|
1
|
Zhang B, Xu P, Ablasser A. Regulation of the cGAS-STING Pathway. Annu Rev Immunol 2025; 43:667-692. [PMID: 40085836 DOI: 10.1146/annurev-immunol-101721-032910] [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] [Indexed: 03/16/2025]
Abstract
The cGAS-cGAMP-STING pathway is essential for immune defense against pathogens. Upon binding DNA, cGAS synthesizes cGAMP, which activates STING, leading to potent innate immune effector responses. However, lacking specific features to distinguish between self and nonself DNA, cGAS-STING immunity requires precise regulation to prevent aberrant activation. Several safeguard mechanisms acting on different levels have evolved to maintain tolerance to self DNA and ensure immune homeostasis under normal conditions. Disruption of these safeguards can lead to erroneous activation by self DNA, resulting in inflammatory conditions but also favorable antitumor immunity. Insights into structural and cellular checkpoints that control and terminate cGAS-STING signaling are essential for comprehending and manipulating DNA-triggered innate immunity in health and disease.
Collapse
Affiliation(s)
- Bing Zhang
- Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland;
| | - Pengbiao Xu
- Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland;
| | - Andrea Ablasser
- Global Health Institute, Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland;
- Institute for Cancer Research (ISREC), Swiss Federal Institute of Technology Lausanne (EPFL), Lausanne, Switzerland
| |
Collapse
|
|
2
|
Liu YQ, Li ZZ, Han YL, Wang QB. The role of efferocytosis in inflammatory bowel disease. Front Immunol 2025; 16:1524058. [PMID: 40040696 PMCID: PMC11876057 DOI: 10.3389/fimmu.2025.1524058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 01/16/2025] [Indexed: 03/06/2025] Open
Abstract
Efferocytosis is the process by which various phagocytes clear apoptotic cells. In recent years, an increasing body of evidence has emphasized the importance of efferocytosis in maintaining internal homeostasis. Intestinal macrophages play a crucial role in modulating intestinal inflammation and promoting tissue repair. Inflammatory bowel disease (IBD) is a chronic, progressive, and relapsing condition, primarily marked by the presence of ulcers in the digestive tract. The exact mechanisms underlying IBD are not yet fully understood, and current treatment approaches mainly aim at repairing the damaged intestinal mucosa and reducing inflammatory responses to ease symptoms.This article provides new perspectives on IBD treatment and clinical management by examining the expression of macrophage efferocytosis-related molecules, the effects of efferocytosis on IBD development, the various roles of macrophage efferocytosis in IBD, and treatment strategies for IBD that focus on efferocytosis.
Collapse
Affiliation(s)
- Yi-Qian Liu
- Institute of Acupuncture and Moxibustion, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Zhan-Zhan Li
- Academy of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, China
| | - Yong-Li Han
- Acupuncture Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Qing-Bo Wang
- Acupuncture Department, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| |
Collapse
|
|
3
|
Qin Y, Chen X, Bao L, Ren L, Dou G, Lian J, Xing S, Li Z, Ding F, Qin W, Liu X, Zhu B, Liu S, Jin Z, Yang X. Lipid metabolism of apoptotic vesicles accelerates cutaneous wound healing by modulating macrophage function. J Nanobiotechnology 2025; 23:106. [PMID: 39939963 PMCID: PMC11823102 DOI: 10.1186/s12951-025-03194-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 02/01/2025] [Indexed: 02/14/2025] Open
Abstract
The application of apoptotic extracellular vesicles (ApoEVs) derived from stem cell in skin wound healing has garnered significant attention. In recent decades, scholars have shown that extracellular vesicles (EVs) established intercellular communication by carrying proteins or microRNAs, the role of lipids in EVs in wound healing has yet to be clarified. Here, we focus on the key role of group X secretory phospholipase A2 (sPLA2-X) in lipid metabolism. Specifically, sPLA2-X significantly increased the production of the anti-inflammatory lipid mediators, resolvin D5 (RvD5), by hydrolyzing phospholipids in ApoEVs. This change not only promoted the uptake of ApoEVs by macrophages, but also effectively inhibited the expression of tumor necrosis factor-alpha (TNF-α) in macrophages, promoting the healing of skin wounds. In summary, this study contributes to our understanding of the mechanisms by which ApoEVs support skin defect repair and offers a potential theoretical approach for using ApoEVs in skin wound treatment. With further research and optimization, it is expected that more efficient and secure ApoEVs-based treatment strategies will be developed, bringing new breakthroughs in clinical treatment of skin injuries and related diseases.
Collapse
Affiliation(s)
- Yuan Qin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology & Clinic of Oral Rare Diseases and Genetic Disease, School of Stomatology, The Fourth Military Medical University, Xi' an, 710032, China
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Xin Chen
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Lili Bao
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology & Clinic of Oral Rare Diseases and Genetic Disease, School of Stomatology, The Fourth Military Medical University, Xi' an, 710032, China
| | - Lili Ren
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Geng Dou
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Jianing Lian
- College of Pharmacy, Shaanxi University of Chinese Medicine, Xi'an, 712046, China
| | - Shujuan Xing
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
- College of Life Science, Northwest University, Xi'an, 710069, China
| | - Zihan Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Feng Ding
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Wen Qin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Xulin Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China
| | - Bin Zhu
- Outpatient Department, General Hospital of Xizang Military Region, Lhasa, 850007, China
| | - Shiyu Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology & Clinic of Oral Rare Diseases and Genetic Disease, School of Stomatology, The Fourth Military Medical University, Xi' an, 710032, China.
| | - Zuolin Jin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Orthodontics, School of Stomatology, The Fourth Military Medical University, Xi'an, 710032, China.
| | - Xiaoshan Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Key Laboratory of Stomatology, Department of Oral Biology & Clinic of Oral Rare Diseases and Genetic Disease, School of Stomatology, The Fourth Military Medical University, Xi' an, 710032, China.
- Stomatological Hospital, School of Stomatology, Southern Medical University, Guangzhou, 510280, China.
| |
Collapse
|
|
4
|
Dong M, Fitzgerald KA. DNA-sensing pathways in health, autoinflammatory and autoimmune diseases. Nat Immunol 2024; 25:2001-2014. [PMID: 39367124 DOI: 10.1038/s41590-024-01966-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 08/07/2024] [Indexed: 10/06/2024]
Abstract
Detection of microbial DNA is a primary means of host defense. In mammalian cells, DNA-sensing pathways induce robust anti-microbial responses and initiation of adaptive immunity, leading to the eventual clearance of the infectious agent. However, while conferring the advantage of broad detection capability, the sequence-independent recognition mechanisms of most DNA sensors pose a significant challenge for mammalian cells to maintain ignorance to self-DNA under homeostatic conditions. In this Review, we summarize the fundamentals of DNA-sensing pathways and the intricate regulatory networks that keep these pathways in check. In addition, we describe how regulatory restraints can be defective and underlie human autoinflammatory and autoimmune diseases. Further, we discuss therapies in development that limit inflammation fueled by self-DNA or inappropriate activation of DNA-sensing pathways.
Collapse
Affiliation(s)
- Mingqi Dong
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Katherine A Fitzgerald
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA.
| |
Collapse
|
|
5
|
Razia S, Takeshita H, Inoue K, Iida R, Ueki M, Yasuda T. Unveiling human DNase II: Molecular characterizations, gene insights and functional implications. Leg Med (Tokyo) 2024; 71:102505. [PMID: 39182441 DOI: 10.1016/j.legalmed.2024.102505] [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: 04/30/2024] [Revised: 06/10/2024] [Accepted: 08/04/2024] [Indexed: 08/27/2024]
Abstract
This review comprehensively explores the molecular characterization, genetic insights, and functional implications of human DNase II, an enzyme crucial for DNA hydrolysis under acidic conditions. We discuss its purification, identification, and characterization, emphasizing the importance of highly purified samples for accurate analyses as well as for understanding the biochemical properties. The discovery and analysis of DNase II's cDNA and gene have provided crucial insights into its genetic regulation and chromosomal location. Genetic polymorphism in DNase II activity levels, characterized by distinct alleles, provides valuable information on the diversity of enzyme function among individuals. Tissue distribution studies reveal its widespread presence across human tissues, hinting at potential endocrine connections. Clinical implications of DNase II variants, including therapeutic strategies targeting the JAK1 pathway, offering insights into disease mechanisms and potential treatments. Overall, this review serves as a valuable resource for advancing our knowledge of DNase II and its impact on human health and disease.
Collapse
Affiliation(s)
- Sultana Razia
- Department of Legal Medicine, Shimane University School of Medicine, Izumo 6938501, Japan.
| | - Haruo Takeshita
- Department of Legal Medicine, Shimane University School of Medicine, Izumo 6938501, Japan; Autopsy Imaging Center, Shimane University Faculty of Medicine, Izumo, Japan
| | - Ken Inoue
- Research and Education Faculty, Medical Sciences Cluster, Health Service Center, Kochi University, Kochi 780-8520, Japan
| | - Reiko Iida
- Molecular Neuroscience Unit, School of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Misuzu Ueki
- Molecular Neuroscience Unit, School of Medical Sciences, University of Fukui, Fukui 910-1193, Japan
| | - Toshihiro Yasuda
- Organization for Life Science Advancement Programs, University of Fukui, Fukai 910-1193, Japan
| |
Collapse
|
|
6
|
Macáková K, Borbélyová V, Tekeľová M, Janko J, Pastorek M, Hokša R, Moravanský N, Šteňová E, Vlková B, Celec P. Effects of exogenous deoxyribonuclease I in collagen antibody-induced arthritis. J Inflamm (Lond) 2024; 21:36. [PMID: 39251994 PMCID: PMC11386490 DOI: 10.1186/s12950-024-00403-z] [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: 06/06/2023] [Accepted: 08/19/2024] [Indexed: 09/11/2024] Open
Abstract
BACKGROUND Rheumatoid arthritis (RA) is associated with a high concentration of extracellular DNA (ecDNA). This could be a consequence of the inflammation, but the ecDNA could also be involved in the unknown etiopathogenesis of RA. Clearance of ecDNA is hypothesized to prevent the development of RA. This study aimed to analyze the effects of exogenous deoxyribonuclease I (DNase I) administration in an animal model of RA. METHODS The collagen antibody-induced arthritis (CAIA) model of RA was induced in adult female DBA/1J mice. CAIA mice were treated with saline or DNase I (10 mg/kg) every 12 h for the whole duration of the experiment. Arthritic scores were assessed. Paw volume and temperature were assessed using a plethysmometer and a thermal camera, respectively. Plasma ecDNA and its subcellular origin were analyzed using fluorometry and real-time PCR. DNase activity was quantified with single radial enzyme diffusion method. RESULTS The CAIA model was successfully induced as proved by a higher volume, temperature and the overall arthritis score in comparison to controls. The administration of DNase I resulted in a nearly two-fold increase in serum DNase activity. Still, it did affect neither plasma ecDNA, nor the arthritis score or other measures of joint inflammation. CONCLUSION Our results suggest that exogenous DNase I does not prevent the development of CAIA in mice. Whether this is true for other animal models of arthritis or clinical RA requires further research. EcDNA does not seem to be involved in the pathogenesis of CAIA. Additional studies are also needed to elucidate the role of ecDNA in the development of RA, focusing especially on its origin and inhibition of ecDNA release.
Collapse
Affiliation(s)
- Kristína Macáková
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, Bratislava, 811 08, Slovakia
| | - Veronika Borbélyová
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, Bratislava, 811 08, Slovakia
| | - Mária Tekeľová
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, Bratislava, 811 08, Slovakia
| | - Jakub Janko
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, Bratislava, 811 08, Slovakia
| | - Michal Pastorek
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, Bratislava, 811 08, Slovakia
| | - Richard Hokša
- Health Care Surveillance Authority Department, Department of Pathology, Antolská 11, 851 07 Bratislava, Slovakia
- Forensic.sk Institute of Forensic Medical Expertise, Boženy Němcovej 8, 811 01 Bratislava, Slovakia
| | - Norbert Moravanský
- Institute of Forensic Medicine, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia
- Forensic.sk Institute of Forensic Medical Expertise, Boženy Němcovej 8, 811 01 Bratislava, Slovakia
| | - Emöke Šteňová
- 1st Department of Internal Medicine, Faculty of Medicine, University Hospital, Comenius University, Mickiewiczova 13, 813 69 Bratislava, Slovakia
| | - Barbora Vlková
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, Bratislava, 811 08, Slovakia
| | - Peter Celec
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Sasinkova 4, Bratislava, 811 08, Slovakia.
- Institute of Pathophysiology, Faculty of Medicine, Comenius University, Sasinkova 4, 811 08 Bratislava, Slovakia.
| |
Collapse
|
|
7
|
Man SM, Kanneganti TD. Innate immune sensing of cell death in disease and therapeutics. Nat Cell Biol 2024; 26:1420-1433. [PMID: 39223376 DOI: 10.1038/s41556-024-01491-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 07/22/2024] [Indexed: 09/04/2024]
Abstract
Innate immunity, cell death and inflammation underpin many aspects of health and disease. Upon sensing pathogens, pathogen-associated molecular patterns or damage-associated molecular patterns, the innate immune system activates lytic, inflammatory cell death, such as pyroptosis and PANoptosis. These genetically defined, regulated cell death pathways not only contribute to the host defence against infectious disease, but also promote pathological manifestations leading to cancer and inflammatory diseases. Our understanding of the underlying mechanisms has grown rapidly in recent years. However, how dying cells, cell corpses and their liberated cytokines, chemokines and inflammatory signalling molecules are further sensed by innate immune cells, and their contribution to further amplify inflammation, trigger antigen presentation and activate adaptive immunity, is less clear. Here, we discuss how pattern-recognition and PANoptosome sensors in innate immune cells recognize and respond to cell-death signatures. We also highlight molecular targets of the innate immune response for potential therapeutic development.
Collapse
Affiliation(s)
- Si Ming Man
- Division of Immunology and Infectious Disease, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory, Australia.
| | | |
Collapse
|
|
8
|
Hao K, Gao KM, Strauss M, Subramanian S, Marshak-Rothstein A. IFNγ initiates TLR9-dependent autoimmune hepatitis in DNase II deficient mice. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.07.10.602775. [PMID: 39071327 PMCID: PMC11275780 DOI: 10.1101/2024.07.10.602775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Patients with biallelic hypomorphic mutation in DNASE2 develop systemic autoinflammation and early-onset liver fibrosis. Prior studies showed that Dnase2 -/- Ifnar -/- double knockout (DKO) mice develop Type I IFN-independent liver inflammation, but immune mechanisms were unclear. We now show that DKO mice recapitulate many features of human autoimmune hepatitis (AIH), including periportal and interstitial inflammation and fibrosis and elevated ALT. Infiltrating cells include CD8+ tissue resident memory T cells, type I innate lymphoid cells, and inflammatory monocyte/macrophage cells that replace the Kupffer cell pool. Importantly, TLR9 expression by bone marrow-derived cells is required for the the development of AIH. TLR9 is highly expressed by inflammatory myeloid cells but not long-lived Kupffer cells. Furthermore, the initial recruitment of TLR9 expressing monocytes and subsequent activation of lymphocytes requires IFNγ signaling. These findings highlight a critical role of feed forward loop between TLR9 expressing monocyte-lineage cells and IFNg producing lymphocytes in autoimmune hepatitis.
Collapse
|
|
9
|
Bérouti M, Lammens K, Heiss M, Hansbauer L, Bauernfried S, Stöckl J, Pinci F, Piseddu I, Greulich W, Wang M, Jung C, Fröhlich T, Carell T, Hopfner KP, Hornung V. Lysosomal endonuclease RNase T2 and PLD exonucleases cooperatively generate RNA ligands for TLR7 activation. Immunity 2024; 57:1482-1496.e8. [PMID: 38697119 PMCID: PMC11470960 DOI: 10.1016/j.immuni.2024.04.010] [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: 10/16/2023] [Revised: 03/06/2024] [Accepted: 04/12/2024] [Indexed: 05/04/2024]
Abstract
Toll-like receptor 7 (TLR7) is essential for recognition of RNA viruses and initiation of antiviral immunity. TLR7 contains two ligand-binding pockets that recognize different RNA degradation products: pocket 1 recognizes guanosine, while pocket 2 coordinates pyrimidine-rich RNA fragments. We found that the endonuclease RNase T2, along with 5' exonucleases PLD3 and PLD4, collaboratively generate the ligands for TLR7. Specifically, RNase T2 generated guanosine 2',3'-cyclic monophosphate-terminated RNA fragments. PLD exonuclease activity further released the terminal 2',3'-cyclic guanosine monophosphate (2',3'-cGMP) to engage pocket 1 and was also needed to generate RNA fragments for pocket 2. Loss-of-function studies in cell lines and primary cells confirmed the critical requirement for PLD activity. Biochemical and structural studies showed that PLD enzymes form homodimers with two ligand-binding sites important for activity. Previously identified disease-associated PLD mutants failed to form stable dimers. Together, our data provide a mechanistic basis for the detection of RNA fragments by TLR7.
Collapse
Affiliation(s)
- Marleen Bérouti
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Katja Lammens
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Matthias Heiss
- Department of Chemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Larissa Hansbauer
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Stefan Bauernfried
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Jan Stöckl
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Francesca Pinci
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Ignazio Piseddu
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany; Department of Medicine II, University Hospital Munich, Munich, Germany
| | - Wilhelm Greulich
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Meiyue Wang
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Christophe Jung
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Thomas Fröhlich
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Thomas Carell
- Department of Chemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Karl-Peter Hopfner
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany
| | - Veit Hornung
- Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität, Munich, Germany.
| |
Collapse
|
|
10
|
Crow YJ, Casanova JL. Human life within a narrow range: The lethal ups and downs of type I interferons. Sci Immunol 2024; 9:eadm8185. [PMID: 38968338 DOI: 10.1126/sciimmunol.adm8185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 06/13/2024] [Indexed: 07/07/2024]
Abstract
The past 20 years have seen the definition of human monogenic disorders and their autoimmune phenocopies underlying either defective or enhanced type I interferon (IFN) activity. These disorders delineate the impact of type I IFNs in natural conditions and demonstrate that only a narrow window of type I IFN activity is beneficial. Insufficient type I IFN predisposes humans to life-threatening viral diseases (albeit unexpectedly few) with a central role in immunity to respiratory and cerebral viral infection. Excessive type I IFN, perhaps counterintuitively, appears to underlie a greater number of autoinflammatory and/or autoimmune conditions known as type I interferonopathies, whose study has revealed multiple molecular programs involved in the induction of type I IFN signaling. These observations suggest that the manipulation of type I IFN activity to within a physiological range may be clinically relevant for the prevention and treatment of viral and inflammatory diseases.
Collapse
Affiliation(s)
- Yanick J Crow
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- Laboratory of Neurogenetics and Neuroinflammation, Imagine Institute, INSERM UMR 1163, Paris, France
- University Paris Cité, Paris, France
| | - Jean-Laurent Casanova
- University Paris Cité, Paris, France
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY, USA
- Howard Hughes Medical Institute, New York, NY, USA
- Department of Pediatrics, Necker Hospital for Sick Children, Paris, France
- Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Imagine Institute, INSERM UMR 1163, Necker Hospital for Sick Children, Paris, France
| |
Collapse
|
|
11
|
Sheng Y, Hu W, Chen S, Zhu X. Efferocytosis by macrophages in physiological and pathological conditions: regulatory pathways and molecular mechanisms. Front Immunol 2024; 15:1275203. [PMID: 38779685 PMCID: PMC11109379 DOI: 10.3389/fimmu.2024.1275203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 04/17/2024] [Indexed: 05/25/2024] Open
Abstract
Efferocytosis is defined as the highly effective phagocytic removal of apoptotic cells (ACs) by professional or non-professional phagocytes. Tissue-resident professional phagocytes ("efferocytes"), such as macrophages, have high phagocytic capacity and are crucial to resolve inflammation and aid in homeostasis. Recently, numerous exciting discoveries have revealed divergent (and even diametrically opposite) findings regarding metabolic immune reprogramming associated with efferocytosis by macrophages. In this review, we highlight the key metabolites involved in the three phases of efferocytosis and immune reprogramming of macrophages under physiological and pathological conditions. The next decade is expected to yield further breakthroughs in the regulatory pathways and molecular mechanisms connecting immunological outcomes to metabolic cues as well as avenues for "personalized" therapeutic intervention.
Collapse
Affiliation(s)
- Yan−Ran Sheng
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Wen−Ting Hu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Siman Chen
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Xiao−Yong Zhu
- Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
- Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Fudan University, Shanghai, China
| |
Collapse
|
|
12
|
Yang K, Jeltema D, Yan N. Innate immune sensing of macromolecule homeostasis. Adv Immunol 2024; 161:17-51. [PMID: 38763701 DOI: 10.1016/bs.ai.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/21/2024]
Abstract
The innate immune system uses a distinct set of germline-encoded pattern recognition receptors to recognize molecular patterns initially thought to be unique to microbial invaders, named pathogen-associated molecular patterns. The concept was later further developed to include similar molecular patterns originating from host cells during tissue damage, known as damage-associated molecular patterns. However, recent advances in the mechanism of monogenic inflammatory diseases have highlighted a much more expansive repertoire of cellular functions that are monitored by innate immunity. Here, we summarize several examples in which an innate immune response is triggered when homeostasis of macromolecule in the cell is disrupted in non-infectious or sterile settings. These ever-growing sensing mechanisms expand the repertoire of innate immune recognition, positioning it not only as a key player in host defense but also as a gatekeeper of cellular homeostasis. Therapeutics inspired by these advances to restore cellular homeostasis and correct the immune system could have far-reaching implications.
Collapse
Affiliation(s)
- Kun Yang
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Devon Jeltema
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Nan Yan
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, United States.
| |
Collapse
|
|
13
|
Abstract
PURPOSE OF REVIEW Type 1 interferons (IFN-I) are of increasing interest across a wide range of autoimmune rheumatic diseases. Historically, research into their role in rheumatoid arthritis (RA) has been relatively neglected, but recent work continues to highlight a potential contribution to RA pathophysiology. RECENT FINDINGS We emphasise the importance of disease stage when examining IFN-I in RA and provide an overview on how IFN-I may have a direct role on a variety of relevant cellular functions. We explore how clinical trajectory may be influenced by increased IFN-I signalling, and also, the limitations of scores composed of interferon response genes. Relevant environmental triggers and inheritable RA genetic risk relating to IFN-I signalling are explored with emphasis on intriguing data potentially linking IFN-I exposure, epigenetic changes, and disease relevant processes. Whilst these data cumulatively illustrate a likely role for IFN-I in RA, they also highlight the knowledge gaps, particularly in populations at risk for RA, and suggest directions for future research to both better understand IFN-I biology and inform targeted therapeutic strategies.
Collapse
Affiliation(s)
- Chung M A Lin
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - John D Isaacs
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Faye A H Cooles
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
- Musculoskeletal Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
| |
Collapse
|
|
14
|
Jiang T, Xia Y, Wang W, Zhao J, Liu W, Liu S, Shi S, Li B, He X, Jin Y. Apoptotic bodies inhibit inflammation by PDL1-PD1-mediated macrophage metabolic reprogramming. Cell Prolif 2024; 57:e13531. [PMID: 37553821 PMCID: PMC10771117 DOI: 10.1111/cpr.13531] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 07/15/2023] [Accepted: 07/19/2023] [Indexed: 08/10/2023] Open
Abstract
Apoptosis triggers immunoregulation to prevent and suppress inflammation and autoimmunity. However, the mechanism by which apoptotic cells modulate immune responses remains largely elusive. In the context of allogeneic mesenchymal stem cells (MSCs) transplantation, long-term immunoregulation is observed in the host despite the short survive of the injected MSCs. In this study, utilizing a mouse model of acute lung injury (ALI), we demonstrate that apoptotic bodies (ABs) released by transplanted human umbilical cord MSCs (UC-MSCs) convert the macrophages from a pro-inflammatory to an anti-inflammatory state, thereby ameliorating the disease. Mechanistically, we identify the expression of programmed cell death 1 ligand 1 (PDL1) on the membrane of UC-MSCs-derived ABs, which interacts with programmed cell death protein 1 (PD1) on host macrophages. This interaction leads to the reprogramming of macrophage metabolism, shifting from glycolysis to mitochondrial oxidative phosphorylation via the Erk-dependent pathway in ALI. Importantly, we have reproduced the PDL1-PD1 effects of ABs on metabolic switch using alveolar macrophages from patients with ALI, suggesting the potential clinical implications of developing therapeutic strategies for the patients.
Collapse
Affiliation(s)
- Tao Jiang
- Department of Thoracic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
| | - Yanmin Xia
- Department of Thoracic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Wenzhe Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Jinbo Zhao
- Department of Thoracic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
| | - Wenhao Liu
- Department of Thoracic Surgery, Tangdu HospitalFourth Military Medical UniversityXi'anChina
| | - Shiyu Liu
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Songtao Shi
- South China Center of Craniofacial Stem Cell Research, Guanghua School of StomatologySun Yat‐sen UniversityGuangzhouChina
| | - Bei Li
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Xiaoning He
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| | - Yan Jin
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of StomatologyThe Fourth Military Medical UniversityXi'anChina
| |
Collapse
|
|
15
|
Miyake K, Shibata T, Fukui R, Murakami Y, Sato R, Hiranuma R. Endosomal Toll-Like Receptors as Therapeutic Targets for Autoimmune Diseases. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1444:97-108. [PMID: 38467975 DOI: 10.1007/978-981-99-9781-7_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/13/2024]
Abstract
Nucleic acid (NA)-sensing Toll-like receptors (TLRs) reside in the endosomal compartment of innate immune cells, such as macrophages and dendritic cells. NAs transported to the endosomal compartment are degraded by DNases and RNases. Degradation products, including single-stranded DNA, oligoRNA, and nucleosides, are recognized by TLR7, TLR8, and TLR9 to drive the defense responses against pathogens. NA degradation influences endosomal TLR responses by generating and degrading TLR ligands. TLR ligand accumulation because of impaired NA degradation causes constitutive TLR activation, leading to autoinflammatory and autoimmune diseases. Furthermore, some genes associated with these diseases promote endosomal TLR responses. Therefore, endosomal TLRs are promising therapeutic targets for TLR-mediated inflammatory diseases, and novel drugs targeting TLRs are being developed.
Collapse
Affiliation(s)
- Kensuke Miyake
- Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
| | - Takuma Shibata
- Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Ryutaro Fukui
- Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Yusuke Murakami
- Faculty of Pharmacy, Department of Pharmaceutical Sciences and Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan
| | - Ryota Sato
- Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Ryosuke Hiranuma
- Division of Innate Immunity, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
|
16
|
Govindarajulu M, Ramesh S, Beasley M, Lynn G, Wallace C, Labeau S, Pathak S, Nadar R, Moore T, Dhanasekaran M. Role of cGAS-Sting Signaling in Alzheimer's Disease. Int J Mol Sci 2023; 24:ijms24098151. [PMID: 37175853 PMCID: PMC10179704 DOI: 10.3390/ijms24098151] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 04/18/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
There is mounting evidence that the development of Alzheimer's disease (AD) interacts extensively with immunological processes in the brain and extends beyond the neuronal compartment. Accumulation of misfolded proteins can activate an innate immune response that releases inflammatory mediators and increases the severity and course of the disease. It is widely known that type-I interferon-driven neuroinflammation in the central nervous system (CNS) accelerates the development of numerous acute and chronic CNS diseases. It is becoming better understood how the cyclic GMP-AMP synthase (cGAS) and its adaptor protein Stimulator of Interferon Genes (STING) triggers type-I IFN-mediated neuroinflammation. We discuss the principal elements of the cGAS-STING signaling pathway and the mechanisms underlying the association between cGAS-STING activity and various AD pathologies. The current understanding of beneficial and harmful cGAS-STING activity in AD and the current treatment pathways being explored will be discussed in this review. The cGAS-STING regulation offers a novel therapeutic opportunity to modulate inflammation in the CNS because it is an upstream regulator of type-I IFNs.
Collapse
Affiliation(s)
- Manoj Govindarajulu
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Sindhu Ramesh
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - McNeil Beasley
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Graham Lynn
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Caleigh Wallace
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Sammie Labeau
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Suhrud Pathak
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Rishi Nadar
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| | - Timothy Moore
- Units Administration, Research Programs, Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, 2316 Walker Building, Auburn, AL 36849, USA
| | - Muralikrishnan Dhanasekaran
- Department of Drug Discovery and Development, Harrison College of Pharmacy, Auburn University, Auburn, AL 36849, USA
| |
Collapse
|
|
17
|
Jiao Y, Yan Z, Yang A. Mitochondria in innate immunity signaling and its therapeutic implications in autoimmune diseases. Front Immunol 2023; 14:1160035. [PMID: 37122709 PMCID: PMC10130412 DOI: 10.3389/fimmu.2023.1160035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 03/28/2023] [Indexed: 05/02/2023] Open
Abstract
Autoimmune diseases are characterized by vast alterations in immune responses, but the pathogenesis remains sophisticated and yet to be fully elucidated. Multiple mechanisms regulating cell differentiation, maturation, and death are critical, among which mitochondria-related cellular organelle functions have recently gained accumulating attention. Mitochondria, as a highly preserved organelle in eukaryotes, have crucial roles in the cellular response to both exogenous and endogenous stress beyond their fundamental functions in chemical energy conversion. In this review, we aim to summarize recent findings on the function of mitochondria in the innate immune response and its aberrancy in autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, etc., mainly focusing on its direct impact on cellular metabolism and its machinery on regulating immune response signaling pathways. More importantly, we summarize the status quo of potential therapeutic targets found in the mitochondrial regulation in the setting of autoimmune diseases and wish to shed light on future studies.
Collapse
Affiliation(s)
- Yuhao Jiao
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhiyu Yan
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
- 4+4 Medical Doctor Program, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China
| | - Aiming Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| |
Collapse
|
|
18
|
MacLauchlan S, Kushwaha P, Tai A, Chen J, Manning C, Swarnkar G, Abu-Amer Y, Fitzgerald KA, Sharma S, Gravallese EM. STING-dependent interferon signatures restrict osteoclast differentiation and bone loss in mice. Proc Natl Acad Sci U S A 2023; 120:e2210409120. [PMID: 37023130 PMCID: PMC10104545 DOI: 10.1073/pnas.2210409120] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 02/14/2023] [Indexed: 04/07/2023] Open
Abstract
Stimulator of interferon genes (STING) is a key mediator of type-I interferon (IFN-I) signaling in response to a variety of stimuli, but the contribution of STING to homeostatic processes is not fully characterized. Previous studies showed that ligand activation of STING limits osteoclast differentiation in vitro through the induction of IFNβ and IFN-I interferon-stimulated genes (ISGs). In a disease model (SAVI) driven by the V154M gain-of-function mutation in STING, fewer osteoclasts form from SAVI precursors in response to receptor activator of NF-kappaB ligand (RANKL) in an IFN-I-dependent manner. Due to the described role of STING-mediated regulation of osteoclastogenesis in activation settings, we sought to determine whether basal STING signaling contributes to bone homeostasis, an unexplored area. Using whole-body and myeloid-specific deficiency, we show that STING signaling prevents trabecular bone loss in mice over time and that myeloid-restricted STING activity is sufficient for this effect. STING-deficient osteoclast precursors differentiate with greater efficiency than wild types. RNA sequencing of wild-type and STING-deficient osteoclast precursor cells and differentiating osteoclasts reveals unique clusters of ISGs including a previously undescribed ISG set expressed in RANKL naïve precursors (tonic expression) and down-regulated during differentiation. We identify a 50 gene tonic ISG signature that is STING dependent and shapes osteoclast differentiation. From this list, we identify interferon-stimulated gene 15 (ISG15) as a tonic STING-regulated ISG that limits osteoclast formation. Thus, STING is an important upstream regulator of tonic IFN-I signatures shaping the commitment to osteoclast fates, providing evidence for a nuanced and unique role for this pathway in bone homeostasis.
Collapse
Affiliation(s)
- Susan MacLauchlan
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA02115
| | - Priyanka Kushwaha
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA02115
| | - Albert Tai
- Department of Immunology, Tufts University School of Medicine, Boston, MA02111
| | - Jia Chen
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA02115
| | - Catherine Manning
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA02115
| | - Gaurav Swarnkar
- Department of Orthopedics and Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO63110
| | - Yousef Abu-Amer
- Department of Orthopedics and Cell Biology and Physiology, Washington University School of Medicine, Saint Louis, MO63110
| | - Katherine A. Fitzgerald
- Department of Medicine, Program in Innate Immunity, University of Massachusetts Chan Medical School, Worcester, MA01655
| | - Shruti Sharma
- Department of Immunology, Tufts University School of Medicine, Boston, MA02111
| | - Ellen M. Gravallese
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA02115
| |
Collapse
|
|
19
|
Urata S, Yoshikawa R, Yasuda J. Calcium Influx Regulates the Replication of Several Negative-Strand RNA Viruses Including Severe Fever with Thrombocytopenia Syndrome Virus. J Virol 2023; 97:e0001523. [PMID: 36794941 PMCID: PMC10062178 DOI: 10.1128/jvi.00015-23] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Accepted: 01/22/2023] [Indexed: 02/17/2023] Open
Abstract
Negative-strand RNA viruses (NSVs) represent one of the most threatening groups of emerging viruses globally. Severe fever with thrombocytopenia syndrome virus (SFTSV) is a highly pathogenic emerging virus that was initially reported in 2011 from China. Currently, no licensed vaccines or therapeutic agents have been approved for use against SFTSV. Here, L-type calcium channel blockers obtained from a U.S. Food and Drug Administration (FDA)-approved compound library were identified as effective anti-SFTSV compounds. Manidipine, a representative L-type calcium channel blocker, restricted SFTSV genome replication and exhibited inhibitory effects against other NSVs. The result from the immunofluorescent assay suggested that manidipine inhibited SFTSV N-induced inclusion body formation, which is believed to be important for the virus genome replication. We have shown that calcium possesses at least two different roles in regulating SFTSV genome replication. Inhibition of calcineurin, the activation of which is triggered by calcium influx, using FK506 or cyclosporine was shown to reduce SFTSV production, suggesting the important role of calcium signaling on SFTSV genome replication. In addition, we showed that globular actin, the conversion of which is facilitated by calcium from filamentous actin (actin depolymerization), supports SFTSV genome replication. We also observed an increased survival rate and a reduction of viral load in the spleen in a lethal mouse model of SFTSV infections after manidipine treatment. Overall, these results provide information regarding the importance of calcium for NSV replication and may thereby contribute to the development of broad-scale protective therapies against pathogenic NSVs. IMPORTANCE SFTS is an emerging infectious disease and has a high mortality rate of up to 30%. There are no licensed vaccines or antivirals against SFTS. In this article, L-type calcium channel blockers were identified as anti-SFTSV compounds through an FDA-approved compound library screen. Our results showed the involvement of L-type calcium channel as a common host factor for several different families of NSVs. The formation of an inclusion body, which is induced by SFTSV N, was inhibited by manidipine. Further experiments showed that SFTSV replication required the activation of calcineurin, a downstream effecter of the calcium channel. In addition, we identified that globular actin, the conversion of which is facilitated by calcium from filamentous actin, supports SFTSV genome replication. We also observed an increased survival rate in a lethal mouse model of SFTSV infection after manidipine treatment. These results facilitate both our understanding of the NSV replication mechanism and the development of novel anti-NSV treatment.
Collapse
Affiliation(s)
- Shuzo Urata
- Department of Emerging Infectious Diseases, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan
- National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, Nagasaki, Japan
| | - Rokusuke Yoshikawa
- Department of Emerging Infectious Diseases, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan
- National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, Nagasaki, Japan
| | - Jiro Yasuda
- Department of Emerging Infectious Diseases, Institute of Tropical Medicine (NEKKEN), Nagasaki University, Nagasaki, Japan
- National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, Nagasaki, Japan
| |
Collapse
|
|
20
|
Bai Q, He X, Hu T. Pan‑cancer analysis of the deoxyribonuclease gene family. Mol Clin Oncol 2023; 18:19. [PMID: 36798465 PMCID: PMC9926046 DOI: 10.3892/mco.2023.2615] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 01/10/2023] [Indexed: 02/05/2023] Open
Abstract
Deoxyribonuclease (DNase) is an enzyme that catalyzes the cleavage of phosphodiester bonds in the main chain of DNA to degrade DNA. DNase serves a vital role in several immune-related diseases. The present study linked the expression of DNase with overall survival (OS), performed pan-cancer co-expression analysis, and assessed the association between DNase and immune infiltration subtypes, tumor microenvironment and drug sensitivity through pan-cancer studies. Furthermore, gene expression data and clinical data were downloaded from The Cancer Genome Atlas. Next, through a series of bioinformatics analyses, DNase expression and survival, immune subtypes, tumor microenvironment and drug sensitivity in 33 tumor types were systematically studied. The expression of the DNase gene family was shown to have an apparent intratumoral heterogeneity. The expression of DNase 2, lysosomal (DNASE2) was the highest in tumors, whereas that of DNASE2 β was the lowest. DNase 1-like 3 (DNASE1L3) was mainly downregulated in tumors, whereas the rest of the DNases were mainly upregulated in tumors. The expression of DNase family members was also found to be associated with the OS rate of patients. DNase family genes may serve an essential role in the tumor microenvironment. DNase family gene expression was related to the content of cytotoxic cells, Immunescore, Stromalscore, Estimatescore and Tumorpurity. The present study also revealed that the DNase genes may be involved in the drug resistance of cancer cells. Finally, the correlation between DNase, and clinical stage and tumor microenvironment in hepatocellular carcinoma (HCC) was studied. In addition, the difference in DNASE1L3 expression between HCC and adjacent normal tissues, and the relationship between DNASE1L3 expression and clinical stage was verified by analyzing three groups in a Gene Expression Omnibus dataset and by performing immunohistochemistry. In conclusion, the present study assessed DNase gene expression, analyzed its relationship with patient OS, performed pan-cancer co-expression analysis, and assessed the association between DNase and immune infiltration subtypes, tumor microenvironment and drug sensitivity. The present study also confirmed the value of further laboratory research on DNases and their prospects in clinical cancer treatment.
Collapse
Affiliation(s)
- Qingquan Bai
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, D-13353 Berlin, Germany,Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, P.R. China,Correspondence to: Dr Qingquan Bai, Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Augustenburger Platz 1, D-13353 Berlin, Germany
| | - Xiao He
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, P.R. China
| | - Tianhui Hu
- Cancer Research Center, School of Medicine, Xiamen University, Xiamen, Fujian 361102, P.R. China,Correspondence to: Dr Qingquan Bai, Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Augustenburger Platz 1, D-13353 Berlin, Germany
| |
Collapse
|
|
21
|
Gao KM, Marshak-Rothstein A, Fitzgerald KA. Type-1 interferon-dependent and -independent mechanisms in cyclic GMP-AMP synthase-stimulator of interferon genes-driven auto-inflammation. Curr Opin Immunol 2023; 80:102280. [PMID: 36638547 DOI: 10.1016/j.coi.2022.102280] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/07/2022] [Accepted: 12/19/2022] [Indexed: 01/13/2023]
Abstract
The cyclic cyclic gaunosine monophosphate adenosine monophosphate (GMP-AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway senses cytosolic dsDNA and initiates immune responses against pathogens. It is also implicated in several auto-inflammatory diseases known as monogenic interferonopathies, specifically Three prime repair exonuclease 1 (Trex1) loss-of-function (LOF), Dnase2 LOF, and stimulator of interferon genes-associated-vasculopathy-with-onset-in-infancy (SAVI). Although monogenic interferonopathies have diverse clinical presentations, they are distinguished by the elevation of type-1 interferons (T1IFNs). However, animal models have demonstrated that T1IFNs contribute to only some disease outcomes and that cGAS-STING activation also promotes T1IFN-independent pathology. For example, while T1IFNs drive the immunopathology associated with Trex1 LOF, disease in Dnase2 LOF is partially independent of T1IFNs, while disease in SAVI appears to occur entirely independent of T1IFNs. Additionally, while the cGAS-STING pathway is well characterized in hematopoietic cells, these animal models point to important roles for STING activity in nonhematopoietic cells in disease. Together, these models illustrate the complex role that cGAS-STING-driven responses play in the pathogenesis of inflammatory diseases across tissues.
Collapse
Affiliation(s)
- Kevin Mj Gao
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA; Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Ann Marshak-Rothstein
- Division of Rheumatology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Katherine A Fitzgerald
- Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
| |
Collapse
|
|
22
|
Gao Z, Gao Z, Zhang H, Hou S, Zhou Y, Liu X. Targeting STING: From antiviral immunity to treat osteoporosis. Front Immunol 2023; 13:1095577. [PMID: 36741390 PMCID: PMC9891206 DOI: 10.3389/fimmu.2022.1095577] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/30/2022] [Indexed: 01/19/2023] Open
Abstract
The cGAS-STING signaling pathway can trigger innate immune responses by detecting dsDNA from outside or within the host. In addition, the cGAS-STING signaling pathway has emerged as a critical mediator of the inflammatory response and a new target for inflammatory diseases. STING activation leads to dimerization and translocation to the endoplasmic reticulum Golgi intermediate compartment or Golgi apparatus catalyzed by TBK1, triggers the production of IRF3 and NF-κB and translocates to the nucleus to induce a subsequent interferon response and pro-inflammatory factor production. Osteoporosis is a degenerative bone metabolic disease accompanied by chronic sterile inflammation. Activating the STING/IFN-β signaling pathway can reduce bone resorption by inhibiting osteoclast differentiation. Conversely, activation of STING/NF-κB leads to the formation of osteoporosis by increasing bone resorption and decreasing bone formation. In addition, activation of STING inhibits the generation of type H vessels with the capacity to osteogenesis, thereby inhibiting bone formation. Here, we outline the mechanism of action of STING and its downstream in osteoporosis and discuss the role of targeting STING in the treatment of osteoporosis, thus providing new ideas for the treatment of osteoporosis.
Collapse
Affiliation(s)
- Zhonghua Gao
- Department of Geriatrics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Zhongguo Gao
- Department of Medical Laboratory Technology, School of Biomedical Engineering, Hubei University of Medicine, Shiyan, Hubei, China
| | - Hao Zhang
- Department of Geriatrics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shoubo Hou
- Department of General Practice, General Hospital of Central Theater Command, Wuhan, Hubei, China
| | - Yunhua Zhou
- Department of Wound Repair Surgery, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Yunhua Zhou, ; Xiangjie Liu,
| | - Xiangjie Liu
- Department of Geriatrics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China,*Correspondence: Yunhua Zhou, ; Xiangjie Liu,
| |
Collapse
|
|
23
|
Zhang X, Ji L, Li MO. Control of tumor-associated macrophage responses by nutrient acquisition and metabolism. Immunity 2023; 56:14-31. [PMID: 36630912 PMCID: PMC9839308 DOI: 10.1016/j.immuni.2022.12.003] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/29/2022] [Accepted: 12/06/2022] [Indexed: 01/11/2023]
Abstract
Metazoan tissue specification is associated with integration of macrophage lineage cells in sub-tissular niches to promote tissue development and homeostasis. Oncogenic transformation, most prevalently of epithelial cell lineages, results in maladaptation of resident tissue macrophage differentiation pathways to generate parenchymal and interstitial tumor-associated macrophages that largely foster cancer progression. In addition to growth factors, nutrients that can be consumed, stored, recycled, or converted to signaling molecules have emerged as crucial regulators of macrophage responses in tumor. Here, we review how nutrient acquisition through plasma membrane transporters and engulfment pathways control tumor-associated macrophage differentiation and function. We also discuss how nutrient metabolism regulates tumor-associated macrophages and how these processes may be targeted for cancer therapy.
Collapse
Affiliation(s)
- Xian Zhang
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Liangliang Ji
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ming O Li
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA.
| |
Collapse
|
|
24
|
Yang Y, Luo S, Peng X, Zhao T, He Q, Wu M, Zhang W, Gong T, Zhang Z. An intra-articular injectable phospholipids-based gel for the treatment of rheumatoid arthritis. Asian J Pharm Sci 2023; 18:100777. [PMID: 36818955 PMCID: PMC9932361 DOI: 10.1016/j.ajps.2023.100777] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2022] [Revised: 11/28/2022] [Accepted: 01/10/2023] [Indexed: 01/19/2023] Open
Abstract
Rheumatoid arthritis (RA) is a chronic inflammatory and destructive arthropathy with a high deformity rate. Despite numerous studies and clinical trials, no curative treatment is available for large weight-bearing joints. Intra-articular (IA) injections could deliver high concentrations of drug to the afflicted joint and improve the drug efficacy while reducing systemic toxicity. However, free drugs are rapidly cleared from synovial fluid and do not significantly halt the progression of joint disease. Herein, a phospholipids-based controlled-release gel was prepared for sustained IA delivery of celastrol (CEL) and the therapeutic efficiency was evaluated in a rheumatoid arthritis rabbit model. The CEL-loaded gel (CEL-gel) contained up to 70% phospholipids yet was easy to inject. After injecting into the joint cavity, CEL-gel achieved sol to gel phase transition without special stimuli and gelling agent. In vitro release and in vivo pharmacokinetic studies evidenced the stable and sustained release action of CEL-gel. A single IA injection of CEL-gel could maintain therapeutic efficiency for about 25 d and showed much better anti-arthritic efficacy compared to repeated injections of free drug solution (CEL-sol). Furthermore, the IA injection of CEL-gel greatly reduced the systemic toxicity of CEL. With good biocompatibility and biodegradability, CEL-gel might be a promising IA drug delivery system.
Collapse
Affiliation(s)
- Yuping Yang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Shiqin Luo
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Xiong Peng
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Ting Zhao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Qin He
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China,Department of Pharmacy, West China Hospital Sichuan University Jintang Hospital, Chengdu, 610000, China
| | - Mengying Wu
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Wei Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| | - Tao Gong
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China,Corresponding author.
| | - Zhirong Zhang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610064, China
| |
Collapse
|
|
25
|
Aditi, McKinnon PJ. Genome integrity and inflammation in the nervous system. DNA Repair (Amst) 2022; 119:103406. [PMID: 36148701 PMCID: PMC9844216 DOI: 10.1016/j.dnarep.2022.103406] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 09/10/2022] [Accepted: 09/12/2022] [Indexed: 01/19/2023]
Abstract
Preservation of genomic integrity is crucial for nervous system development and function. DNA repair deficiency results in several human diseases that are characterized by both neurodegeneration and neuroinflammation. Recent research has highlighted a role for compromised genomic integrity as a key factor driving neuropathology and triggering innate immune signaling to cause inflammation. Here we review the mechanisms by which DNA damage engages innate immune signaling and how this may promote neurological disease. We also consider the contributions of different neural cell types towards DNA damage-driven neuroinflammation. A deeper knowledge of genome maintenance mechanisms that prevent aberrant immune activation in neural cells will guide future therapies to ameliorate neurological disease.
Collapse
Affiliation(s)
- Aditi
- Center for Pediatric Neurological Disease Research, St. Jude Pediatric Translational Neuroscience Initiative, Dept. Cell & Mol. Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Peter J McKinnon
- Center for Pediatric Neurological Disease Research, St. Jude Pediatric Translational Neuroscience Initiative, Dept. Cell & Mol. Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
| |
Collapse
|
|
26
|
Saas P, Vetter M, Maraux M, Bonnefoy F, Perruche S. Resolution therapy: Harnessing efferocytic macrophages to trigger the resolution of inflammation. Front Immunol 2022; 13:1021413. [PMID: 36389733 PMCID: PMC9651061 DOI: 10.3389/fimmu.2022.1021413] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Accepted: 10/12/2022] [Indexed: 09/03/2023] Open
Abstract
Several chronic inflammatory diseases are associated with non-resolving inflammation. Conventional anti-inflammatory drugs fail to completely cure these diseases. Resolution pharmacology is a new therapeutic approach based on the use of pro-resolving mediators that accelerate the resolution phase of inflammation by targeting the productive phase of inflammation. Indeed, pro-resolving mediators prevent leukocyte recruitment and induce apoptosis of accumulated leukocytes. This approach is now called resolution therapy with the introduction of complex biological drugs and cell-based therapies. The main objective of resolution therapy is to specifically reduce the duration of the resolution phase to accelerate the return to homeostasis. Under physiological conditions, macrophages play a critical role in the resolution of inflammation. Indeed, after the removal of apoptotic cells (a process called efferocytosis), macrophages display anti-inflammatory reprogramming and subsequently secrete multiple pro-resolving factors. These factors can be used as resolution therapy. Here, we review the different mechanisms leading to anti-inflammatory reprogramming of macrophages after efferocytosis and the pro-resolving factors released by these efferocytic macrophages. We classify these mechanisms in three different categories: macrophage reprogramming induced by apoptotic cell-derived factors, by molecules expressed by apoptotic cells (i.e., "eat-me" signals), and induced by the digestion of apoptotic cell-derived materials. We also evoke that macrophage reprogramming may result from cooperative mechanisms, for instance, implicating the apoptotic cell-induced microenvironment (including cellular metabolites, specific cytokines or immune cells). Then, we describe a new drug candidate belonging to this resolution therapy. This candidate, called SuperMApo, corresponds to the secretome of efferocytic macrophages. We discuss its production, the pro-resolving factors present in this drug, as well as the results obtained in experimental models of chronic (e.g., arthritis, colitis) and acute (e.g., peritonitis or xenogeneic graft-versus-host disease) inflammatory diseases.
Collapse
Affiliation(s)
- Philippe Saas
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, LabEx LipSTIC, Besançon, France
| | - Mathieu Vetter
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, LabEx LipSTIC, Besançon, France
| | - Melissa Maraux
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, LabEx LipSTIC, Besançon, France
| | - Francis Bonnefoy
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, LabEx LipSTIC, Besançon, France
- MED’INN’Pharma, Besançon, France
| | - Sylvain Perruche
- University Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, RIGHT, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, LabEx LipSTIC, Besançon, France
- MED’INN’Pharma, Besançon, France
| |
Collapse
|
|
27
|
MacLauchlan S, Fitzgerald KA, Gravallese EM. Intracellular Sensing of DNA in Autoinflammation and Autoimmunity. Arthritis Rheumatol 2022; 74:1615-1624. [PMID: 35656967 PMCID: PMC9529773 DOI: 10.1002/art.42256] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 03/25/2022] [Accepted: 05/27/2022] [Indexed: 11/10/2022]
Abstract
Evidence has shown that DNA is a pathogen-associated molecular pattern, posing a unique challenge in the discrimination between endogenous and foreign DNA. This challenge is highlighted by certain autoinflammatory diseases that arise from monogenic mutations and result in periodic flares of inflammation, typically in the absence of autoantibodies or antigen-specific T lymphocytes. Several autoinflammatory diseases arise due to mutations in genes that normally prevent the accrual of endogenous DNA or are due to mutations that cause activation of intracellular DNA-sensing pathway components. Evidence from genetically modified murine models further support an ability of endogenous DNA and DNA sensing to drive disease pathogenesis, prompting the question of whether endogenous DNA can also induce inflammation in human autoimmune diseases. In this review, we discuss the current understanding of intracellular DNA sensing and downstream signaling pathways as they pertain to autoinflammatory disease, including the development of monogenic disorders such as Stimulator of interferon genes-associated vasculopathy with onset in infancy and Aicardi-Goutières syndrome. In addition, we discuss systemic rheumatic diseases, including certain forms of systemic lupus erythematosus, familial chilblain lupus, and other diseases with established links to intracellular DNA-sensing pathways, and highlight the lessons learned from these examples as they apply to the development of therapies targeting these pathways.
Collapse
Affiliation(s)
- Susan MacLauchlan
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| | - Katherine A. Fitzgerald
- Program in Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School
| | - Ellen M. Gravallese
- Division of Rheumatology, Inflammation, and Immunity, Department of Medicine, Brigham and Women’s Hospital, Boston, MA
| |
Collapse
|
|
28
|
Zhong B, Shu HB. MITA/STING-mediated antiviral immunity and autoimmunity: the evolution, mechanism, and intervention. Curr Opin Immunol 2022; 78:102248. [PMID: 36193584 DOI: 10.1016/j.coi.2022.102248] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 08/27/2022] [Indexed: 01/29/2023]
Abstract
Mediator of IRF3 activation (MITA, also known as stimulator of interferon genes (STING) and endoplasmic reticulum interferon stimulator (ERIS)) is an ER-associated protein that senses cellular and bacterium-derived cyclic dinucleotide (CDN), leading to induction of type-I interferons (IFNs) and innate immune responses against viruses and bacteria. Recently, it has become clear that sensing of CDN and induction of autophagy are two evolutionarily conserved functions of MITA, predating its role in mediating type-I IFN induction. Studies have shown that MITA-mediated signaling promotes a number of autoimmune disorders caused by gene mutations in human. Here, we summarize the most recent progress on MITA-mediated signaling in a view of evolution and highlight the roles of MITA in human inflammatory disorders caused by gene mutations and in genetically modified mouse models. We also briefly introduce the chemicals targeting MITA and discuss their potential in treatment of MITA-mediated inflammatory diseases. Finally, we propose several key questions that should be addressed for targeting MITA for treatment of related autoimmune diseases.
Collapse
Affiliation(s)
- Bo Zhong
- Department of Gastrointestinal Surgery, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Research Unit of Innate Immune and Inflammatory Diseases, Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430071, China.
| | - Hong-Bing Shu
- Department of Infectious Diseases, Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Research Unit of Innate Immune and Inflammatory Diseases, Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan 430071, China.
| |
Collapse
|
|
29
|
Singh B, Li K, Cui K, Peng Q, Cowan DB, Wang DZ, Chen K, Chen H. Defective efferocytosis of vascular cells in heart disease. Front Cardiovasc Med 2022; 9:1031293. [PMID: 36247464 PMCID: PMC9561431 DOI: 10.3389/fcvm.2022.1031293] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Accepted: 09/13/2022] [Indexed: 11/13/2022] Open
Abstract
The efficient phagocytic clearance of dying cells and apoptotic cells is one of the processes that is essential for the maintenance of physiologic tissue function and homeostasis, which is termed "efferocytosis." Under normal conditions, "find me" and "eat me" signals are released by apoptotic cells to stimulate the engulfment and efferocytosis of apoptotic cells. In contrast, abnormal efferocytosis is related to chronic and non-resolving inflammatory diseases such as atherosclerosis. In the initial steps of atherosclerotic lesion development, monocyte-derived macrophages display efficient efferocytosis that restricts plaque progression; however, this capacity is reduced in more advanced lesions. Macrophage reprogramming as a result of the accumulation of apoptotic cells and augmented inflammation accounts for this diminishment of efferocytosis. Furthermore, defective efferocytosis plays an important role in necrotic core formation, which triggers plaque rupture and acute thrombotic cardiovascular events. Recent publications have focused on the essential role of macrophage efferocytosis in cardiac pathophysiology and have pointed toward new therapeutic strategies to modulate macrophage efferocytosis for cardiac tissue repair. In this review, we discuss the molecular and cellular mechanisms that regulate efferocytosis in vascular cells, including macrophages and other phagocytic cells and detail how efferocytosis-related molecules contribute to the maintenance of vascular hemostasis and how defective efferocytosis leads to the formation and progression of atherosclerotic plaques.
Collapse
Affiliation(s)
- Bandana Singh
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Kathryn Li
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Kui Cui
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Qianman Peng
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Douglas B. Cowan
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| | - Da-Zhi Wang
- Center for Regenerative Medicine, University of South Florida Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States
| | - Kaifu Chen
- Basic and Translational Research Division, Department of Cardiology, Boston Children's Hospital, Boston, MA, United States
| | - Hong Chen
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, United States
| |
Collapse
|
|
30
|
Abstract
As brutally demonstrated by the COVID-19 pandemic, an effective immune system is essential for survival. Developed over evolutionary time, viral nucleic acid detection is a central pillar in the defensive armamentarium used to combat foreign microbial invasion. To ensure cellular homeostasis, such a strategy necessitates the efficient discrimination of pathogen-derived DNA and RNA from that of the host. In 2011, it was suggested that an upregulation of type I interferon signalling might serve as a defining feature of a novel set of Mendelian inborn errors of immunity, where antiviral sensors are triggered by host nucleic acids due to a failure of self versus non-self discrimination. These rare disorders have played a surprisingly significant role in informing our understanding of innate immunity and the relevance of type I interferon signalling for human health and disease. Here we consider what we have learned in this time, and how the field may develop in the future.
Collapse
Affiliation(s)
- Yanick J Crow
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK.
- Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Université de Paris, Paris, France.
| | - Daniel B Stetson
- Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA
| |
Collapse
|
|
31
|
Lou H, Ling GS, Cao X. Autoantibodies in systemic lupus erythematosus: From immunopathology to therapeutic target. J Autoimmun 2022; 132:102861. [PMID: 35872103 DOI: 10.1016/j.jaut.2022.102861] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Accepted: 06/26/2022] [Indexed: 11/26/2022]
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple organ inflammatory damage and wide spectrum of autoantibodies. The autoantibodies, especially anti-dsDNA and anti-Sm autoantibodies are highly specific to SLE, and participate in the immune complex formation and inflammatory damage on multiple end-organs such as kidney, skin, and central nervous system (CNS). However, the underlying mechanisms of autoantibody-induced tissue damage and systemic inflammation are still not fully understood. Single cell analysis of autoreactive B cells and monoclonal antibody screening from patients with active SLE has improved our understanding on the origin of autoreactive B cells and the antigen targets of the pathogenic autoantibodies. B cell depletion therapies have been widely studied in the clinics, but the development of more specific therapies against the pathogenic B cell subset and autoantibodies with improved efficacy and safety still remain a big challenge. A more comprehensive autoantibody profiling combined with functional characterization of autoantibodies in diseases development will shed new insights on the etiology and pathogenesis of SLE and guide a specific treatment to individual SLE patients.
Collapse
Affiliation(s)
- Hantao Lou
- Ludwig Institute of Cancer Research, University of Oxford, Oxford, OX3 7DR, UK; Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK.
| | - Guang Sheng Ling
- School of Biomedical Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xuetao Cao
- Chinese Academy for Medical Sciences Oxford Institute, Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK; Nankai-Oxford International Advanced Institute, College of Life Sciences, Nankai University, Tianjin, 300071, China.
| |
Collapse
|
|
32
|
Mosallanejad K, Kagan JC. Control of innate immunity by the cGAS-STING pathway. Immunol Cell Biol 2022; 100:409-423. [PMID: 35485309 PMCID: PMC9250635 DOI: 10.1111/imcb.12555] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/05/2022] [Accepted: 04/26/2022] [Indexed: 11/30/2022]
Abstract
Within the cytoplasm of mammalian cells is a protein called cyclic GMP-AMP synthase (cGAS), which acts to defend against infection and other threats to the host. cGAS operates in this manner through its ability to detect a molecular occurrence that should not exist in healthy cells - the existence of DNA in the cytosol. Upon DNA binding, cGAS synthesizes cyclic GMP-AMP (cGAMP), a cyclic dinucleotide that activates the endoplasmic reticulum-localized protein stimulator of interferon genes (STING). STING-mediated signaling culminates in host defensive responses typified by inflammatory cytokine and interferon expression, and the induction of autophagy. Studies over the past several years have established a consensus in the field of the enzymatic activities of cGAS in vitro, as it relates to DNA-induced production of cGAMP. However, much additional work is needed to understand the regulation of cGAS functions within cells, where multiple sources of DNA can create a problem of self and non-self discrimination. In this review, we provide an overview of how the cGAS-STING pathway mediates innate immune responses during infection and other cellular stresses. We then highlight recent progress in the understanding of the increasingly diverse ways in which this DNA-sensing machinery is regulated inside cells, including how cGAS remains inactive to host-derived DNA under conditions of homeostasis.
Collapse
Affiliation(s)
- Kenta Mosallanejad
- Harvard Medical School and Division of Gastroenterology, Boston Children’s Hospital Boston, MA 02115, USA
| | - Jonathan C Kagan
- Harvard Medical School and Division of Gastroenterology, Boston Children’s Hospital Boston, MA 02115, USA
| |
Collapse
|
|
33
|
Abstract
Inflammation plays indispensable roles in building the immune responses such as acquired immunity against harmful pathogens. Furthermore, it is essential for maintaining biological homeostasis in ever-changing conditions. Pattern-recognition receptors (PRRs) reside in cell membranes, endosomes or cytoplasm, and function as triggers for inflammatory responses. Binding of pathogen- or self-derived components, such as DNA, to PRRs activates downstream signaling cascades, resulting in the production of a series of pro-inflammatory cytokines and type I interferons (IFNs). While these series of responses are essential for host defense, the unexpected release of DNA from the nucleus or mitochondria of host cells can lead to autoimmune and autoinflammatory diseases. In this review, we focus on DNA-sensing mechanisms via PRRs and the disorders and extraordinary conditions caused by self-derived DNA.
Collapse
Affiliation(s)
- Daisuke Ori
- Division of Biological Science, Graduate School of Science and Technology, Laboratory of Molecular Immunobiology, Nara Institute of Science and Technology (NAIST), Ikoma, Japan
| | - Taro Kawai
- Division of Biological Science, Graduate School of Science and Technology, Laboratory of Molecular Immunobiology, Nara Institute of Science and Technology (NAIST), Ikoma, Japan
| |
Collapse
|
|
34
|
Zhang W, Chen Y, Liu Q, Zhou M, Wang K, Wang Y, Nie J, Gui S, Peng D, He Z, Li Z. Emerging nanotherapeutics alleviating rheumatoid arthritis by readjusting the seeds and soils. J Control Release 2022; 345:851-879. [DOI: 10.1016/j.jconrel.2022.04.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Revised: 03/31/2022] [Accepted: 04/02/2022] [Indexed: 12/12/2022]
|
|
35
|
Li T, Yum S, Li M, Chen X, Zuo X, Chen ZJ. TBK1 recruitment to STING mediates autoinflammatory arthritis caused by defective DNA clearance. J Exp Med 2022; 219:e20211539. [PMID: 34901991 PMCID: PMC8672646 DOI: 10.1084/jem.20211539] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 10/28/2021] [Accepted: 11/17/2021] [Indexed: 01/02/2023] Open
Abstract
Defective DNA clearance in DNase II-/- mice leads to lethal inflammatory diseases that can be rescued by deleting cGAS or STING, but the role of distinct signaling pathways downstream of STING in the disease manifestation is not known. We found that the STING S365A mutation, which abrogates IRF3 binding and type I interferon induction, rescued the embryonic lethality of DNase II-/- mice. However, the STING S365A mutant retains the ability to recruit TBK1 and activate NF-κB, and DNase II-/-STING-S365A mice exhibited severe polyarthritis, which was alleviated by neutralizing antibodies against TNF-α or IL-6 receptor. In contrast, the STING L373A mutation or C-terminal tail truncation, which disrupts TBK1 binding and therefore prevents activation of both IRF3 and NF-κB, completely rescued the phenotypes of DNase II-/- mice. These results demonstrate that TBK1 recruitment to STING mediates autoinflammatory arthritis independently of type I interferons. Inhibiting TBK1 binding to STING may be a therapeutic strategy for certain autoinflammatory diseases instigated by self-DNA.
Collapse
Affiliation(s)
- Tong Li
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX
- Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Seoyun Yum
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX
- Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX
| | - Minghao Li
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX
- Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX
| | - Xiang Chen
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX
- Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX
- Howard Hughes Medical Institute, Chevy Chase, MD
| | - Xiaoxia Zuo
- Department of Rheumatology and Immunology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Zhijian J. Chen
- Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX
- Center for Inflammation Research, University of Texas Southwestern Medical Center, Dallas, TX
- Howard Hughes Medical Institute, Chevy Chase, MD
| |
Collapse
|
|
36
|
Wan J, Yuan L, Jing H, Zheng Q, Xiao H. Defective apoptotic cell clearance activates innate immune response to protect Caenorhabditis elegans against pathogenic bacteria. Virulence 2021; 12:75-83. [PMID: 33372828 PMCID: PMC7781629 DOI: 10.1080/21505594.2020.1857982] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 11/01/2020] [Accepted: 11/21/2020] [Indexed: 12/25/2022] Open
Abstract
Appropriate clearance of dead cells generated by apoptosis is critical to the development of multicellular organisms and tissue homeostasis. In mammals, the removal of apoptotic cell is mediated by polarized monocyte/macrophage populations of the innate immune system. The innate immune system is essential for anti-viral and anti-microbial defense. However, our current understanding of the relationship between apoptotic cell clearance and the innate immune response has remained rather limited. Here, we study how apoptotic cell clearance programs contribute to the innate immune response in C. elegans. We find apoptotic cell clearance mutant worms are more resistant to pathogenic bacteria of Pseudomonas aeruginosa PA14 and Salmonella typhimurium SL1344 due to significant upregulation of innate immune-dependent pathogen response genes. In addition, genetic epistasis analysis indicates that defects in apoptotic cell clearance can activate the innate immune response through PMK-1 p38 MAPK and MPK-1/ERK MAPK pathways in C. elegans. Taken together, our results provide evidence that insufficient clearance of apoptotic cell can protect Caenorhabditis elegans from bacterial infection through innate immune response activation.
Collapse
Affiliation(s)
- Jinlong Wan
- Key Laboratory of the Ministry of Education for Medicinal Plant Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in the Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
| | - Lei Yuan
- Key Laboratory of the Ministry of Education for Medicinal Plant Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in the Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
| | - Huiru Jing
- Key Laboratory of the Ministry of Education for Medicinal Plant Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in the Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
| | - Qian Zheng
- Key Laboratory of the Ministry of Education for Medicinal Plant Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in the Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
| | - Hui Xiao
- Key Laboratory of the Ministry of Education for Medicinal Plant Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in the Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi’an, China
| |
Collapse
|
|
37
|
DNA Repair Inhibition Leads to Active Export of Repetitive Sequences to the Cytoplasm Triggering an Inflammatory Response. J Neurosci 2021; 41:9286-9307. [PMID: 34593604 DOI: 10.1523/jneurosci.0845-21.2021] [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: 04/18/2021] [Revised: 07/25/2021] [Accepted: 09/01/2021] [Indexed: 01/02/2023] Open
Abstract
Adult-onset neurodegenerative diseases are often accompanied by evidence of a chronic inflammation that includes activation of microglial cells and altered levels of brain cytokines. Aspects of this response are likely secondary reactions to neurodegeneration, but for many illnesses the inflammation may itself be an early and even causative disease event. In such cases, the inflammation is referred to as "sterile" as it occurs in the absence of an actual bacterial or viral pathogen. A potent trigger of sterile inflammation in CNS microglia has been shown to be the presence of DNA in the cytoplasm (cytoDNA) induced either by direct DNA damage or by inhibited DNA repair. We have shown that cytoDNA comes from the cell nucleus as a result of insufficient DNA damage repair. Using wild-type and Atm -/- mouse microglia, we extend these observations here by showing that its genomic origins are not random, but rather are heavily biased toward transcriptionally inactive, intergenic regions, in particular repetitive elements and AT-rich sequences. Once released from the genome, in both males and females, we show that cytoDNA is actively exported to the cytoplasm by a CRM1-dependent mechanism. In the cytoplasm, it is degraded either by a cytosolic exonuclease, Trex1, or an autophagy pathway that ends with degradation in the lysosome. Blocking the accumulation of cytoDNA prevents the emergence of the sterile inflammation reaction. These findings offer new insights into the emergence of sterile inflammation and offer novel approaches that may be of use in combatting a wide range of neurodegenerative conditions.SIGNIFICANCE STATEMENT Sterile inflammation describes a state where the defenses of the immune system are activated in the absence of a true pathogen. A potent trigger of this unorthodox response is the presence of DNA in the cytoplasm, which immune cells interpret as an invading virus or pathogen. We show that when DNA damage increases, fragments of the cell's own genome are actively exported to the cytoplasm where they are normally degraded. If this degradation is incomplete an immune reaction is triggered. Both age and stress increase DNA damage, and as age-related neurodegenerative diseases are frequently accompanied by a chronic low-level inflammation, strategies that reduce the induction of cytoplasmic DNA or speed its clearance become attractive therapeutic targets.
Collapse
|
|
38
|
Zubair K, You C, Kwon G, Kang K. Two Faces of Macrophages: Training and Tolerance. Biomedicines 2021; 9:biomedicines9111596. [PMID: 34829825 PMCID: PMC8615871 DOI: 10.3390/biomedicines9111596] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/25/2021] [Accepted: 10/29/2021] [Indexed: 01/16/2023] Open
Abstract
Macrophages are present in almost all body tissues. They detect and quickly respond to “environmental signals” in the tissue. Macrophages have been associated with numerous beneficial roles, such as host defense, wound healing, and tissue regeneration; however, they have also been linked to the development of diverse illnesses, particularly cancers and autoimmune disorders. Complex signaling, epigenetic, and metabolic pathways drive macrophage training and tolerance. The induced intracellular program differs depending on the type of initial stimuli and the tissue microenvironment. Due to the essential roles of macrophages in homeostatic and their association with the pathogenesis of inflammatory diseases, recent studies have investigated the molecular mechanisms of macrophage training and tolerance. This review discusses the role of factors involved in macrophage training and tolerance, along with the current studies in human diseases.
Collapse
|
|
39
|
Zhu H, Zhao M, Chang C, Chan V, Lu Q, Wu H. The complex role of AIM2 in autoimmune diseases and cancers. Immun Inflamm Dis 2021; 9:649-665. [PMID: 34014039 PMCID: PMC8342223 DOI: 10.1002/iid3.443] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Accepted: 04/09/2021] [Indexed: 12/13/2022] Open
Abstract
Absent in melanoma 2 (AIM2) is a novel member of interferon (IFN)-inducible PYHIN proteins. In innate immune cells, AIM2 servers as a cytoplasmic double-stranded DNA sensor, playing a crucial role in the initiation of the innate immune response as a component of the inflammasome. AIM2 expression is increased in patients with systemic lupus erythematosus (SLE), psoriasis, and primary Sjogren's syndrome, indicating that AIM2 might be involved in the pathogenesis of autoimmune diseases. Meanwhile, AIM2 also plays an antitumorigenesis role in an inflammasome independent-manner. In melanoma, AIM2 is initially identified as a tumor suppressor factor. However, AIM2 is also found to contribute to lung tumorigenesis via the inflammasome-dependent release of interleukin 1β and regulation of mitochondrial dynamics. Additionally, AIM2 reciprocally dampening the cGAS-STING pathway causes immunosuppression of macrophages and evasion of antitumor immunity during antibody treatment. To summarize the complicated effect and role of AIM2 in autoimmune diseases and cancers, herein, we provide an overview of the emerging research progress on the function and regulatory pathway of AIM2 in innate and adaptive immune cells, as well as tumor cells, and discuss its pathogenic role in autoimmune diseases, such as SLE, psoriasis, primary Sjogren's syndrome, and cancers, such as melanomas, non-small-cell lung cancer, colon cancer, hepatocellular carcinoma, renal carcinoma, and so on, hopefully providing potential therapeutic and diagnostic strategies for clinical use.
Collapse
Affiliation(s)
- Huan Zhu
- Department of Dermatology, Hunan Key Laboratory of Medical EpigenomicsThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Ming Zhao
- Department of Dermatology, Hunan Key Laboratory of Medical EpigenomicsThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Christopher Chang
- Division of Rheumatology, Allergy and Clinical ImmunologyUniversity of California at Davis School of MedicineDavisCaliforniaUSA
| | - Vera Chan
- Division of Rheumatology and Clinical Immunology, Department of MedicineThe University of Hong KongHong KongChina
| | - Qianjin Lu
- Department of Dermatology, Hunan Key Laboratory of Medical EpigenomicsThe Second Xiangya Hospital of Central South UniversityChangshaChina
- Institute of DermatologyChinese Academy of Medical Sciences and Peking Union Medical CollegeNanjingChina
| | - Haijing Wu
- Department of Dermatology, Hunan Key Laboratory of Medical EpigenomicsThe Second Xiangya Hospital of Central South UniversityChangshaChina
| |
Collapse
|
|
40
|
Akhmetova K, Balasov M, Chesnokov I. Drosophila STING protein has a role in lipid metabolism. eLife 2021; 10:e67358. [PMID: 34467853 PMCID: PMC8443252 DOI: 10.7554/elife.67358] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 08/31/2021] [Indexed: 12/27/2022] Open
Abstract
Stimulator of interferon genes (STING) plays an important role in innate immunity by controlling type I interferon response against invaded pathogens. In this work, we describe a previously unknown role of STING in lipid metabolism in Drosophila. Flies with STING deletion are sensitive to starvation and oxidative stress, have reduced lipid storage, and downregulated expression of lipid metabolism genes. We found that Drosophila STING interacts with lipid synthesizing enzymes acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN). ACC and FASN also interact with each other, indicating that all three proteins may be components of a large multi-enzyme complex. The deletion of Drosophila STING leads to disturbed ACC localization and decreased FASN enzyme activity. Together, our results demonstrate a previously undescribed role of STING in lipid metabolism in Drosophila.
Collapse
Affiliation(s)
- Katarina Akhmetova
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, School of MedicineBirminghamUnited States
| | - Maxim Balasov
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, School of MedicineBirminghamUnited States
| | - Igor Chesnokov
- Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, School of MedicineBirminghamUnited States
| |
Collapse
|
|
41
|
Hashimoto T, Yoshida K, Hashiramoto A, Matsui K. Cell-Free DNA in Rheumatoid Arthritis. Int J Mol Sci 2021; 22:8941. [PMID: 34445645 PMCID: PMC8396202 DOI: 10.3390/ijms22168941] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 08/14/2021] [Accepted: 08/16/2021] [Indexed: 02/07/2023] Open
Abstract
Endogenous DNA derived from the nuclei or mitochondria is released into the bloodstream following cell damage or death. Extracellular DNA, called cell-free DNA (cfDNA), is associated with various pathological conditions. Recently, multiple aspects of cfDNA have been assessed, including cfDNA levels, integrity, methylation, and mutations. Rheumatoid arthritis (RA) is the most common form of autoimmune arthritis, and treatment of RA has highly varied outcomes. cfDNA in patients with RA is elevated in peripheral blood and synovial fluid and is associated with disease activity. Profiling of cfDNA in patients with RA may then be utilized in various aspects of clinical practice, such as the prediction of prognosis and treatment responses; monitoring disease state; and as a diagnostic marker. In this review, we discuss cfDNA in patients with RA, particularly the sources of cfDNA and the correlation of cfDNA with RA pathogenesis. We also highlight the potential of analyzing cfDNA profiles to guide individualized treatment approaches for RA.
Collapse
Affiliation(s)
- Teppei Hashimoto
- Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 6638501, Japan;
| | - Kohsuke Yoshida
- Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe 6540142, Japan; (K.Y.); (A.H.)
| | - Akira Hashiramoto
- Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe 6540142, Japan; (K.Y.); (A.H.)
| | - Kiyoshi Matsui
- Division of Diabetes, Endocrinology and Clinical Immunology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya 6638501, Japan;
| |
Collapse
|
|
42
|
Lukácsi S, Farkas Z, Saskői É, Bajtay Z, Takács-Vellai K. Conserved and Distinct Elements of Phagocytosis in Human and C. elegans. Int J Mol Sci 2021; 22:ijms22168934. [PMID: 34445642 PMCID: PMC8396242 DOI: 10.3390/ijms22168934] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/12/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
Endocytosis provides the cellular nutrition and homeostasis of organisms, but pathogens often take advantage of this entry point to infect host cells. This is counteracted by phagocytosis that plays a key role in the protection against invading microbes both during the initial engulfment of pathogens and in the clearance of infected cells. Phagocytic cells balance two vital functions: preventing the accumulation of cell corpses to avoid pathological inflammation and autoimmunity, whilst maintaining host defence. In this review, we compare elements of phagocytosis in mammals and the nematode Caenorhabditis elegans. Initial recognition of infection requires different mechanisms. In mammals, pattern recognition receptors bind pathogens directly, whereas activation of the innate immune response in the nematode rather relies on the detection of cellular damage. In contrast, molecules involved in efferocytosis—the engulfment and elimination of dying cells and cell debris—are highly conserved between the two species. Therefore, C. elegans is a powerful model to research mechanisms of the phagocytic machinery. Finally, we show that both mammalian and worm studies help to understand how the two phagocytic functions are interconnected: emerging data suggest the activation of innate immunity as a consequence of defective apoptotic cell clearance.
Collapse
Affiliation(s)
- Szilvia Lukácsi
- MTA-ELTE Immunology Research Group, Eötvös Loránd Research Network (ELKH), Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary; (S.L.); (Z.B.)
| | - Zsolt Farkas
- Department of Biological Anthropology, Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary; (Z.F.); (É.S.)
| | - Éva Saskői
- Department of Biological Anthropology, Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary; (Z.F.); (É.S.)
| | - Zsuzsa Bajtay
- MTA-ELTE Immunology Research Group, Eötvös Loránd Research Network (ELKH), Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary; (S.L.); (Z.B.)
- Department of Immunology, Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary
| | - Krisztina Takács-Vellai
- Department of Biological Anthropology, Eötvös Loránd University, Pázmány Péter s. 1/C, 1117 Budapest, Hungary; (Z.F.); (É.S.)
- Correspondence:
| |
Collapse
|
|
43
|
Lind NA, Rael VE, Pestal K, Liu B, Barton GM. Regulation of the nucleic acid-sensing Toll-like receptors. Nat Rev Immunol 2021; 22:224-235. [PMID: 34272507 PMCID: PMC8283745 DOI: 10.1038/s41577-021-00577-0] [Citation(s) in RCA: 186] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2021] [Indexed: 02/08/2023]
Abstract
Many of the ligands for Toll-like receptors (TLRs) are unique to microorganisms, such that receptor activation unequivocally indicates the presence of something foreign. However, a subset of TLRs recognizes nucleic acids, which are present in both the host and foreign microorganisms. This specificity enables broad recognition by virtue of the ubiquity of nucleic acids but also introduces the possibility of self-recognition and autoinflammatory or autoimmune disease. Defining the regulatory mechanisms required to ensure proper discrimination between foreign and self-nucleic acids by TLRs is an area of intense research. Progress over the past decade has revealed a complex array of regulatory mechanisms that ensure maintenance of this delicate balance. These regulatory mechanisms can be divided into a conceptual framework with four categories: compartmentalization, ligand availability, receptor expression and signal transduction. In this Review, we discuss our current understanding of each of these layers of regulation. Activation of nucleic acid-sensing Toll-like receptors is finely tuned to limit self-reactivity while maintaining recognition of foreign microorganisms. The authors describe recent progress made in defining the regulatory mechanisms that facilitate this delicate balance.
Collapse
Affiliation(s)
- Nicholas A Lind
- Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Victoria E Rael
- Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Kathleen Pestal
- Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA
| | - Bo Liu
- Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.,CAS Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
| | - Gregory M Barton
- Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA, USA.
| |
Collapse
|
|
44
|
Activation of Endogenous Retrovirus, Brain Infections and Environmental Insults in Neurodegeneration and Alzheimer's Disease. Int J Mol Sci 2021; 22:ijms22147263. [PMID: 34298881 PMCID: PMC8303979 DOI: 10.3390/ijms22147263] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Revised: 06/29/2021] [Accepted: 07/03/2021] [Indexed: 12/18/2022] Open
Abstract
Chronic neurodegenerative diseases are complex, and their pathogenesis is uncertain. Alzheimer’s disease (AD) is a neurodegenerative brain alteration that is responsible for most dementia cases in the elderly. AD etiology is still uncertain; however, chronic neuroinflammation is a constant component of brain pathology. Infections have been associated with several neurological diseases and viruses of the Herpes family appear to be a probable cause of AD neurodegenerative alterations. Several different factors may contribute to the AD clinical progression. Exogeneous viruses or other microbes and environmental pollutants may directly induce neurodegeneration by activating brain inflammation. In this paper, we suggest that exogeneous brain insults may also activate retrotransposons and silent human endogenous retroviruses (HERVs). The initial inflammation of small brain areas induced by virus infections or other brain insults may activate HERV dis-regulation that contributes to neurodegenerative mechanisms. Chronic HERV activation in turn may cause progressive neurodegeneration that thereafter merges in cognitive impairment and dementia in genetically susceptible people. Specific treatment for exogenous end endogenous pathogens and decreasing pollutant exposure may show beneficial effect in early intervention protocol to prevent the progression of cognitive deterioration in the elderly.
Collapse
|
|
45
|
Nakayama E, Kato F, Tajima S, Ogawa S, Yan K, Takahashi K, Sato Y, Suzuki T, Kawai Y, Inagaki T, Taniguchi S, Le TT, Tang B, Prow NA, Uda A, Maeki T, Lim CK, Khromykh AA, Suhrbier A, Saijo M. Neuroinvasiveness of the MR766 strain of Zika virus in IFNAR-/- mice maps to prM residues conserved amongst African genotype viruses. PLoS Pathog 2021; 17:e1009788. [PMID: 34310650 PMCID: PMC8341709 DOI: 10.1371/journal.ppat.1009788] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 08/05/2021] [Accepted: 07/07/2021] [Indexed: 12/23/2022] Open
Abstract
Zika virus (ZIKV) strains are classified into the African and Asian genotypes. The higher virulence of the African MR766 strain, which has been used extensively in ZIKV research, in adult IFNα/β receptor knockout (IFNAR-/-) mice is widely viewed as an artifact associated with mouse adaptation due to at least 146 passages in wild-type suckling mouse brains. To gain insights into the molecular determinants of MR766's virulence, a series of genes from MR766 were swapped with those from the Asian genotype PRVABC59 isolate, which is less virulent in IFNAR-/- mice. MR766 causes 100% lethal infection in IFNAR-/- mice, but when the prM gene of MR766 was replaced with that of PRVABC59, the chimera MR/PR(prM) showed 0% lethal infection. The reduced virulence was associated with reduced neuroinvasiveness, with MR766 brain titers ≈3 logs higher than those of MR/PR(prM) after subcutaneous infection, but was not significantly different in brain titers of MR766 and MR/PR(prM) after intracranial inoculation. MR/PR(prM) also showed reduced transcytosis when compared with MR766 in vitro. The high neuroinvasiveness of MR766 in IFNAR-/- mice could be linked to the 10 amino acids that differ between the prM proteins of MR766 and PRVABC59, with 5 of these changes affecting positive charge and hydrophobicity on the exposed surface of the prM protein. These 10 amino acids are highly conserved amongst African ZIKV isolates, irrespective of suckling mouse passage, arguing that the high virulence of MR766 in adult IFNAR-/- mice is not the result of mouse adaptation.
Collapse
Affiliation(s)
- Eri Nakayama
- Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Fumihiro Kato
- Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
| | - Shigeru Tajima
- Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
| | - Shinya Ogawa
- Department of Applied Biological Chemistry, School of Agriculture and Life Sciences, The University of Tokyo, Tokyo, Japan
| | - Kexin Yan
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Kenta Takahashi
- Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Yuko Sato
- Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Tadaki Suzuki
- Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Yasuhiro Kawai
- Management Department of Biosafety and Laboratory Animal, Division of Biosafety Control and Research, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takuya Inagaki
- Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
| | - Satoshi Taniguchi
- Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
| | - Thuy T. Le
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Bing Tang
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Natalie A. Prow
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- Australian Infectious Disease Research Centre, GVN Center of Excellence, The University of Queensland and QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Akihiko Uda
- Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takahiro Maeki
- Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
| | - Chang-Kweng Lim
- Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
| | - Alexander A. Khromykh
- Australian Infectious Disease Research Centre, GVN Center of Excellence, The University of Queensland and QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Andreas Suhrbier
- QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
- Australian Infectious Disease Research Centre, GVN Center of Excellence, The University of Queensland and QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Masayuki Saijo
- Department of Virology I, National Institute of Infectious Diseases, Tokyo, Japan
| |
Collapse
|
|
46
|
Fu Y, Sui B, Xiang L, Yan X, Wu D, Shi S, Hu X. Emerging understanding of apoptosis in mediating mesenchymal stem cell therapy. Cell Death Dis 2021; 12:596. [PMID: 34108448 PMCID: PMC8190192 DOI: 10.1038/s41419-021-03883-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 12/18/2022]
Abstract
Mesenchymal stem cell transplantation (MSCT) has been recognized as a potent and promising approach to achieve immunomodulation and tissue regeneration, but the mechanisms of how MSCs exert therapeutic effects remain to be elucidated. Increasing evidence suggests that transplanted MSCs only briefly remain viable in recipients, after which they undergo apoptosis in the host circulation or in engrafted tissues. Intriguingly, apoptosis of infused MSCs has been revealed to be indispensable for their therapeutic efficacy, while recipient cells can also develop apoptosis as a beneficial response in restoring systemic and local tissue homeostasis. It is notable that apoptotic cells produce apoptotic extracellular vesicles (apoEVs), traditionally known as apoptotic bodies (apoBDs), which possess characterized miRnomes and proteomes that contribute to their specialized function and to intercellular communication. Importantly, it has been demonstrated that the impact of apoEVs is long-lasting in health and disease contexts, and they critically mediate the efficacy of MSCT. In this review, we summarize the emerging understanding of apoptosis in mediating MSCT, highlighting the potential of apoEVs as cell-free therapeutics.
Collapse
Affiliation(s)
- Yu Fu
- Fujian Key Laboratory of Developmental and Neural Biology & Southern Center for Biomedical Research, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, 350117, China.,South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, 510055, China
| | - Bingdong Sui
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, 510055, China.,Research and Development Center for Tissue Engineering, The Fourth Military Medical University, Xi'an, Shaanxi, 710032, China
| | - Lei Xiang
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, 510055, China
| | - Xutong Yan
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, 510055, China
| | - Di Wu
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, 510055, China
| | - Songtao Shi
- South China Center of Craniofacial Stem Cell Research, Guanghua School and Hospital of Stomatology, Sun Yat-sen University, Guangzhou, Guangdong, 510055, China.
| | - Xuefeng Hu
- Fujian Key Laboratory of Developmental and Neural Biology & Southern Center for Biomedical Research, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian, 350117, China.
| |
Collapse
|
|
47
|
Amadio R, Piperno GM, Benvenuti F. Self-DNA Sensing by cGAS-STING and TLR9 in Autoimmunity: Is the Cytoskeleton in Control? Front Immunol 2021; 12:657344. [PMID: 34084165 PMCID: PMC8167430 DOI: 10.3389/fimmu.2021.657344] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 04/06/2021] [Indexed: 12/11/2022] Open
Abstract
Modified or misplaced DNA can be recognized as a danger signal by mammalian cells. Activation of cellular responses to DNA has evolved as a defense mechanism to microbial infections, cellular stress, and tissue damage, yet failure to control this mechanism can lead to autoimmune diseases. Several monogenic and multifactorial autoimmune diseases have been associated with type-I interferons and interferon-stimulated genes (ISGs) induced by deregulated recognition of self-DNA. Hence, understanding how cellular mechanism controls the pathogenic responses to self-nucleic acid has important clinical implications. Fine-tuned membrane trafficking and cellular compartmentalization are two major factors that balance activation of DNA sensors and availability of self-DNA ligands. Intracellular transport and organelle architecture are in turn regulated by cytoskeletal dynamics, yet the precise impact of actin remodeling on DNA sensing remains elusive. This review proposes a critical analysis of the established and hypothetical connections between self-DNA recognition and actin dynamics. As a paradigm of this concept, we discuss recent evidence of deregulated self-DNA sensing in the prototypical actin-related primary immune deficiency (Wiskott-Aldrich syndrome). We anticipate a broader impact of actin-dependent processes on tolerance to self-DNA in autoimmune disorders.
Collapse
Affiliation(s)
- Roberto Amadio
- Cellular Immunology, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
- Department of Biomedical Sciences, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy
| | - Giulia Maria Piperno
- Cellular Immunology, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| | - Federica Benvenuti
- Cellular Immunology, International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy
| |
Collapse
|
|
48
|
Abstract
Significance: Genomic instability, a hallmark of cancer, renders cancer cells susceptible to genomic stress from both endogenous and exogenous origins, resulting in the increased tendency to accrue DNA damage, chromosomal instability, or aberrant DNA localization. Apart from the cell autonomous tumor-promoting effects, genomic stress in cancer cells could have a profound impact on the tumor microenvironment. Recent Advances: Recently, it is increasingly appreciated that harnessing genomic stress could provide a promising strategy to revive antitumor immunity, and thereby offer new therapeutic opportunities in cancer treatment. Critical Issues: Genomic stress is closely intertwined with antitumor immunity via mechanisms involving the direct crosstalk with DNA damage response components, upregulation of immune-stimulatory/inhibitory ligands, release of damage-associated molecular patterns, increase of neoantigen repertoire, and activation of DNA sensing pathways. A better understanding of these mechanisms will provide molecular basis for exploiting the genomic stress to boost antitumor immunity. Future Directions: Future research should pay attention to the heterogeneity between individual cancers in the genomic instability and the associated immune response, and how to balance the toxicity and benefit by specifying the types, potency, and treatment sequence of genomic stress inducer in therapeutic practice. Antioxid. Redox Signal. 34, 1128-1150.
Collapse
Affiliation(s)
- Congying Pu
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Siyao Tao
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Jun Xu
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| | - Min Huang
- Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.,University of Chinese Academy of Sciences, Beijing, China
| |
Collapse
|
|
49
|
Wei F, Liu S, Chen M, Tian G, Zha K, Yang Z, Jiang S, Li M, Sui X, Chen Z, Guo Q. Host Response to Biomaterials for Cartilage Tissue Engineering: Key to Remodeling. Front Bioeng Biotechnol 2021; 9:664592. [PMID: 34017827 PMCID: PMC8129172 DOI: 10.3389/fbioe.2021.664592] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2021] [Accepted: 04/14/2021] [Indexed: 12/18/2022] Open
Abstract
Biomaterials play a core role in cartilage repair and regeneration. The success or failure of an implanted biomaterial is largely dependent on host response following implantation. Host response has been considered to be influenced by numerous factors, such as immune components of materials, cytokines and inflammatory agents induced by implants. Both synthetic and native materials involve immune components, which are also termed as immunogenicity. Generally, the innate and adaptive immune system will be activated and various cytokines and inflammatory agents will be consequently released after biomaterials implantation, and further triggers host response to biomaterials. This will guide the constructive remolding process of damaged tissue. Therefore, biomaterial immunogenicity should be given more attention. Further understanding the specific biological mechanisms of host response to biomaterials and the effects of the host-biomaterial interaction may be beneficial to promote cartilage repair and regeneration. In this review, we summarized the characteristics of the host response to implants and the immunomodulatory properties of varied biomaterial. We hope this review will provide scientists with inspiration in cartilage regeneration by controlling immune components of biomaterials and modulating the immune system.
Collapse
Affiliation(s)
- Fu Wei
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries, PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China.,Department of Orthopedics, The First Affiliated Hospital of University of South China, Hengyang, China
| | - Shuyun Liu
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries, PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Mingxue Chen
- Department of Orthopedic Surgery, Beijing Jishuitan Hospital, Fourth Clinical College of Peking University, Beijing, China
| | - Guangzhao Tian
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries, PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Kangkang Zha
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries, PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Zhen Yang
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries, PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | | | - Muzhe Li
- Department of Orthopedics, The First Affiliated Hospital of University of South China, Hengyang, China
| | - Xiang Sui
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries, PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| | - Zhiwei Chen
- Department of Orthopedics, The First Affiliated Hospital of University of South China, Hengyang, China
| | - Quanyi Guo
- Beijing Key Lab of Regenerative Medicine in Orthopedics, Key Laboratory of Musculoskeletal Trauma and War Injuries, PLA, Institute of Orthopedics, Chinese PLA General Hospital, Beijing, China
| |
Collapse
|
|
50
|
Mike JK, Ferriero DM. Efferocytosis Mediated Modulation of Injury after Neonatal Brain Hypoxia-Ischemia. Cells 2021; 10:1025. [PMID: 33925299 PMCID: PMC8146813 DOI: 10.3390/cells10051025] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/22/2021] [Accepted: 04/23/2021] [Indexed: 02/06/2023] Open
Abstract
Neonatal brain hypoxia-ischemia (HI) is a leading cause of morbidity and long-term disabilities in children. While we have made significant progress in describing HI mechanisms, the limited therapies currently offered for HI treatment in the clinical setting stress the importance of discovering new targetable pathways. Efferocytosis is an immunoregulatory and homeostatic process of clearance of apoptotic cells (AC) and cellular debris, best described in the brain during neurodevelopment. The therapeutic potential of stimulating defective efferocytosis has been recognized in neurodegenerative diseases. In this review, we will explore the involvement of efferocytosis after a stroke and HI as a promising target for new HI therapies.
Collapse
Affiliation(s)
- Jana Krystofova Mike
- Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA;
| | - Donna Marie Ferriero
- Department of Pediatrics, University of California San Francisco, San Francisco, CA 94143, USA;
- Department of Neurology Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143, USA
| |
Collapse
|