demonstrate a remarkable degree of tissue-specific functionality and have diverse origins that vary by tissue site and inflammation status. With our understanding of this diversity has come an appreciation of the longevity and replicative capacity of tissue-resident macrophages and thus the realisation that macrophages may persist through tissue perturbations and inflammatory events with important consequences for cell function. Here, we discuss our current understanding of the parameters that regulate macrophage survival and function, focusing on the relative importance of the tissue environment versus cell-intrinsic factors, such as origin, how long a cell has been resident within a tissue and prior history of activation. Thus, we reconsider the view of macrophages as wholly plastic cells and raise many unanswered questions about the relative importance of cell life-history versus environment in macrophage programming and function.
Collapse
Affiliation(s)
- Stephen J Jenkins
- Centre for Inflammation Research, Queens Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Judith E Allen
- Lydia Becker Institute of Immunology & Inflammation, Wellcome Centre for Cell Matrix Research, School of Biological Sciences, University of Manchester, Manchester, UK
| |
Collapse
|
|
22
|
Chaudhary R, Morris RJ, Steinson E. The multifactorial roles of microglia and macrophages in the maintenance and progression of glioblastoma. J Neuroimmunol 2021; 357:577633. [PMID: 34153803 DOI: 10.1016/j.jneuroim.2021.577633] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/26/2021] [Accepted: 06/11/2021] [Indexed: 01/18/2023]
Abstract
The functional characteristics of glial cells, in particular microglia, have attained considerable importance in several diseases, including glioblastoma, the most hostile and malignant type of intracranial tumor. Microglia performs a highly significant role in the brain's inflammatory response mechanism. They exhibit anti-tumor properties via phagocytosis and the activation of a number of different cytotoxic substances. Some tumor-derived factors, however, transform these microglial cells into immunosuppressive and tumor-supportive, facilitating survival and progression of tumorigenic cells. Glioma-associated microglia and/or macrophages (GAMs) accounts for a large proportion of glioma infiltrating cells. Once within the tumor, GAMs exhibit a distinct phenotype of initiation that subsequently supports the growth and development of tumorigenic cells, angiogenesis and stimulates the infiltration of healthy brain regions. Interventions that suppress or prohibit the induction of GAMs at the tumor site or attenuate their immunological activities accommodating anti-tumor actions are likely to exert positive impact on glioblastoma treatment. In the present paper, we aim to summarize the most recent knowledge of microglia and its physiology, as well as include a very brief description of different molecular factors involved in microglia and glioblastoma interplay. We further address some of the major signaling pathways that regulate the baseline motility of glioblastoma progression. Finally, we discussed a number of therapeutic approaches regarding glioblastoma treatment.
Collapse
Affiliation(s)
- Rishabh Chaudhary
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Raebareli Road, Lucknow, India.
| | - Rhianna J Morris
- Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom
| | - Emma Steinson
- School of Chemistry and Molecular Biosciences, The University of Queensland, St Lucia, QLD, Australia
| |
Collapse
|
|
23
|
Fu M, Song J. Single-Cell Transcriptomics Reveals the Cellular Heterogeneity of Cardiovascular Diseases. Front Cardiovasc Med 2021; 8:643519. [PMID: 34179129 PMCID: PMC8225933 DOI: 10.3389/fcvm.2021.643519] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 05/13/2021] [Indexed: 12/23/2022] Open
Abstract
"A world in a wild flower, and a bodhi in a leaf," small cells contain huge secrets. The vasculature is composed of many multifunctional cell subpopulations, each of which is involved in the occurrence and development of cardiovascular diseases. Single-cell transcriptomics captures the full picture of genes expressed within individual cells, identifies rare or de novo cell subpopulations, analyzes single-cell trajectory and stem cell or progenitor cell lineage conversion, and compares healthy tissue and disease-related tissue at single-cell resolution. Single-cell transcriptomics has had a profound effect on the field of cardiovascular research over the past decade, as evidenced by the construction of cardiovascular cell landscape, as well as the clarification of cardiovascular diseases and the mechanism of stem cell or progenitor cell differentiation. The classification and proportion of cell subpopulations in vasculature vary with species, location, genotype, and disease, exhibiting unique gene expression characteristics in organ development, disease progression, and regression. Specific gene markers are expected to be the diagnostic criteria, therapeutic targets, or prognostic indicators of diseases. Therefore, treatment of vascular disease still has lots of potentials to develop. Herein, we summarize the cell clusters and gene expression patterns in normal vasculature and atherosclerosis, aortic aneurysm, and pulmonary hypertension to reveal vascular heterogeneity and new regulatory factors of cardiovascular disease in the use of single-cell transcriptomics and discuss its current limitations and promising clinical potential.
Collapse
Affiliation(s)
- Mengxia Fu
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- The Cardiomyopathy Research Group at Fuwai Hospital, Beijing, China
| | - Jiangping Song
- State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- The Cardiomyopathy Research Group at Fuwai Hospital, Beijing, China
- Department of Cardiovascular Surgery, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
|
24
|
Lyadova I, Gerasimova T, Nenasheva T. Macrophages Derived From Human Induced Pluripotent Stem Cells: The Diversity of Protocols, Future Prospects, and Outstanding Questions. Front Cell Dev Biol 2021; 9:640703. [PMID: 34150747 PMCID: PMC8207294 DOI: 10.3389/fcell.2021.640703] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/25/2021] [Indexed: 12/23/2022] Open
Abstract
Macrophages (Mφ) derived from induced pluripotent stem cells (iMphs) represent a novel and promising model for studying human Mφ function and differentiation and developing new therapeutic strategies based on or oriented at Mφs. iMphs have several advantages over the traditionally used human Mφ models, such as immortalized cell lines and monocyte-derived Mφs. The advantages include the possibility of obtaining genetically identical and editable cells in a potentially scalable way. Various applications of iMphs are being developed, and their number is rapidly growing. However, the protocols of iMph differentiation that are currently used vary substantially, which may lead to differences in iMph differentiation trajectories and properties. Standardization of the protocols and identification of minimum required conditions that would allow obtaining iMphs in a large-scale, inexpensive, and clinically suitable mode are needed for future iMph applications. As a first step in this direction, the current review discusses the fundamental basis for the generation of human iMphs, performs a detailed analysis of the generalities and the differences between iMph differentiation protocols currently employed, and discusses the prospects of iMph applications.
Collapse
Affiliation(s)
- Irina Lyadova
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, Russia
| | | | | |
Collapse
|
|
25
|
Hume DA, Caruso M, Keshvari S, Patkar OL, Sehgal A, Bush SJ, Summers KM, Pridans C, Irvine KM. The Mononuclear Phagocyte System of the Rat. THE JOURNAL OF IMMUNOLOGY 2021; 206:2251-2263. [PMID: 33965905 DOI: 10.4049/jimmunol.2100136] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 03/01/2021] [Indexed: 12/14/2022]
Abstract
The laboratory rat continues to be the model of choice for many studies of physiology, behavior, and complex human diseases. Cells of the mononuclear phagocyte system (MPS; monocytes, macrophages, and dendritic cells) are abundant residents in every tissue in the body and regulate postnatal development, homeostasis, and innate and acquired immunity. Recruitment and proliferation of MPS cells is an essential component of both initiation and resolution of inflammation. The large majority of current knowledge of MPS biology is derived from studies of inbred mice, but advances in technology and resources have eliminated many of the advantages of the mouse as a model. In this article, we review the tools available and the current state of knowledge of development, homeostasis, regulation, and diversity within the MPS of the rat.
Collapse
Affiliation(s)
- David A Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Melanie Caruso
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Sahar Keshvari
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Omkar L Patkar
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Anuj Sehgal
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Stephen J Bush
- Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - Kim M Summers
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Clare Pridans
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.,Simons Initiative for the Developing Brain, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Katharine M Irvine
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| |
Collapse
|
|
26
|
Echinacea purpurea L. (Moench) Hemagglutinin Effect on Immune Response In Vivo. PLANTS 2021; 10:plants10050936. [PMID: 34067195 PMCID: PMC8151625 DOI: 10.3390/plants10050936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 04/30/2021] [Accepted: 05/06/2021] [Indexed: 11/23/2022]
Abstract
Echinacea purpurea L. (Moench) is used in traditional and conventional medicine. However, there is lack of data on the biological activities of primary plant metabolite lectins. The aim of our experiment was to find out how lectin LysM (lysine motif), which was previously purified, affects the immune response in vivo. Eight-week-old BALB/c male mice (n = 15) received four weekly 250 μg/kg peritonial injections of purified Echinacea purpurea L. (Moench) roots’ LysM lectin. The control animal group (n = 15) received 50 μL peritoneal injections of fresh Echinacea purpurea L. (Moench) root tincture, and the negative control animal group (n = 15) received 50 μL peritoneal injections of physiological solution. At the fifth experimental week, the animals were sedated with carbon dioxide, and later euthanized by cervical dislocation, and then their blood and spleen samples were collected. The leukocytes’ formula and lymphocytes’ count was estimated in blood samples, the T lymphocytes’ density was evaluated in spleen zones. A statistically significant (p < 0.05) difference between each group was observed in the leukocytes’ formula (monocytes’ percentage, also little, medium and giant size lymphocytes). The purple coneflower fresh roots’ tincture significantly decreased (p < 0.05) the T lymphocytes’ quantity in peritoneal lymphoid sheaths (PALS) compared with the physiological solution injection’s group (p < 0.05) and the lectin injection’s group (p < 0.001). Meanwhile, lectin injections caused a significant (p < 0.01) increase in the T lymphocytes in a spleen PALS zone, compared with the physiological solution and tincture injection’s group. Our data suggests that LysM lectin acts as an immunostimulant, while fresh purple coneflower tincture causes immunosuppression.
Collapse
|
|
27
|
Heme catabolism by tumor-associated macrophages controls metastasis formation. Nat Immunol 2021; 22:595-606. [PMID: 33903766 DOI: 10.1038/s41590-021-00921-5] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Accepted: 03/19/2021] [Indexed: 02/02/2023]
Abstract
Although the pathological significance of tumor-associated macrophage (TAM) heterogeneity is still poorly understood, TAM reprogramming is viewed as a promising anticancer therapy. Here we show that a distinct subset of TAMs (F4/80hiCD115hiC3aRhiCD88hi), endowed with high rates of heme catabolism by the stress-responsive enzyme heme oxygenase-1 (HO-1), plays a critical role in shaping a prometastatic tumor microenvironment favoring immunosuppression, angiogenesis and epithelial-to-mesenchymal transition. This population originates from F4/80+HO-1+ bone marrow (BM) precursors, accumulates in the blood of tumor bearers and preferentially localizes at the invasive margin through a mechanism dependent on the activation of Nrf2 and coordinated by the NF-κB1-CSF1R-C3aR axis. Inhibition of F4/80+HO-1+ TAM recruitment or myeloid-specific deletion of HO-1 blocks metastasis formation and improves anticancer immunotherapy. Relative expression of HO-1 in peripheral monocyte subsets, as well as in tumor lesions, discriminates survival among metastatic melanoma patients. Overall, these results identify a distinct cancer-induced HO-1+ myeloid subgroup as a new antimetastatic target and prognostic blood marker.
Collapse
|
|
28
|
Blériot C, Chakarov S, Ginhoux F. Determinants of Resident Tissue Macrophage Identity and Function. Immunity 2021; 52:957-970. [PMID: 32553181 DOI: 10.1016/j.immuni.2020.05.014] [Citation(s) in RCA: 315] [Impact Index Per Article: 78.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/27/2020] [Accepted: 05/27/2020] [Indexed: 12/23/2022]
Abstract
Resident tissue macrophages (RTMs) have a broad spectrum of immune- and non-immune-related tissue-supporting activities. The roots of this heterogeneity and versatility are only beginning to be understood. Here, we propose a conceptual framework for considering the RTM heterogeneity that organizes the factors shaping RTM identity within four cardinal points: (1) ontogeny and the view that adult RTM populations comprise a defined mixture of cells that arise from either embryonic precursors or adult monocytes; (2) local factors unique to the niche of residence, evolving during development and aging; (3) inflammation status; and (4) the cumulative effect of time spent in a specific tissue that contributes to the resilient adaptation of macrophages to their dynamic environment. We review recent findings within this context and discuss the technological advances that are revolutionizing the study of macrophage biology.
Collapse
Affiliation(s)
- Camille Blériot
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648, Singapore
| | - Svetoslav Chakarov
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648, Singapore
| | - Florent Ginhoux
- Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), 8A Biomedical Grove, Immunos Building #3-4, Biopolis, Singapore 138648, Singapore; Shanghai Institute of Immunology, Shanghai JiaoTong University School of Medicine, 280 South Chongqing Road, Shanghai 200025, China; Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore 169856, Singapore.
| |
Collapse
|
|
29
|
Louwe PA, Badiola Gomez L, Webster H, Perona-Wright G, Bain CC, Forbes SJ, Jenkins SJ. Recruited macrophages that colonize the post-inflammatory peritoneal niche convert into functionally divergent resident cells. Nat Commun 2021; 12:1770. [PMID: 33741914 PMCID: PMC7979918 DOI: 10.1038/s41467-021-21778-0] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Accepted: 02/10/2021] [Indexed: 02/07/2023] Open
Abstract
Inflammation generally leads to recruitment of monocyte-derived macrophages. What regulates the fate of these cells and to what extent they can assume the identity and function of resident macrophages is unclear. Here, we show that macrophages elicited into the peritoneal cavity during mild inflammation persist long-term but are retained in an immature transitory state of differentiation due to the presence of enduring resident macrophages. By contrast, severe inflammation results in ablation of resident macrophages and a protracted phase wherein the cavity is incapable of sustaining a resident phenotype, yet ultimately elicited cells acquire a mature resident identity. These macrophages also have transcriptionally and functionally divergent features that result from inflammation-driven alterations to the peritoneal cavity micro-environment and, to a lesser extent, effects of origin and time-of-residency. Hence, rather than being predetermined, the fate of inflammation-elicited peritoneal macrophages seems to be regulated by the environment.
Collapse
Affiliation(s)
- P A Louwe
- Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom
| | - L Badiola Gomez
- Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom
| | - H Webster
- Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, G12 8TA, United Kingdom
| | - G Perona-Wright
- Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, G12 8TA, United Kingdom
| | - C C Bain
- Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom
| | - S J Forbes
- Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, United Kingdom
| | - S J Jenkins
- Centre for Inflammation Research, Queens Medical Research Institute, Edinburgh, EH16 4TJ, United Kingdom.
| |
Collapse
|
|
30
|
Zhao L, Wang Q, Zhou B, Zhang L, Zhu H. The Role of Immune Cells in the Pathogenesis of Idiopathic Inflammatory Myopathies. Aging Dis 2021; 12:247-260. [PMID: 33532139 PMCID: PMC7801271 DOI: 10.14336/ad.2020.0410] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/10/2020] [Indexed: 12/15/2022] Open
Abstract
Idiopathic inflammatory myopathies (IIMs) are chronic autoimmune disorders involving multiple organs, such as the muscle, skin, lungs and joints. Although the detailed pathogenesis of IIMs remains unclear, immune mechanisms have long been recognised as of key importance. Immune cells contribute to many inflammatory processes via intercellular interactions and secretion of inflammatory factors, and many studies have demonstrated the participation of a variety of immune cells, such as T cells and B cells, in the development of IIMs. Here, we summarise the current knowledge regarding immune cells in IIM patients and discuss their potential roles in IIM pathogenesis.
Collapse
Affiliation(s)
- Lijuan Zhao
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Qi Wang
- Department of Radiology, Hunan Provincial People's Hospital and The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China.
| | - Bin Zhou
- Department of Nephrology, The Affiliated Hospital of Qingdao University, Qingdao, China.
| | - Lihua Zhang
- Department of Rheumatology, Hunan Provincial People's Hospital and The First Affiliated Hospital of Hunan Normal University, Changsha, Hunan, China.
| | - Honglin Zhu
- Department of Rheumatology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| |
Collapse
|
|
31
|
Kaur S, Sehgal A, Wu AC, Millard SM, Batoon L, Sandrock CJ, Ferrari-Cestari M, Levesque JP, Hume DA, Raggatt LJ, Pettit AR. Stable colony-stimulating factor 1 fusion protein treatment increases hematopoietic stem cell pool and enhances their mobilisation in mice. J Hematol Oncol 2021; 14:3. [PMID: 33402221 PMCID: PMC7786999 DOI: 10.1186/s13045-020-00997-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/11/2020] [Indexed: 12/12/2022] Open
Abstract
Background Prior chemotherapy and/or underlying morbidity commonly leads to poor mobilisation of hematopoietic stem cells (HSC) for transplantation in cancer patients. Increasing the number of available HSC prior to mobilisation is a potential strategy to overcome this deficiency. Resident bone marrow (BM) macrophages are essential for maintenance of niches that support HSC and enable engraftment in transplant recipients. Here we examined potential of donor treatment with modified recombinant colony-stimulating factor 1 (CSF1) to influence the HSC niche and expand the HSC pool for autologous transplantation. Methods We administered an acute treatment regimen of CSF1 Fc fusion protein (CSF1-Fc, daily injection for 4 consecutive days) to naive C57Bl/6 mice. Treatment impacts on macrophage and HSC number, HSC function and overall hematopoiesis were assessed at both the predicted peak drug action and during post-treatment recovery. A serial treatment strategy using CSF1-Fc followed by granulocyte colony-stimulating factor (G-CSF) was used to interrogate HSC mobilisation impacts. Outcomes were assessed by in situ imaging and ex vivo standard and imaging flow cytometry with functional validation by colony formation and competitive transplantation assay. Results CSF1-Fc treatment caused a transient expansion of monocyte-macrophage cells within BM and spleen at the expense of BM B lymphopoiesis and hematopoietic stem and progenitor cell (HSPC) homeostasis. During the recovery phase after cessation of CSF1-Fc treatment, normalisation of hematopoiesis was accompanied by an increase in the total available HSPC pool. Multiple approaches confirmed that CD48−CD150+ HSC do not express the CSF1 receptor, ruling out direct action of CSF1-Fc on these cells. In the spleen, increased HSC was associated with expression of the BM HSC niche macrophage marker CD169 in red pulp macrophages, suggesting elevated spleen engraftment with CD48−CD150+ HSC was secondary to CSF1-Fc macrophage impacts. Competitive transplant assays demonstrated that pre-treatment of donors with CSF1-Fc increased the number and reconstitution potential of HSPC in blood following a HSC mobilising regimen of G-CSF treatment. Conclusion These results indicate that CSF1-Fc conditioning could represent a therapeutic strategy to overcome poor HSC mobilisation and subsequently improve HSC transplantation outcomes.
Collapse
Affiliation(s)
- Simranpreet Kaur
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia
| | - Anuj Sehgal
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia
| | - Andy C Wu
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia
| | - Susan M Millard
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia
| | - Lena Batoon
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia
| | - Cheyenne J Sandrock
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia
| | - Michelle Ferrari-Cestari
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia
| | - Jean-Pierre Levesque
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia
| | - David A Hume
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia
| | - Liza J Raggatt
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia
| | - Allison R Pettit
- Mater Research Institute-The University of Queensland, Faculty of Medicine, Translational Research Institute, 37 Kent St, Woolloongabba, 4102, Australia.
| |
Collapse
|
|
32
|
Özdemir BC. Androgen Signaling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1270:169-183. [PMID: 33123999 DOI: 10.1007/978-3-030-47189-7_10] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
The key function of mesenchymal/stromal androgen receptor (AR) signaling for prostate development has been well documented by tissue recombination experiments. Some studies have addressed the expression and function of AR in stromal cells in prostate cancer, yet our understanding of the role of stromal AR in other tissues beyond prostate is still insufficient.Genomic analysis has revealed that cellular responses to androgens differ between epithelial and stromal cells. AR in stromal cells seems not to act via classical AR transcription factors such as FOXA1 but rather depends on the JUN/AP1 complex. Stromal AR appears to have tumor-promoting and tumor-protective functions depending on tumor stage. Loss of AR signaling in fibroblasts has been detected already in premalignant lesions in the skin and prostate and has been associated with tumor induction in xenografts of skin cancer and aggressive disease features and poor patient prognosis in prostate cancer. Moreover, AR expression is found on virtually all tissue-infiltrating immune cells and plays critical roles in immune cell function. These findings suggest a potential deleterious impact of current androgen deprivation therapies which inhibit both epithelial and stromal AR, highlighting the need to develop tissue-specific AR inhibitors.
Collapse
Affiliation(s)
- Berna C Özdemir
- Department of Oncology, Lausanne University Hospital, Lausanne, Switzerland. .,International Cancer Prevention Institute, Epalinges, Switzerland.
| |
Collapse
|
|
33
|
Sreejit G, Fleetwood AJ, Murphy AJ, Nagareddy PR. Origins and diversity of macrophages in health and disease. Clin Transl Immunology 2020; 9:e1222. [PMID: 33363732 PMCID: PMC7750014 DOI: 10.1002/cti2.1222] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 12/14/2022] Open
Abstract
Macrophages are the first immune cells in the developing embryo and have a central role in organ development, homeostasis, immunity and repair. Over the last century, our understanding of these cells has evolved from being thought of as simple phagocytic cells to master regulators involved in governing a myriad of cellular processes. A better appreciation of macrophage biology has been matched with a clearer understanding of their diverse origins and the flexibility of their metabolic and transcriptional machinery. The understanding of the classical mononuclear phagocyte system in its original form has now been expanded to include the embryonic origin of tissue-resident macrophages. A better knowledge of the intrinsic similarities and differences between macrophages of embryonic or monocyte origin has highlighted the importance of ontogeny in macrophage dysfunction in disease. In this review, we provide an update on origin and classification of tissue macrophages, the mechanisms of macrophage specialisation and their role in health and disease. The importance of the macrophage niche in providing trophic factors and a specialised environment for macrophage differentiation and specialisation is also discussed.
Collapse
Affiliation(s)
- Gopalkrishna Sreejit
- Division of Cardiac SurgeryDepartment of SurgeryThe Ohio State University Wexner Medical CenterColumbusOHUSA
| | - Andrew J Fleetwood
- Division of ImmunometabolismBaker Heart and Diabetes InstituteMelbourneVICAustralia
| | - Andrew J Murphy
- Division of ImmunometabolismBaker Heart and Diabetes InstituteMelbourneVICAustralia
| | - Prabhakara R Nagareddy
- Division of Cardiac SurgeryDepartment of SurgeryThe Ohio State University Wexner Medical CenterColumbusOHUSA
| |
Collapse
|
|
34
|
Central and local controls of monocytopoiesis influence the outcome of Leishmania infection. Cytokine 2020; 147:155325. [PMID: 33039254 DOI: 10.1016/j.cyto.2020.155325] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 09/27/2020] [Accepted: 09/28/2020] [Indexed: 12/15/2022]
Abstract
Leishmaniases represent a complex of tropical and subtropical diseases caused by an intracellular protozoon of the genus Leishmania. The principal cells controlling the interaction between the host and the parasite Leishmania are monocytes and macrophages, as these cells play a decisive role in establishing the pathogenesis or cure. These cells are involved in controlling the growth of Leishmania and in modulating the adaptive immune responses. The heterogeneity and extensive plasticity of monocytes allow these cells to adjust their functional phenotypes in response to the pathogen-directed immunological cues. In Leishmania-infected host, the rate of myelopoiesis is augmented by enhanced monocytic lineage commitment and proliferation of myeloid progenitor cells both in the BM and at the site of infection. These newly generated monocytes play as "safe haven" for the parasite and also as the antigen-presenting cells for T cells to cause deregulated cytokine production. This altered monocytopoiesis is characterized by tissue-specific immune responses, spatiotemporal dynamics of immunoregulation and functional heterogeneity. In the presence of Th1 cytokines, monocytes exhibit a pro-inflammatory phenotype that protects the host from Leishmania. By contrast, in an environment of Th2 cytokines, monocytes display anti-inflammatory phenotype with pro-parasitic functions. In this review, we summarize the involvement of cytokines in the regulation of monocytopoiesis and differentiation of macrophages during leishmanial infection. Understanding the role of cytokines in regulating interactions between Leishmania and the host monocytes is key to developing new therapeutic interventions against leishmaniases.
Collapse
|
|
35
|
Summers KM, Bush SJ, Hume DA. Network analysis of transcriptomic diversity amongst resident tissue macrophages and dendritic cells in the mouse mononuclear phagocyte system. PLoS Biol 2020; 18:e3000859. [PMID: 33031383 PMCID: PMC7575120 DOI: 10.1371/journal.pbio.3000859] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 10/20/2020] [Accepted: 09/08/2020] [Indexed: 02/07/2023] Open
Abstract
The mononuclear phagocyte system (MPS) is a family of cells including progenitors, circulating blood monocytes, resident tissue macrophages, and dendritic cells (DCs) present in every tissue in the body. To test the relationships between markers and transcriptomic diversity in the MPS, we collected from National Center for Biotechnology Information Gene Expression Omnibus (NCBI-GEO) a total of 466 quality RNA sequencing (RNA-seq) data sets generated from mouse MPS cells isolated from bone marrow, blood, and multiple tissues. The primary data were randomly downsized to a depth of 10 million reads and requantified. The resulting data set was clustered using the network analysis tool BioLayout. A sample-to-sample matrix revealed that MPS populations could be separated based upon tissue of origin. Cells identified as classical DC subsets, cDC1s and cDC2s, and lacking Fcgr1 (encoding the protein CD64) were contained within the MPS cluster, no more distinct than other MPS cells. A gene-to-gene correlation matrix identified large generic coexpression clusters associated with MPS maturation and innate immune function. Smaller coexpression gene clusters, including the transcription factors that drive them, showed higher expression within defined isolated cells, including monocytes, macrophages, and DCs isolated from specific tissues. They include a cluster containing Lyve1 that implies a function in endothelial cell (EC) homeostasis, a cluster of transcripts enriched in intestinal macrophages, and a generic lymphoid tissue cDC cluster associated with Ccr7. However, transcripts encoding Adgre1, Itgax, Itgam, Clec9a, Cd163, Mertk, Mrc1, Retnla, and H2-a/e (encoding class II major histocompatibility complex [MHC] proteins) and many other proposed macrophage subset and DC lineage markers each had idiosyncratic expression profiles. Coexpression of immediate early genes (for example, Egr1, Fos, Dusp1) and inflammatory cytokines and chemokines (tumour necrosis factor [Tnf], Il1b, Ccl3/4) indicated that all tissue disaggregation and separation protocols activate MPS cells. Tissue-specific expression clusters indicated that all cell isolation procedures also co-purify other unrelated cell types that may interact with MPS cells in vivo. Comparative analysis of RNA-seq and single-cell RNA-seq (scRNA-seq) data from the same lung cell populations indicated that MPS heterogeneity implied by global cluster analysis may be even greater at a single-cell level. This analysis highlights the power of large data sets to identify the diversity of MPS cellular phenotypes and the limited predictive value of surface markers to define lineages, functions, or subpopulations.
Collapse
Affiliation(s)
- Kim M. Summers
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
| | - Stephen J. Bush
- Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
| | - David A. Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia
- * E-mail:
| |
Collapse
|
|
36
|
Karagianni AE, Lisowski ZM, Hume DA, Scott Pirie R. The equine mononuclear phagocyte system: The relevance of the horse as a model for understanding human innate immunity. Equine Vet J 2020; 53:231-249. [PMID: 32881079 DOI: 10.1111/evj.13341] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 07/07/2020] [Accepted: 08/13/2020] [Indexed: 12/11/2022]
Abstract
The mononuclear phagocyte system (MPS) is a family of cells of related function that includes bone marrow progenitors, blood monocytes and resident tissue macrophages. Macrophages are effector cells in both innate and acquired immunity. They are a major resident cell population in every organ and their numbers increase in response to proinflammatory stimuli. Their function is highly regulated by a wide range of agonists, including lymphokines, cytokines and products of microorganisms. Macrophage biology has been studied most extensively in mice, yet direct comparisons of rodent and human macrophages have revealed many functional differences. In this review, we provide an overview of the equine MPS, describing the variation in the function and phenotype of macrophages depending on their location and the similarities and differences between the rodent, human and equine immune response. We discuss the use of the horse as a large animal model in which to study macrophage biology and pathological processes shared with humans. Finally, following the recent update to the horse genome, facilitating further comparative analysis of regulated gene expression between the species, we highlight the importance of future transcriptomic macrophage studies in the horse, the findings of which may also be applicable to human as well as veterinary research.
Collapse
Affiliation(s)
- Anna E Karagianni
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, UK
| | - Zofia M Lisowski
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, UK
| | - David A Hume
- Mater Research Institute-UQ, Translational Research Institute, Woolloongabba, QLD, Australia
| | - R Scott Pirie
- The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian, UK
| |
Collapse
|
|
37
|
Becerra-Diaz M, Song M, Heller N. Androgen and Androgen Receptors as Regulators of Monocyte and Macrophage Biology in the Healthy and Diseased Lung. Front Immunol 2020; 11:1698. [PMID: 32849595 PMCID: PMC7426504 DOI: 10.3389/fimmu.2020.01698] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Accepted: 06/25/2020] [Indexed: 12/14/2022] Open
Abstract
Androgens, the predominant male sex hormones, drive the development and maintenance of male characteristics by binding to androgen receptor (AR). As androgens are systemically distributed throughout the whole organism, they affect many tissues and cell types in addition to those in male sexual organs. It is now clear that the immune system is a target of androgen action. In the lungs, many immune cells express ARs and are responsive to androgens. In this review, we describe the effects of androgens and ARs on lung myeloid immune cells-monocytes and macrophages-as they relate to health and disease. In particular, we highlight the effect of androgens on lung diseases, such as asthma, chronic obstructive pulmonary disease and lung fibrosis. We also discuss the therapeutic use of androgens and how circulating androgens correlate with lung disease. In addition to human studies, we also discuss how mouse models have helped to uncover the effect of androgens on monocytes and macrophages in lung disease. Although the role of estrogen and other female hormones has been broadly analyzed in the literature, we focus on the new perspectives of androgens as modulators of the immune system that target myeloid cells during lung inflammation.
Collapse
Affiliation(s)
| | | | - Nicola Heller
- Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, United States
| |
Collapse
|
|
38
|
Nasser H, Adhikary P, Abdel-Daim A, Noyori O, Panaampon J, Kariya R, Okada S, Ma W, Baba M, Takizawa H, Yamane M, Niwa H, Suzu S. Establishment of bone marrow-derived M-CSF receptor-dependent self-renewing macrophages. Cell Death Discov 2020; 6:63. [PMID: 32714570 PMCID: PMC7378060 DOI: 10.1038/s41420-020-00300-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 07/13/2020] [Indexed: 02/07/2023] Open
Abstract
Recent studies have revealed that tissue macrophages are derived from yolk sac precursors or fetal liver monocytes, in addition to bone marrow monocytes. The relative contribution of these cells to the tissue macrophage pool is not fully understood, but embryo-derived cells are supposed to be more important because of their capacity to self-renew. Here, we show the presence of adult bone marrow-derived macrophages that retain self-renewing capacity. The self-renewing macrophages were readily obtained by long-term culture of mouse bone marrow cells with macrophage colony-stimulating factor (M-CSF), a key cytokine for macrophage development. They were non-tumorigenic and proliferated in the presence of M-CSF in unlimited numbers. Despite several differences from non-proliferating macrophages, they retained many features of cells of the monocytic lineage, including the differentiation into dendritic cells or osteoclasts. Among the transcription factors involved in the self-renewal of embryonic stem cells, Krüppel-like factor 2 (KLF2) was strongly upregulated upon M-CSF stimulation in the self-renewing macrophages, which was accompanied by the downregulation of MafB, a transcription factor that suppresses KLF2 expression. Indeed, knockdown of KLF2 led to cell cycle arrest and diminished cell proliferation in the self-renewing macrophages. Our new cell model would be useful to unravel differences in phenotype, function, and molecular mechanism of proliferation among self-renewing macrophages with different origins.
Collapse
Affiliation(s)
- Hesham Nasser
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811 Japan
- Department of Clinical Pathology, Faculty of Medicine, Suez Canal University, Ismailia, 41511 Egypt
| | - Partho Adhikary
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811 Japan
- Present Address: Faculty of Pharmaceutical Sciences, The University of British Columbia, Vancouver, V6T 1Z3 Canada
| | - Amira Abdel-Daim
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811 Japan
| | - Osamu Noyori
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811 Japan
| | - Jutatip Panaampon
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan
| | - Ryusho Kariya
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan
| | - Seiji Okada
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan
| | - Wenjuan Ma
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811 Japan
| | - Masaya Baba
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811 Japan
| | - Hitoshi Takizawa
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811 Japan
- Center for Metabolic Regulation of Healthy Aging, Kumamoto University, Kumamoto, 860-8556 Japan
| | - Mariko Yamane
- Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, 860-0811 Japan
- Present Address: Laboratory for Bioinformatics Research, RIKEN Center for Biosystems Dynamics Research, Hyogo, 650-0047 Japan
| | - Hitoshi Niwa
- Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, 860-0811 Japan
| | - Shinya Suzu
- Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, 860-0811 Japan
- International Research Center for Medical Sciences, Kumamoto University, Kumamoto, 860-0811 Japan
| |
Collapse
|
|
39
|
Luque-Martin R, Mander PK, Leenen PJM, Winther MPJ. Classic and new mediators for in vitro modelling of human macrophages. J Leukoc Biol 2020; 109:549-560. [PMID: 32592421 PMCID: PMC7984372 DOI: 10.1002/jlb.1ru0620-018r] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 06/04/2020] [Accepted: 06/05/2020] [Indexed: 02/06/2023] Open
Abstract
Macrophages are key immune cells in the activation and regulation of immune responses. These cells are present in all tissues under homeostatic conditions and in many disease settings. Macrophages can exhibit a wide range of phenotypes depending on local and systemic cues that drive the differentiation and activation process. Macrophage heterogeneity is also defined by their ontogeny. Tissue macrophages can either derive from circulating blood monocytes or are seeded as tissue-resident macrophages during embryonic development. In humans, the study of in vivo-generated macrophages is often difficult with laborious and cell-changing isolation procedures. Therefore, translatable, reproducible, and robust in vitro models for human macrophages in health and disease are necessary. Most of the methods for studying monocyte-derived macrophages are based on the use of limited factors to differentiate the monocytes into macrophages. Current knowledge shows that the in vivo situation is more complex, and a wide range of molecules in the tissue microenvironment promote and impact on monocyte to macrophage differentiation as well as activation. In this review, macrophage heterogeneity is discussed and the human in vitro models that can be applied for research, especially for monocyte-derived macrophages. We also focus on new molecules (IL-34, platelet factor 4, etc.) used to generate macrophages expressing different phenotypes.
Collapse
Affiliation(s)
- Rosario Luque-Martin
- Amsterdam University Medical Centers, University of Amsterdam, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | | | - Pieter J M Leenen
- Erasmus University Medical Center, Department of Immunology, Rotterdam, The Netherlands
| | - Menno P J Winther
- Amsterdam University Medical Centers, University of Amsterdam, Department of Medical Biochemistry, Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.,Institute for Cardiovascular Prevention (IPEK), Munich, Germany
| |
Collapse
|
|
40
|
Ross JT, Nesseler N, Leligdowicz A, Zemans RL, Mahida RY, Minus E, Langelier C, Gotts JE, Matthay MA. The ex vivo perfused human lung is resistant to injury by high-dose S. pneumoniae bacteremia. Am J Physiol Lung Cell Mol Physiol 2020; 319:L218-L227. [PMID: 32519893 DOI: 10.1152/ajplung.00053.2020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Few patients with bacteremia from a nonpulmonary source develop acute respiratory distress syndrome (ARDS). However, the mechanisms that protect the lung from injury in bacteremia have not been identified. We simulated bacteremia by adding Streptococcus pneumoniae to the perfusate of the ex vivo perfused human lung model. In contrast to a pneumonia model in which bacteria were instilled into the distal air spaces of one lobe, injection of high doses of S. pneumoniae into the perfusate was not associated with alveolar epithelial injury as demonstrated by low protein permeability of the alveolar epithelium, intact alveolar fluid clearance, and the absence of alveolar edema. Unexpectedly, the ex vivo human lung rapidly cleared large quantities of S. pneumoniae even though the perfusate had very few intravascular phagocytes and lacked immunoglobulins or complement. The bacteria were cleared in part by the small number of neutrophils in the perfusate, alveolar macrophages in the airspaces, and probably by interstitial pathways. Together, these findings identify one mechanism by which the lung and the alveolar epithelium are protected from injury in bacteremia.
Collapse
Affiliation(s)
- James T Ross
- Department of Surgery, University of California San Francisco, San Francisco, California
| | - Nicolas Nesseler
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, California.,Department of Anesthesia and Critical Care, Pontchaillou, University Hospital of Rennes, Rennes, France.,University Rennes, CHU de Rennes, Inra, Inserm, Institut NUMECAN-UMR_A 1341, UMR_S 1241, Rennes, France.,University Rennes, CHU Rennes, Inserm, CIC 1414 (Centre d'Investigation Clinique de Rennes), Rennes, France
| | - Aleksandra Leligdowicz
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, California.,Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Rachel L Zemans
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
| | - Rahul Y Mahida
- Birmingham Acute Care Research Group, Institute of Inflammation and Aging, University of Birmingham, Birmingham, United Kingdom
| | | | - Chaz Langelier
- Division of Infectious Diseases, Department of Medicine, University of California San Francisco, San Francisco, California
| | - Jeffrey E Gotts
- Department of Medicine, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California
| | - Michael A Matthay
- Departments of Medicine and Anesthesia, Cardiovascular Research Institute, University of California San Francisco, San Francisco, California
| |
Collapse
|
|
41
|
Nenasheva T, Gerasimova T, Serdyuk Y, Grigor'eva E, Kosmiadi G, Nikolaev A, Dashinimaev E, Lyadova I. Macrophages Derived From Human Induced Pluripotent Stem Cells Are Low-Activated "Naïve-Like" Cells Capable of Restricting Mycobacteria Growth. Front Immunol 2020; 11:1016. [PMID: 32582159 PMCID: PMC7287118 DOI: 10.3389/fimmu.2020.01016] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 04/28/2020] [Indexed: 12/17/2022] Open
Abstract
In peripheral tissues, immune protection critically depends on the activity of tissue resident macrophages, which makes our understanding of the biology of these cells of great significance. Until recently, human macrophage studies were largely based on the analysis of monocyte-derived macrophages that differ from tissue resident macrophages by many characteristics. To model tissue resident macrophages, methods of generating macrophages from pluripotent stem cells have been developed. However, the immunological properties of macrophages derived from pluripotent stem cells remain under-investigated. In this study, we aimed to perform the multifarious immunological characteristics of macrophages generated from human induced pluripotent stem cells (iMϕs), including an analysis of their phenotype, secretory and antibacterial activities, as well as their comparison with macrophages derived from blood monocytes and infected lung tissue. We report that iMϕs displayed the morphology and the CD11b+CD45+CD14+ phenotype typical for mononuclear phagocytes. The cells co-expressed markers known to be associated with classically (CD80, CD86, CCR5) and alternatively (CD163 and CD206) activated macrophages, with a bias toward a higher expression of the latter. iMϕs secreted pro-inflammatory (IL-6, CXCL8, CCL2, CCL4, CXCL1, CXCL10) and anti-inflammatory (IL-10, IL-1RA, CCL22) cytokines with a high IL-10/IL-12p70 index (>20). iMϕs were phagocytic and restricted Mycobacterium tuberculosis growth in vitro by >75%. iMϕs differed from blood monocytes/macrophages by a lower expression level of HLA-DR and the CD14+CD16int phenotype and shared several phenotypic characteristics with lung macrophages. In response to LPS, iMϕs up-regulated HLA-DR and produced TNF-α. IFN-γ increased iMϕ reactivity to LPS, but did not increase iMϕ mycobactericidal capacity. The results characterize iMϕs as differentiated but low-activated/low-polarized “naïve-like” macrophages that are capable of mounting inflammatory and antibacterial responses when exposed to inflammatory stimuli or pathogens. iMϕs represent a valuable model for studying antibacterial responses of tissue resident macrophages and for developing approaches to modulating macrophage activity.
Collapse
Affiliation(s)
- Tatiana Nenasheva
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, Russia.,Laboratory of Biotechnology, Department of Immunology, Central Tuberculosis Research Institute, Moscow, Russia
| | - Tatiana Gerasimova
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, Russia
| | - Yana Serdyuk
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, Russia.,Laboratory of Biotechnology, Department of Immunology, Central Tuberculosis Research Institute, Moscow, Russia
| | - Elena Grigor'eva
- Laboratory of Developmental Epigenetics, Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - George Kosmiadi
- Laboratory of Biotechnology, Department of Immunology, Central Tuberculosis Research Institute, Moscow, Russia
| | - Alexander Nikolaev
- Laboratory of Biotechnology, Department of Immunology, Central Tuberculosis Research Institute, Moscow, Russia
| | - Erdem Dashinimaev
- Center for Genome Technologies, Pirogov Russian National Research Medical University, Moscow, Russia.,Laboratory of Cell Biology, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, Russia
| | - Irina Lyadova
- Laboratory of Cellular and Molecular Basis of Histogenesis, Koltzov Institute of Developmental Biology of the Russian Academy of Sciences, Moscow, Russia.,Laboratory of Biotechnology, Department of Immunology, Central Tuberculosis Research Institute, Moscow, Russia
| |
Collapse
|
|
42
|
Pfefferle A, Jacobs B, Haroun-Izquierdo A, Kveberg L, Sohlberg E, Malmberg KJ. Deciphering Natural Killer Cell Homeostasis. Front Immunol 2020; 11:812. [PMID: 32477340 PMCID: PMC7235169 DOI: 10.3389/fimmu.2020.00812] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 04/08/2020] [Indexed: 12/23/2022] Open
Abstract
Natural killer (NK) cells have a central role within the innate immune system, eliminating virally infected, foreign and transformed cells through their natural cytotoxic capacity. Release of their cytotoxic granules is tightly controlled through the balance of a large repertoire of inhibitory and activating receptors, and it is the unique combination of these receptors expressed by individual cells that confers immense diversity both in phenotype and functionality. The diverse, yet unique, NK cell repertoire within an individual is surprisingly stable over time considering the constant renewal of these cells at steady state. Here we give an overview of NK cell differentiation and discuss metabolic requirements, intra-lineage plasticity and transcriptional reprogramming during IL-15-driven homeostatic proliferation. New insights into the regulation of NK cell differentiation and homeostasis could pave the way for the successful implementation of NK cell-based immunotherapy against cancer.
Collapse
Affiliation(s)
- Aline Pfefferle
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Benedikt Jacobs
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Alvaro Haroun-Izquierdo
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Lise Kveberg
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ebba Sohlberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Karl-Johan Malmberg
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.,Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.,The KG Jebsen Center for Cancer Immunotherapy, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| |
Collapse
|
|
43
|
Zhao M, Jung Y, Jiang Z, Svensson KJ. Regulation of Energy Metabolism by Receptor Tyrosine Kinase Ligands. Front Physiol 2020; 11:354. [PMID: 32372975 PMCID: PMC7186430 DOI: 10.3389/fphys.2020.00354] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 03/26/2020] [Indexed: 12/14/2022] Open
Abstract
Metabolic diseases, such as diabetes, obesity, and fatty liver disease, have now reached epidemic proportions. Receptor tyrosine kinases (RTKs) are a family of cell surface receptors responding to growth factors, hormones, and cytokines to mediate a diverse set of fundamental cellular and metabolic signaling pathways. These ligands signal by endocrine, paracrine, or autocrine means in peripheral organs and in the central nervous system to control cellular and tissue-specific metabolic processes. Interestingly, the expression of many RTKs and their ligands are controlled by changes in metabolic demand, for example, during starvation, feeding, or obesity. In addition, studies of RTKs and their ligands in regulating energy homeostasis have revealed unexpected diversity in the mechanisms of action and their specific metabolic functions. Our current understanding of the molecular, biochemical and genetic control of energy homeostasis by the endocrine RTK ligands insulin, FGF21 and FGF19 are now relatively well understood. In addition to these classical endocrine signals, non-endocrine ligands can govern local energy regulation, and the intriguing crosstalk between the RTK family and the TGFβ receptor family demonstrates a signaling network that diversifies metabolic process between tissues. Thus, there is a need to increase our molecular and mechanistic understanding of signal diversification of RTK actions in metabolic disease. Here we review the known and emerging molecular mechanisms of RTK signaling that regulate systemic glucose and lipid metabolism, as well as highlighting unexpected roles of non-classical RTK ligands that crosstalk with other receptor pathways.
Collapse
Affiliation(s)
- Meng Zhao
- Department of Pathology, Stanford University, Stanford, CA, United States.,Stanford Diabetes Research Center, Stanford, CA, United States
| | - Yunshin Jung
- Department of Pathology, Stanford University, Stanford, CA, United States.,Stanford Diabetes Research Center, Stanford, CA, United States
| | - Zewen Jiang
- Department of Pathology, Stanford University, Stanford, CA, United States.,Stanford Diabetes Research Center, Stanford, CA, United States
| | - Katrin J Svensson
- Department of Pathology, Stanford University, Stanford, CA, United States.,Stanford Diabetes Research Center, Stanford, CA, United States
| |
Collapse
|
|
44
|
Wu Z, Harne R, Chintoan-Uta C, Hu TJ, Wallace R, MacCallum A, Stevens MP, Kaiser P, Balic A, Hume DA. Regulation and function of macrophage colony-stimulating factor (CSF1) in the chicken immune system. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2020; 105:103586. [PMID: 31870792 PMCID: PMC6996135 DOI: 10.1016/j.dci.2019.103586] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 12/18/2019] [Accepted: 12/18/2019] [Indexed: 05/11/2023]
Abstract
Macrophage colony-stimulating factor (CSF1) is an essential growth factor to control the proliferation, differentiation and survival of cells of the macrophage lineage in vertebrates. We have previously produced a recombinant chicken CSF1-Fc fusion protein and administrated it to birds which produced a substantial expansion of tissue macrophage populations. To further study the biology of CSF1 in the chicken, here we generated anti-chicken CSF1 antibodies (ROS-AV181 and 183) using CSF1-Fc as an immunogen. The specific binding of each monoclonal antibody was confirmed by ELISA, Western blotting and immunohistochemistry on tissue sections. Using the anti-CSF1 antibodies, we show that chicken bone marrow derived macrophages (BMDM) express CSF1 on their surface, and that the level appears to be regulated further by exogenous CSF1. By capture ELISA circulating CSF1 levels increased transiently in both layer and broiler embryos around the day of hatch. The levels of CSF1 in broilers was higher than in layers during the first week after hatch. Antibody ROS-AV183 was able to block CSF1 biological activity in vitro and treatment of hatchlings using this neutralising antibody in vivo impacted on some tissue macrophage populations, but not blood monocytes. After anti-CSF1 treatment, CSF1R-transgene reporter expressing cells were reduced in the bursa of Fabricius and cecal tonsil and TIM4+ Kupffer cells in the liver were almost completely ablated. Anti-CSF1 treatment also produced a reduction in overall bone density, trabecular volume and TRAP+ osteoclasts. Our novel neutralising antibody provides a new tool to study the roles of CSF1 in birds.
Collapse
Affiliation(s)
- Zhiguang Wu
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Rakhi Harne
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Cosmin Chintoan-Uta
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Tuan-Jun Hu
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Robert Wallace
- The Department of Orthopedic Surgery, University of Edinburgh, Chancellor's Building, Edinburgh BioQuarter, 49 Little France Crescent, Edinburgh, EH16 4SB, UK
| | - Amanda MacCallum
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Mark P Stevens
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Pete Kaiser
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK
| | - Adam Balic
- The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.
| | - David A Hume
- Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, 4104, Australia.
| |
Collapse
|
|
45
|
Roberts ME, Barvalia M, Silva JAFD, Cederberg RA, Chu W, Wong A, Tai DC, Chen S, Matos I, Priatel JJ, Cullis PR, Harder KW. Deep Phenotyping by Mass Cytometry and Single-Cell RNA-Sequencing Reveals LYN-Regulated Signaling Profiles Underlying Monocyte Subset Heterogeneity and Lifespan. Circ Res 2020; 126:e61-e79. [PMID: 32151196 DOI: 10.1161/circresaha.119.315708] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
RATIONALE Monocytes are key effectors of the mononuclear phagocyte system, playing critical roles in regulating tissue homeostasis and coordinating inflammatory reactions, including those involved in chronic inflammatory diseases such as atherosclerosis. Monocytes have traditionally been divided into 2 major subsets termed conventional monocytes and patrolling monocytes (pMo) but recent systems immunology approaches have identified marked heterogeneity within these cells, and much of what regulates monocyte population homeostasis remains unknown. We and others have previously identified LYN tyrosine kinase as a key negative regulator of myeloid cell biology; however, LYN's role in regulating specific monocyte subset homeostasis has not been investigated. OBJECTIVE We sought to comprehensively profile monocytes to elucidate the underlying heterogeneity within monocytes and dissect how Lyn deficiency affects monocyte subset composition, signaling, and gene expression. We further tested the biological significance of these findings in a model of atherosclerosis. METHODS AND RESULTS Mass cytometric analysis of monocyte subsets and signaling pathway activation patterns in conventional monocytes and pMos revealed distinct baseline signaling profiles and far greater heterogeneity than previously described. Lyn deficiency led to a selective expansion of pMos and alterations in specific signaling pathways within these cells, revealing a critical role for LYN in pMo physiology. LYN's role in regulating pMos was cell-intrinsic and correlated with an increased circulating half-life of Lyn-deficient pMos. Furthermore, single-cell RNA sequencing revealed marked perturbations in the gene expression profiles of Lyn-/- monocytes with upregulation of genes involved in pMo development, survival, and function. Lyn deficiency also led to a significant increase in aorta-associated pMos and protected Ldlr-/- mice from high-fat diet-induced atherosclerosis. CONCLUSIONS Together our data identify LYN as a key regulator of pMo development and a potential therapeutic target in inflammatory diseases regulated by pMos.
Collapse
Affiliation(s)
- Morgan E Roberts
- From the Department of Microbiology and Immunology (M.E.R., M.B., J.A.F.D.S., R.A.C., W.C., A.W., I.M., K.W.H.), University of British Columbia, Vancouver, Canada
| | - Maunish Barvalia
- From the Department of Microbiology and Immunology (M.E.R., M.B., J.A.F.D.S., R.A.C., W.C., A.W., I.M., K.W.H.), University of British Columbia, Vancouver, Canada
| | - Jessica A F D Silva
- From the Department of Microbiology and Immunology (M.E.R., M.B., J.A.F.D.S., R.A.C., W.C., A.W., I.M., K.W.H.), University of British Columbia, Vancouver, Canada
| | - Rachel A Cederberg
- From the Department of Microbiology and Immunology (M.E.R., M.B., J.A.F.D.S., R.A.C., W.C., A.W., I.M., K.W.H.), University of British Columbia, Vancouver, Canada
| | - William Chu
- From the Department of Microbiology and Immunology (M.E.R., M.B., J.A.F.D.S., R.A.C., W.C., A.W., I.M., K.W.H.), University of British Columbia, Vancouver, Canada
| | - Amanda Wong
- From the Department of Microbiology and Immunology (M.E.R., M.B., J.A.F.D.S., R.A.C., W.C., A.W., I.M., K.W.H.), University of British Columbia, Vancouver, Canada
| | - Daven C Tai
- Department of Pediatrics (D.C.T.), University of British Columbia, Vancouver, Canada.,British Columbia Children's Hospital Research Institute, Vancouver, Canada (D.C.T., J.J.P.)
| | - Sam Chen
- Department of Biochemistry and Molecular Biology (S.C., P.R.C.), University of British Columbia, Vancouver, Canada
| | - Israel Matos
- From the Department of Microbiology and Immunology (M.E.R., M.B., J.A.F.D.S., R.A.C., W.C., A.W., I.M., K.W.H.), University of British Columbia, Vancouver, Canada
| | - John J Priatel
- Department of Pathology and Laboratory Medicine (J.J.P.), University of British Columbia, Vancouver, Canada.,British Columbia Children's Hospital Research Institute, Vancouver, Canada (D.C.T., J.J.P.)
| | - Pieter R Cullis
- Department of Biochemistry and Molecular Biology (S.C., P.R.C.), University of British Columbia, Vancouver, Canada
| | - Kenneth W Harder
- From the Department of Microbiology and Immunology (M.E.R., M.B., J.A.F.D.S., R.A.C., W.C., A.W., I.M., K.W.H.), University of British Columbia, Vancouver, Canada
| |
Collapse
|
|
46
|
Abstract
The cervix is the essential gatekeeper for birth. Incomplete cervix remodeling contributes to problems with delivery at or post-term while preterm birth is a major factor in perinatal morbidity and mortality in newborns. Lack of cervix biopsies from women during the period preceding term or preterm birth have led to use of rodent models to advanced understanding of the mechanism for prepartum cervix remodeling. The critical transition from a soft cervix to a compliant prepartum lower uterine segment has only recently been recognized to occur in various mammalian species when progesterone in circulation is at or near the peak of pregnancy in preparation for birth. In rodents, characterization of ripening resembles an inflammatory process with a temporal coincidence of decreased density of cell nuclei, decline in cross-linked extracellular collagen, and increased presence of macrophages in the cervix. Although a role for inflammation in parturition and cervix remodeling is not a new concept, a comprehensive examination of literature in this review reveals that many conclusions are drawn from comparisons before and after ripening has occurred, not during the process. The present review focuses on essential phenotypes and functions of resident myeloid and possibly other immune cells to bridge the gap with evidence that specific biomarkers may assess the progress of ripening both at term and with preterm birth. Moreover, use of endpoints to determine the effectiveness of various therapeutic approaches to forestall remodeling and reduce risks for preterm birth, or facilitate ripening to promote parturition will improve the postpartum well-being of mothers and newborns.
Collapse
Affiliation(s)
- Steven M Yellon
- Department of Basic Sciences, Longo Center for Perinatal Biology, School of Medicine, Loma Linda University, Loma Linda, CA, United States
| |
Collapse
|
|
47
|
Salei N, Rambichler S, Salvermoser J, Papaioannou NE, Schuchert R, Pakalniškytė D, Li N, Marschner JA, Lichtnekert J, Stremmel C, Cernilogar FM, Salvermoser M, Walzog B, Straub T, Schotta G, Anders HJ, Schulz C, Schraml BU. The Kidney Contains Ontogenetically Distinct Dendritic Cell and Macrophage Subtypes throughout Development That Differ in Their Inflammatory Properties. J Am Soc Nephrol 2020; 31:257-278. [PMID: 31932472 DOI: 10.1681/asn.2019040419] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 10/20/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Mononuclear phagocytes (MPs), including macrophages, monocytes, and dendritic cells (DCs), are phagocytic cells with important roles in immunity. The developmental origin of kidney DCs has been highly debated because of the large phenotypic overlap between macrophages and DCs in this tissue. METHODS We used fate mapping, RNA sequencing, flow cytometry, confocal microscopy, and histo-cytometry to assess the origin and phenotypic and functional properties of renal DCs in healthy kidney and of DCs after cisplatin and ischemia reperfusion-induced kidney injury. RESULTS Adult kidney contains at least four subsets of MPs with prominent Clec9a-expression history indicating a DC origin. We demonstrate that these populations are phenotypically, functionally, and transcriptionally distinct from each other. We also show these kidney MPs exhibit unique age-dependent developmental heterogeneity. Kidneys from newborn mice contain a prominent population of embryonic-derived MHCIInegF4/80hiCD11blow macrophages that express T cell Ig and mucin domain containing 4 (TIM-4) and MER receptor tyrosine kinase (MERTK). These macrophages are replaced within a few weeks after birth by phenotypically similar cells that express MHCII but lack TIM-4 and MERTK. MHCII+F4/80hi cells exhibit prominent Clec9a-expression history in adulthood but not early life, indicating additional age-dependent developmental heterogeneity. In AKI, MHCIInegF4/80hi cells reappear in adult kidneys as a result of MHCII downregulation by resident MHCII+F4/80hi cells, possibly in response to prostaglandin E2 (PGE2). RNA sequencing further suggests MHCII+F4/80hi cells help coordinate the recruitment of inflammatory cells during renal injury. CONCLUSIONS Distinct developmental programs contribute to renal DC and macrophage populations throughout life, which could have important implications for therapies targeting these cells.
Collapse
Affiliation(s)
- Natallia Salei
- Walter Brendel Centre of Experimental Medicine, University Hospital Munich.,Institute for Cardiovascular Physiology and Pathophysiology
| | - Stephan Rambichler
- Walter Brendel Centre of Experimental Medicine, University Hospital Munich.,Institute for Cardiovascular Physiology and Pathophysiology
| | - Johanna Salvermoser
- Walter Brendel Centre of Experimental Medicine, University Hospital Munich.,Institute for Cardiovascular Physiology and Pathophysiology
| | - Nikos E Papaioannou
- Walter Brendel Centre of Experimental Medicine, University Hospital Munich.,Institute for Cardiovascular Physiology and Pathophysiology
| | - Ronja Schuchert
- Medical Clinic and Polyclinic I and.,DZHK (Deutsches Zentrum für Herz-Kreislaufforschung [German Center for Cardiovascular Research]), Partner Site Munich Heart Alliance, Munich, Germany; and
| | - Dalia Pakalniškytė
- Walter Brendel Centre of Experimental Medicine, University Hospital Munich.,Institute for Cardiovascular Physiology and Pathophysiology
| | - Na Li
- Division of Nephrology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shen Zhen, China.,Division of Nephrology, Medical Clinic and Polyclinic IV, University Hospital Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Julian A Marschner
- Division of Nephrology, Medical Clinic and Polyclinic IV, University Hospital Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Julia Lichtnekert
- Division of Nephrology, Medical Clinic and Polyclinic IV, University Hospital Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Christopher Stremmel
- Medical Clinic and Polyclinic I and.,DZHK (Deutsches Zentrum für Herz-Kreislaufforschung [German Center for Cardiovascular Research]), Partner Site Munich Heart Alliance, Munich, Germany; and
| | | | - Melanie Salvermoser
- Walter Brendel Centre of Experimental Medicine, University Hospital Munich.,Institute for Cardiovascular Physiology and Pathophysiology
| | - Barbara Walzog
- Walter Brendel Centre of Experimental Medicine, University Hospital Munich.,Institute for Cardiovascular Physiology and Pathophysiology
| | | | - Gunnar Schotta
- Division of Molecular Biology.,Center for Integrated Protein Science Munich, Biomedical Center, Faculty of Medicine, Ludwig Maximilian University of Munich, Martinsried, Germany
| | - Hans-Joachim Anders
- Division of Nephrology, Medical Clinic and Polyclinic IV, University Hospital Munich, Ludwig Maximilian University of Munich, Munich, Germany
| | - Christian Schulz
- Medical Clinic and Polyclinic I and.,DZHK (Deutsches Zentrum für Herz-Kreislaufforschung [German Center for Cardiovascular Research]), Partner Site Munich Heart Alliance, Munich, Germany; and
| | - Barbara U Schraml
- Walter Brendel Centre of Experimental Medicine, University Hospital Munich, .,Institute for Cardiovascular Physiology and Pathophysiology
| |
Collapse
|
|
48
|
Syed SN, Frank AC, Raue R, Brüne B. MicroRNA-A Tumor Trojan Horse for Tumor-Associated Macrophages. Cells 2019; 8:E1482. [PMID: 31766495 PMCID: PMC6953083 DOI: 10.3390/cells8121482] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/19/2019] [Accepted: 11/19/2019] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs (miRs) significantly contribute to the regulation of gene expression, by virtue of their ability to interact with a broad, yet specific set of target genes. MiRs are produced and released by almost every cell type and play an important role in horizontal gene regulation in the tumor microenvironment (TME). In the TME, both tumor and stroma cells cross-communicate via diverse factors including miRs, which are taking central stage as a therapeutic target of anti-tumor therapy. One of the immune escape strategies adopted by tumor cells is to release miRs as a Trojan horse to hijack circulating or tumor-localized monocytes/macrophages to tune them for pro-tumoral functions. On the other hand, macrophage-derived miRs exert anti-tumor functions. The transfer of miRs from host to recipient cells depends on the supramolecular structure and composition of miR carriers, which determine the distinct uptake mechanism by recipient cells. In this review, we provide a recent update on the miR-mediated crosstalk between tumor cells and macrophages and their mode of uptake in the TME.
Collapse
Affiliation(s)
- Shahzad Nawaz Syed
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (S.N.S.); (A.-C.F.); (R.R.)
| | - Ann-Christin Frank
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (S.N.S.); (A.-C.F.); (R.R.)
| | - Rebecca Raue
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (S.N.S.); (A.-C.F.); (R.R.)
| | - Bernhard Brüne
- Institute of Biochemistry I, Faculty of Medicine, Goethe-University Frankfurt, 60590 Frankfurt, Germany; (S.N.S.); (A.-C.F.); (R.R.)
- Project Group Translational Medicine and Pharmacology TMP, Fraunhofer Institute for Molecular Biology and Applied Ecology, 60596 Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt, 60590 Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe-University Frankfurt, 60596 Frankfurt, Germany
| |
Collapse
|
|
49
|
Abstract
Quorum sensing is a type of cellular communication that was first described in bacteria, consisting of gene expression regulation in response to changes in cell-population density. Bacteria synthesize and secrete diffusive molecules called autoinducers, which concentration varies accordingly with cell density and can be detected by the producing cells themselves. Once autoinducer concentration reaches a critical threshold, all bacteria within the autoinducer-rich environment react by modifying their genetic expression and adopt a coordinated behavior (e.g., biofilm formation, virulence factor expression, or swarming motility). Recent advances highlight the possibility that such type of communication is not restricted to bacteria, but can exist among other cell types, including immune cells and more specifically monocyte-derived cells (1). For such cells, quorum sensing mechanisms may not only regulate their population size and synchronize their behavior at homeostasis but also alter their activity and function in unexpected ways during immune reactions. Although the nature of immune autoinducers and cellular mechanisms remains to be fully characterized, quorum sensing mechanisms in the immune system challenge our traditional conception of immune cell interactions and likely represent an important mode of communication at homeostasis or during an immune response. In this mini-review, we briefly present the prototypic features of quorum sensing in bacteria and discuss the existing evidence for quorum sensing within the immune system. Mainly, we review quorum sensing mechanisms among monocyte-derived cells, such as the regulation of inflammation by the density of monocyte-derived cells that produce nitric oxide and discuss the relevance of such models in the context of immune-related pathologies.
Collapse
Affiliation(s)
- Jérémy Postat
- Dynamics of Immune Responses Unit, Institut Pasteur, INSERM U1223, Paris, France
- Sorbonne Paris Cité, Cellule Pasteur, University Paris Diderot, Paris, France
| | - Philippe Bousso
- Dynamics of Immune Responses Unit, Institut Pasteur, INSERM U1223, Paris, France
| |
Collapse
|
|
50
|
Okabe Y. Molecular control of the identity of tissue-resident macrophages. Int Immunol 2019; 30:485-491. [PMID: 30371831 DOI: 10.1093/intimm/dxy019] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Accepted: 02/21/2018] [Indexed: 12/23/2022] Open
Abstract
Macrophages are present in virtually almost all tissues, exhibiting highly heterogeneous phenotypes as a consequence of adaptation to local tissue environments. Tissue-resident macrophages perform specialized functions that are essential for the maintenance of tissue homeostasis, and abnormalities of their functions are linked to various pathologies. Recent advances have shown that tissue-specific transcriptional programs are responsible for functional specialization of macrophages in different tissues. Here, I discuss the molecular basis of tissue-resident macrophage specialization and how it is regulated by tissue environmental cues.
Collapse
Affiliation(s)
- Yasutaka Okabe
- Laboratory of Molecular Genetics, Institute for Frontier Life and Medical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
| |
Collapse
|