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Fang X, Zhang H, Zhou H, Shen S, Lao Z, Zhang Z, Bian Y, Zhou C, Jin H, Tong P, Huang Y, Zhou H, Zeng H, Fu F, Wu C, Zheng W, Ruan H. Systemic Lupus Erythematosus Exacerbates Hip Arthritis by Promoting Chondrocyte Pyroptosis in the Femoral Head via Activating the NF-κB Pathway. J Cell Mol Med 2025; 29:e70531. [PMID: 40179133 PMCID: PMC11967699 DOI: 10.1111/jcmm.70531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Revised: 03/19/2025] [Accepted: 03/24/2025] [Indexed: 04/05/2025] Open
Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by chronic inflammation and immune dysregulation, significantly impacting multiple organ systems, including the joints. While SLE is known to contribute to musculoskeletal complications, its role in hip arthritis development and the underlying mechanisms remain poorly understood. This study aims to investigate the relationship between SLE and hip arthritis progression using MRL/lpr mice, which exhibit early-onset SLE, compared with MRL/MpJ control mice at 14 weeks of age. Through comprehensive histological, immunohistochemical and molecular analyses, we evaluated articular cartilage (AC) degeneration, extracellular matrix (ECM) metabolism, inflammatory responses, and chondrocyte pyroptosis. Our results demonstrated that MRL/lpr mice developed an accelerated hip arthritis-like phenotype, manifesting as enhanced AC degeneration, impaired chondrocyte proliferation, heightened apoptosis and promoted inflammatory cytokine production. Notably, SLE markedly stimulated chondrocyte pyroptosis by increasing pyroptosis-related proteins, including NLRP3, ASC, CASPASE-1 and GSDMD, via activating the NF-κB pathway. These findings establish a novel mechanistic link between SLE and hip arthritis progression, demonstrating that SLE promotes chondrocyte pyroptosis to exacerbate AC degeneration via NF-κB activation, highlighting chondrocyte pyroptosis as a key driver of SLE-associated hip arthritis and a potential therapeutic target for mitigating SLE-induced joint manifestations.
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Affiliation(s)
- Xuliang Fang
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Helou Zhang
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Huiqing Zhou
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Shuchao Shen
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Zhaobai Lao
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Zhiguo Zhang
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Yishan Bian
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Chengcong Zhou
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Hongting Jin
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Peijian Tong
- Department of OrthopaedicsThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Yanqun Huang
- Hangzhou Fuyang Hospital of TCM Orthopedics and TraumatologyHangzhouChina
| | - Hong Zhou
- Hangzhou Fuyang Hospital of TCM Orthopedics and TraumatologyHangzhouChina
| | - Hanbing Zeng
- The Second Clinical Medical College, Zhejiang Chinese Medical UniversityHangzhouChina
| | - Fangda Fu
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Chengliang Wu
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
| | - Wenbiao Zheng
- Department of OrthopedicsTaizhou Municipal HospitalTaizhouChina
| | - Hongfeng Ruan
- Institute of Orthopaedics and TraumatologyThe First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine)HangzhouChina
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Kono DH, Hahn BH. Animal models of systemic lupus erythematosus (SLE). DUBOIS' LUPUS ERYTHEMATOSUS AND RELATED SYNDROMES 2025:189-234. [DOI: 10.1016/b978-0-323-93232-5.00024-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Zhang W, Zhu C, Liao Y, Zhou M, Xu W, Zou Z. Caspase-8 in inflammatory diseases: a potential therapeutic target. Cell Mol Biol Lett 2024; 29:130. [PMID: 39379817 PMCID: PMC11463096 DOI: 10.1186/s11658-024-00646-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 09/23/2024] [Indexed: 10/10/2024] Open
Abstract
Caspase-8, a renowned cysteine-aspartic protease within its enzyme family, initially garnered attention for its regulatory role in extrinsic apoptosis. With advancing research, a growing body of evidence has substantiated its involvement in other cell death processes, such as pyroptosis and necroptosis, as well as its modulatory effects on inflammasomes and proinflammatory cytokines. PANoptosis, an emerging concept of cell death, encompasses pyroptosis, apoptosis, and necroptosis, providing insight into the often overlapping cellular mortality observed during disease progression. The activation or deficiency of caspase-8 enzymatic activity is closely linked to PANoptosis, positioning caspase-8 as a key regulator of cell survival or death across various physiological and pathological processes. Aberrant expression of caspase-8 is closely associated with the development and progression of a range of inflammatory diseases, including immune system disorders, neurodegenerative diseases (NDDs), sepsis, and cancer. This paper delves into the regulatory role and impact of caspase-8 in these conditions, aiming to elucidate potential therapeutic strategies for the future intervention.
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Affiliation(s)
- Wangzheqi Zhang
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Chenglong Zhu
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yan Liao
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Miao Zhou
- Department of Anesthesiology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
| | - Wenyun Xu
- Department of Anesthesiology, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
| | - Zui Zou
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
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Kratochvilova A, Knopfova L, Gregorkova J, Gruber R, Janeckova E, Chai Y, Matalova E. FasL impacts Tgfb signaling in osteoblastic cells. Cells Dev 2024; 179:203929. [PMID: 38810946 DOI: 10.1016/j.cdev.2024.203929] [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: 01/19/2024] [Revised: 04/26/2024] [Accepted: 05/26/2024] [Indexed: 05/31/2024]
Abstract
Fas ligand (FasL, CD178) belongs to classical apoptotic molecules, however, recent evidence expands the spectrum of FasL functions into non-apoptotic processes which also applies for the bone. Tgfb subfamily members (Tgfb1, Tgfb2, Tgfb3) represent major components in osteogenic pathways and extracellular matrix. Their possible association with FasL has not yet been investigated but can be postulated. To test such a hypothesis, FasL deficient (gld) calvaria-derived cells were examined with a focus on the expression of Tgfb receptor ligands. The qPCR analysis revealed significantly increased expression of Tgfb1, Tgfb2 and Tgfb3 in gld cells. To check the vice versa effect, the gld cells were stimulated by soluble FasL. As a consequence, a dramatic decrease in expression levels of all three ligands was observed. This phenomenon was also confirmed in IDG-SW3 (osteoblastic cells of endochondral origin). TFLink gateway identified Fosl2 as an exclusive candidate of FasL capable to impact expression of all three Tgfb ligands. However, Fosl2 siRNA did not cause any significant changes in expression of Tgfb ligands. Therefore, the upregulation of the three ligands is likely to occur separately. In this respect, we tested the only exclusive candidate transcription factor for Tgfb3, Prrx1. Additionally, an overlapping candidate for Tgfb1 and Tgfb2, Mef2c capable to modulate expression of sclerostin, was examined. Prrx1 as well as Mef2c were found upregulated in gld samples and their expression decreased after addition of FasL. The same effect of FasL treatment was observed in the IDG-SW3 model. Taken together, FasL deficiency causes an increase in the expression of Tgfb ligands and stimulation by FasL reduces Tgfb expression in osteoblastic cells. The candidates mediating the effect comprise Prrx1 for Tgfb3 and Mef2c for Tgfb1/2. These results indicate FasL as a novel cytokine interfering with Tgfb signaling and thus the complex osteogenic network. The emerging non-apoptotic functions of FasL in bone development and maintenance should also be considered in treatment strategies such as the anti-osteoporotic factor.
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Affiliation(s)
- Adela Kratochvilova
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
| | - Lucia Knopfova
- Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic; International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Janka Gregorkova
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic
| | | | | | - Yang Chai
- University of Southern California, Los Angeles, USA
| | - Eva Matalova
- Institute of Animal Physiology and Genetics, Czech Academy of Sciences, Brno, Czech Republic; University of Veterinary Sciences, Brno, Czech Republic.
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Huysentruyt J, Steels W, Ruiz Perez M, Verstraeten B, Vadi M, Divert T, Flies K, Takahashi N, Lambrecht BN, Declercq W, Vanden Berghe T, Maelfait J, Vandenabeele P, Tougaard P. RIPK1 protects naive and regulatory T cells from TNFR1-induced apoptosis. Cell Death Differ 2024; 31:820-832. [PMID: 38734851 PMCID: PMC11164875 DOI: 10.1038/s41418-024-01301-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Revised: 04/17/2024] [Accepted: 04/18/2024] [Indexed: 05/13/2024] Open
Abstract
The T cell population size is stringently controlled before, during, and after immune responses, as improper cell death regulation can result in autoimmunity and immunodeficiency. RIPK1 is an important regulator of peripheral T cell survival and homeostasis. However, whether different peripheral T cell subsets show a differential requirement for RIPK1 and which programmed cell death pathway they engage in vivo remains unclear. In this study, we demonstrate that conditional ablation of Ripk1 in conventional T cells (Ripk1ΔCD4) causes peripheral T cell lymphopenia, as witnessed by a profound loss of naive CD4+, naive CD8+, and FoxP3+ regulatory T cells. Interestingly, peripheral naive CD8+ T cells in Ripk1ΔCD4 mice appear to undergo a selective pressure to retain RIPK1 expression following activation. Mixed bone marrow chimeras revealed a competitive survival disadvantage for naive, effector, and memory T cells lacking RIPK1. Additionally, tamoxifen-induced deletion of RIPK1 in CD4-expressing cells in adult life confirmed the importance of RIPK1 in post-thymic survival of CD4+ T cells. Ripk1K45A mice showed no change in peripheral T cell subsets, demonstrating that the T cell lymphopenia was due to the scaffold function of RIPK1 rather than to its kinase activity. Enhanced numbers of Ripk1ΔCD4 naive T cells expressed the proliferation marker Ki-67+ despite the peripheral lymphopenia and single-cell RNA sequencing revealed T cell-specific transcriptomic alterations that were reverted by additional caspase-8 deficiency. Furthermore, Ripk1ΔCD4Casp8 ΔCD4 and Ripk1ΔCD4Tnfr1-/- double-knockout mice rescued the peripheral T cell lymphopenia, revealing that RIPK1-deficient naive CD4+ and CD8+ cells and FoxP3+ regulatory T cells specifically die from TNF- and caspase-8-mediated apoptosis in vivo. Altogether, our findings emphasize the essential role of RIPK1 as a scaffold in maintaining the peripheral T cell compartment and preventing TNFR1-induced apoptosis.
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Affiliation(s)
- Jelle Huysentruyt
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Wolf Steels
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Mario Ruiz Perez
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Bruno Verstraeten
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Mike Vadi
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Tatyana Divert
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Kayleigh Flies
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Nozomi Takahashi
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Bart N Lambrecht
- Department of Internal Medicine and Pediatrics, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- Laboratory of Mucosal Immunology, VIB-UGent Center for Inflammation Research, Ghent University, Ghent, Belgium
- Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium
- Department of Pulmonary Medicine, Erasmus MC, Rotterdam, Netherlands
| | - Wim Declercq
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Tom Vanden Berghe
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Jonathan Maelfait
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Peter Vandenabeele
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium.
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
| | - Peter Tougaard
- Cell death and Inflammation Unit, VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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Abstract
Regulated cell death mediated by dedicated molecular machines, known as programmed cell death, plays important roles in health and disease. Apoptosis, necroptosis and pyroptosis are three such programmed cell death modalities. The caspase family of cysteine proteases serve as key regulators of programmed cell death. During apoptosis, a cascade of caspase activation mediates signal transduction and cellular destruction, whereas pyroptosis occurs when activated caspases cleave gasdermins, which can then form pores in the plasma membrane. Necroptosis, a form of caspase-independent programmed necrosis mediated by RIPK3 and MLKL, is inhibited by caspase-8-mediated cleavage of RIPK1. Disruption of cellular homeostatic mechanisms that are essential for cell survival, such as normal ionic and redox balance and lysosomal flux, can also induce cell death without invoking programmed cell death mechanisms. Excitotoxicity, ferroptosis and lysosomal cell death are examples of such cell death modes. In this Review, we provide an overview of the major cell death mechanisms, highlighting the latest insights into their complex regulation and execution, and their relevance to human diseases.
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Affiliation(s)
- Junying Yuan
- Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Shanghai, China.
- Shanghai Key Laboratory of Aging Studies, Shanghai, China.
| | - Dimitry Ofengeim
- Sanofi, Rare and Neurological Diseases Research, Cambridge, MA, USA.
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Newton K, Strasser A, Kayagaki N, Dixit VM. Cell death. Cell 2024; 187:235-256. [PMID: 38242081 DOI: 10.1016/j.cell.2023.11.044] [Citation(s) in RCA: 321] [Impact Index Per Article: 321.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/18/2023] [Accepted: 11/30/2023] [Indexed: 01/21/2024]
Abstract
Cell death supports morphogenesis during development and homeostasis after birth by removing damaged or obsolete cells. It also curtails the spread of pathogens by eliminating infected cells. Cell death can be induced by the genetically programmed suicide mechanisms of apoptosis, necroptosis, and pyroptosis, or it can be a consequence of dysregulated metabolism, as in ferroptosis. Here, we review the signaling mechanisms underlying each cell-death pathway, discuss how impaired or excessive activation of the distinct cell-death processes can promote disease, and highlight existing and potential therapies for redressing imbalances in cell death in cancer and other diseases.
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Affiliation(s)
- Kim Newton
- Physiological Chemistry Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
| | - Andreas Strasser
- WEHI: Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, VIC 3010, Australia.
| | - Nobuhiko Kayagaki
- Physiological Chemistry Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
| | - Vishva M Dixit
- Physiological Chemistry Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
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Carlsen L, Zhang S, Tian X, De La Cruz A, George A, Arnoff TE, El-Deiry WS. The role of p53 in anti-tumor immunity and response to immunotherapy. Front Mol Biosci 2023; 10:1148389. [PMID: 37602328 PMCID: PMC10434531 DOI: 10.3389/fmolb.2023.1148389] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 07/04/2023] [Indexed: 08/22/2023] Open
Abstract
p53 is a transcription factor that regulates the expression of genes involved in tumor suppression. p53 mutations mediate tumorigenesis and occur in approximately 50% of human cancers. p53 regulates hundreds of target genes that induce various cell fates including apoptosis, cell cycle arrest, and DNA damage repair. p53 also plays an important role in anti-tumor immunity by regulating TRAIL, DR5, TLRs, Fas, PKR, ULBP1/2, and CCL2; T-cell inhibitory ligand PD-L1; pro-inflammatory cytokines; immune cell activation state; and antigen presentation. Genetic alteration of p53 can contribute to immune evasion by influencing immune cell recruitment to the tumor, cytokine secretion in the TME, and inflammatory signaling pathways. In some contexts, p53 mutations increase neoantigen load which improves response to immune checkpoint inhibition. Therapeutic restoration of mutated p53 can restore anti-cancer immune cell infiltration and ameliorate pro-tumor signaling to induce tumor regression. Indeed, there is clinical evidence to suggest that restoring p53 can induce an anti-cancer immune response in immunologically cold tumors. Clinical trials investigating the combination of p53-restoring compounds or p53-based vaccines with immunotherapy have demonstrated anti-tumor immune activation and tumor regression with heterogeneity across cancer type. In this Review, we discuss the impact of wild-type and mutant p53 on the anti-tumor immune response, outline clinical progress as far as activating p53 to induce an immune response across a variety of cancer types, and highlight open questions limiting effective clinical translation.
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Affiliation(s)
- Lindsey Carlsen
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
- Pathobiology Graduate Program, Warren Alpert Medical School, Brown University, Providence, RI, United States
| | - Shengliang Zhang
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
| | - Xiaobing Tian
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
| | - Arielle De La Cruz
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
| | - Andrew George
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
| | - Taylor E. Arnoff
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
| | - Wafik S. El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, Providence, RI, United States
- Legorreta Cancer Center, Brown University, Providence, RI, United States
- Pathobiology Graduate Program, Warren Alpert Medical School, Brown University, Providence, RI, United States
- Hematology-Oncology Division, Department of Medicine, Lifespan Health System and Warren Alpert Medical School, Brown University, Providence, RI, United States
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Vitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost PJ, Kanneganti TD, et alVitale I, Pietrocola F, Guilbaud E, Aaronson SA, Abrams JM, Adam D, Agostini M, Agostinis P, Alnemri ES, Altucci L, Amelio I, Andrews DW, Aqeilan RI, Arama E, Baehrecke EH, Balachandran S, Bano D, Barlev NA, Bartek J, Bazan NG, Becker C, Bernassola F, Bertrand MJM, Bianchi ME, Blagosklonny MV, Blander JM, Blandino G, Blomgren K, Borner C, Bortner CD, Bove P, Boya P, Brenner C, Broz P, Brunner T, Damgaard RB, Calin GA, Campanella M, Candi E, Carbone M, Carmona-Gutierrez D, Cecconi F, Chan FKM, Chen GQ, Chen Q, Chen YH, Cheng EH, Chipuk JE, Cidlowski JA, Ciechanover A, Ciliberto G, Conrad M, Cubillos-Ruiz JR, Czabotar PE, D'Angiolella V, Daugaard M, Dawson TM, Dawson VL, De Maria R, De Strooper B, Debatin KM, Deberardinis RJ, Degterev A, Del Sal G, Deshmukh M, Di Virgilio F, Diederich M, Dixon SJ, Dynlacht BD, El-Deiry WS, Elrod JW, Engeland K, Fimia GM, Galassi C, Ganini C, Garcia-Saez AJ, Garg AD, Garrido C, Gavathiotis E, Gerlic M, Ghosh S, Green DR, Greene LA, Gronemeyer H, Häcker G, Hajnóczky G, Hardwick JM, Haupt Y, He S, Heery DM, Hengartner MO, Hetz C, Hildeman DA, Ichijo H, Inoue S, Jäättelä M, Janic A, Joseph B, Jost PJ, Kanneganti TD, Karin M, Kashkar H, Kaufmann T, Kelly GL, Kepp O, Kimchi A, Kitsis RN, Klionsky DJ, Kluck R, Krysko DV, Kulms D, Kumar S, Lavandero S, Lavrik IN, Lemasters JJ, Liccardi G, Linkermann A, Lipton SA, Lockshin RA, López-Otín C, Luedde T, MacFarlane M, Madeo F, Malorni W, Manic G, Mantovani R, Marchi S, Marine JC, Martin SJ, Martinou JC, Mastroberardino PG, Medema JP, Mehlen P, Meier P, Melino G, Melino S, Miao EA, Moll UM, Muñoz-Pinedo C, Murphy DJ, Niklison-Chirou MV, Novelli F, Núñez G, Oberst A, Ofengeim D, Opferman JT, Oren M, Pagano M, Panaretakis T, Pasparakis M, Penninger JM, Pentimalli F, Pereira DM, Pervaiz S, Peter ME, Pinton P, Porta G, Prehn JHM, Puthalakath H, Rabinovich GA, Rajalingam K, Ravichandran KS, Rehm M, Ricci JE, Rizzuto R, Robinson N, Rodrigues CMP, Rotblat B, Rothlin CV, Rubinsztein DC, Rudel T, Rufini A, Ryan KM, Sarosiek KA, Sawa A, Sayan E, Schroder K, Scorrano L, Sesti F, Shao F, Shi Y, Sica GS, Silke J, Simon HU, Sistigu A, Stephanou A, Stockwell BR, Strapazzon F, Strasser A, Sun L, Sun E, Sun Q, Szabadkai G, Tait SWG, Tang D, Tavernarakis N, Troy CM, Turk B, Urbano N, Vandenabeele P, Vanden Berghe T, Vander Heiden MG, Vanderluit JL, Verkhratsky A, Villunger A, von Karstedt S, Voss AK, Vousden KH, Vucic D, Vuri D, Wagner EF, Walczak H, Wallach D, Wang R, Wang Y, Weber A, Wood W, Yamazaki T, Yang HT, Zakeri Z, Zawacka-Pankau JE, Zhang L, Zhang H, Zhivotovsky B, Zhou W, Piacentini M, Kroemer G, Galluzzi L. Apoptotic cell death in disease-Current understanding of the NCCD 2023. Cell Death Differ 2023; 30:1097-1154. [PMID: 37100955 PMCID: PMC10130819 DOI: 10.1038/s41418-023-01153-w] [Show More Authors] [Citation(s) in RCA: 174] [Impact Index Per Article: 87.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/10/2023] [Accepted: 03/17/2023] [Indexed: 04/28/2023] Open
Abstract
Apoptosis is a form of regulated cell death (RCD) that involves proteases of the caspase family. Pharmacological and genetic strategies that experimentally inhibit or delay apoptosis in mammalian systems have elucidated the key contribution of this process not only to (post-)embryonic development and adult tissue homeostasis, but also to the etiology of multiple human disorders. Consistent with this notion, while defects in the molecular machinery for apoptotic cell death impair organismal development and promote oncogenesis, the unwarranted activation of apoptosis promotes cell loss and tissue damage in the context of various neurological, cardiovascular, renal, hepatic, infectious, neoplastic and inflammatory conditions. Here, the Nomenclature Committee on Cell Death (NCCD) gathered to critically summarize an abundant pre-clinical literature mechanistically linking the core apoptotic apparatus to organismal homeostasis in the context of disease.
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Affiliation(s)
- Ilio Vitale
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy.
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy.
| | - Federico Pietrocola
- Department of Biosciences and Nutrition, Karolinska Institute, Huddinge, Sweden
| | - Emma Guilbaud
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Stuart A Aaronson
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York City, NY, USA
| | - John M Abrams
- Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Dieter Adam
- Institut für Immunologie, Kiel University, Kiel, Germany
| | - Massimiliano Agostini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patrizia Agostinis
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Emad S Alnemri
- Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Lucia Altucci
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Naples, Italy
- BIOGEM, Avellino, Italy
| | - Ivano Amelio
- Division of Systems Toxicology, Department of Biology, University of Konstanz, Konstanz, Germany
| | - David W Andrews
- Sunnybrook Research Institute, Toronto, ON, Canada
- Departments of Biochemistry and Medical Biophysics, University of Toronto, Toronto, ON, Canada
| | - Rami I Aqeilan
- Hebrew University of Jerusalem, Lautenberg Center for Immunology & Cancer Research, Institute for Medical Research Israel-Canada (IMRIC), Faculty of Medicine, Jerusalem, Israel
| | - Eli Arama
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Eric H Baehrecke
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Siddharth Balachandran
- Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Daniele Bano
- Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Bonn, Germany
| | - Nickolai A Barlev
- Department of Biomedicine, Nazarbayev University School of Medicine, Astana, Kazakhstan
| | - Jiri Bartek
- Department of Medical Biochemistry and Biophysics, Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden
- Danish Cancer Society Research Center, Copenhagen, Denmark
| | - Nicolas G Bazan
- Neuroscience Center of Excellence, School of Medicine, Louisiana State University Health New Orleans, New Orleans, LA, USA
| | - Christoph Becker
- Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Francesca Bernassola
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Mathieu J M Bertrand
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Marco E Bianchi
- Università Vita-Salute San Raffaele, School of Medicine, Milan, Italy and Ospedale San Raffaele IRCSS, Milan, Italy
| | | | - J Magarian Blander
- Department of Medicine, Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, New York, NY, USA
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, NY, USA
- Sandra and Edward Meyer Cancer Center, New York, NY, USA
| | | | - Klas Blomgren
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
- Pediatric Hematology and Oncology, Karolinska University Hospital, Stockholm, Sweden
| | - Christoph Borner
- Institute of Molecular Medicine and Cell Research, Medical Faculty, Albert Ludwigs University of Freiburg, Freiburg, Germany
| | - Carl D Bortner
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Pierluigi Bove
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Patricia Boya
- Centro de Investigaciones Biologicas Margarita Salas, CSIC, Madrid, Spain
| | - Catherine Brenner
- Université Paris-Saclay, CNRS, Institut Gustave Roussy, Aspects métaboliques et systémiques de l'oncogénèse pour de nouvelles approches thérapeutiques, Villejuif, France
| | - Petr Broz
- Department of Immunobiology, University of Lausanne, Epalinges, Vaud, Switzerland
| | - Thomas Brunner
- Department of Biology, University of Konstanz, Konstanz, Germany
| | - Rune Busk Damgaard
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - George A Calin
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michelangelo Campanella
- Department of Comparative Biomedical Sciences, The Royal Veterinary College, University of London, London, UK
- UCL Consortium for Mitochondrial Research, London, UK
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | | | - Francesco Cecconi
- Cell Stress and Survival Unit, Center for Autophagy, Recycling and Disease (CARD), Danish Cancer Society Research Center, Copenhagen, Denmark
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francis K-M Chan
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Guo-Qiang Chen
- State Key Lab of Oncogene and its related gene, Ren-Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Quan Chen
- College of Life Sciences, Nankai University, Tianjin, China
| | - Youhai H Chen
- Shenzhen Institute of Advanced Technology (SIAT), Shenzhen, Guangdong, China
| | - Emily H Cheng
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jerry E Chipuk
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John A Cidlowski
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Department of Health and Human Services, Research Triangle Park, Durham, NC, USA
| | - Aaron Ciechanover
- The Technion-Integrated Cancer Center, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | | | - Marcus Conrad
- Helmholtz Munich, Institute of Metabolism and Cell Death, Neuherberg, Germany
| | - Juan R Cubillos-Ruiz
- Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, NY, USA
| | - Peter E Czabotar
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Mads Daugaard
- Department of Urologic Sciences, Vancouver Prostate Centre, Vancouver, BC, Canada
| | - Ted M Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Valina L Dawson
- Institute for Cell Engineering and the Departments of Neurology, Neuroscience and Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Ruggero De Maria
- Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Università Cattolica del Sacro Cuore, Rome, Italy
| | - Bart De Strooper
- VIB Centre for Brain & Disease Research, Leuven, Belgium
- Department of Neurosciences, Leuven Brain Institute, KU Leuven, Leuven, Belgium
- The Francis Crick Institute, London, UK
- UK Dementia Research Institute at UCL, University College London, London, UK
| | - Klaus-Michael Debatin
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Ralph J Deberardinis
- Howard Hughes Medical Institute and Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Alexei Degterev
- Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, MA, USA
| | - Giannino Del Sal
- Department of Life Sciences, University of Trieste, Trieste, Italy
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-Padriciano, Trieste, Italy
- IFOM ETS, the AIRC Institute of Molecular Oncology, Milan, Italy
| | - Mohanish Deshmukh
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA
| | | | - Marc Diederich
- College of Pharmacy, Seoul National University, Seoul, South Korea
| | - Scott J Dixon
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Brian D Dynlacht
- Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, NY, USA
| | - Wafik S El-Deiry
- Division of Hematology/Oncology, Brown University and the Lifespan Cancer Institute, Providence, RI, USA
- Legorreta Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA
- Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA
| | - John W Elrod
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Kurt Engeland
- Molecular Oncology, University of Leipzig, Leipzig, Germany
| | - Gian Maria Fimia
- Department of Epidemiology, Preclinical Research and Advanced Diagnostics, National Institute for Infectious Diseases 'L. Spallanzani' IRCCS, Rome, Italy
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Claudia Galassi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Carlo Ganini
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- Biochemistry Laboratory, Dermopatic Institute of Immaculate (IDI) IRCCS, Rome, Italy
| | - Ana J Garcia-Saez
- CECAD, Institute of Genetics, University of Cologne, Cologne, Germany
| | - Abhishek D Garg
- Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Carmen Garrido
- INSERM, UMR, 1231, Dijon, France
- Faculty of Medicine, Université de Bourgogne Franche-Comté, Dijon, France
- Anti-cancer Center Georges-François Leclerc, Dijon, France
| | - Evripidis Gavathiotis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, New York, NY, USA
| | - Motti Gerlic
- Department of Clinical Microbiology and Immunology, Sackler school of Medicine, Tel Aviv university, Tel Aviv, Israel
| | - Sourav Ghosh
- Department of Neurology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - Douglas R Green
- Department of Immunology, St Jude Children's Research Hospital, Memphis, TN, USA
| | - Lloyd A Greene
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA
| | - Hinrich Gronemeyer
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch, France
- Université de Strasbourg, Illkirch, France
| | - Georg Häcker
- Faculty of Medicine, Institute of Medical Microbiology and Hygiene, Medical Center, University of Freiburg, Freiburg, Germany
- BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - György Hajnóczky
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - J Marie Hardwick
- Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
- Departments of Molecular Microbiology and Immunology, Pharmacology, Oncology and Neurology, Johns Hopkins Bloomberg School of Public Health and School of Medicine, Baltimore, MD, USA
| | - Ygal Haupt
- VITTAIL Ltd, Melbourne, VIC, Australia
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Sudan He
- Institute of Systems Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Suzhou Institute of Systems Medicine, Suzhou, Jiangsu, China
| | - David M Heery
- School of Pharmacy, University of Nottingham, Nottingham, UK
| | | | - Claudio Hetz
- Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile
- Center for Geroscience, Brain Health and Metabolism, Santiago, Chile
- Center for Molecular Studies of the Cell, Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile
- Buck Institute for Research on Aging, Novato, CA, USA
| | - David A Hildeman
- Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Hidenori Ichijo
- Laboratory of Cell Signaling, The University of Tokyo, Tokyo, Japan
| | - Satoshi Inoue
- National Cancer Center Research Institute, Tokyo, Japan
| | - Marja Jäättelä
- Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Society Research Center, Copenhagen, Denmark
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Ana Janic
- Department of Medicine and Life Sciences, Pompeu Fabra University, Barcelona, Spain
| | - Bertrand Joseph
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Philipp J Jost
- Clinical Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | | | - Michael Karin
- Departments of Pharmacology and Pathology, School of Medicine, University of California San Diego, San Diego, CA, USA
| | - Hamid Kashkar
- CECAD Research Center, Institute for Molecular Immunology, University of Cologne, Cologne, Germany
| | - Thomas Kaufmann
- Institute of Pharmacology, University of Bern, Bern, Switzerland
| | - Gemma L Kelly
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Oliver Kepp
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
| | - Adi Kimchi
- Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
| | - Richard N Kitsis
- Department of Biochemistry, Albert Einstein College of Medicine, New York, NY, USA
- Department of Medicine, Albert Einstein College of Medicine, New York, NY, USA
- Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY, USA
- Institute for Aging Research, Albert Einstein College of Medicine, New York, NY, USA
- Department of Cell Biology, Albert Einstein College of Medicine, New York, NY, USA
- Einstein-Mount Sinai Diabetes Research Center, Albert Einstein College of Medicine, New York, NY, USA
| | | | - Ruth Kluck
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Dmitri V Krysko
- Cell Death Investigation and Therapy Lab, Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Ghent (CRIG), Ghent, Belgium
| | - Dagmar Kulms
- Department of Dermatology, Experimental Dermatology, TU-Dresden, Dresden, Germany
- National Center for Tumor Diseases Dresden, TU-Dresden, Dresden, Germany
| | - Sharad Kumar
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
- Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia
| | - Sergio Lavandero
- Universidad de Chile, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Advanced Center for Chronic Diseases (ACCDiS), Santiago, Chile
- Department of Internal Medicine, Cardiology Division, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Inna N Lavrik
- Translational Inflammation Research, Medical Faculty, Otto von Guericke University, Magdeburg, Germany
| | - John J Lemasters
- Departments of Drug Discovery & Biomedical Sciences and Biochemistry & Molecular Biology, Medical University of South Carolina, Charleston, SC, USA
| | - Gianmaria Liccardi
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Biotechnology Center, Technische Universität Dresden, Dresden, Germany
| | - Stuart A Lipton
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA, USA
- Department of Neurology, Yale School of Medicine, New Haven, CT, USA
| | - Richard A Lockshin
- Department of Biology, Queens College of the City University of New York, Flushing, NY, USA
- St. John's University, Jamaica, NY, USA
| | - Carlos López-Otín
- Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, Oviedo, Spain
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Heinrich Heine University, Duesseldorf, Germany
| | - Marion MacFarlane
- Medical Research Council Toxicology Unit, University of Cambridge, Cambridge, UK
| | - Frank Madeo
- Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria
- BioTechMed Graz, Graz, Austria
- Field of Excellence BioHealth - University of Graz, Graz, Austria
| | - Walter Malorni
- Center for Global Health, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gwenola Manic
- IIGM - Italian Institute for Genomic Medicine, c/o IRCSS Candiolo, Torino, Italy
- Candiolo Cancer Institute, FPO -IRCCS, Candiolo, Italy
| | - Roberto Mantovani
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
| | - Saverio Marchi
- Department of Clinical and Molecular Sciences, Marche Polytechnic University, Ancona, Italy
| | - Jean-Christophe Marine
- VIB Center for Cancer Biology, Leuven, Belgium
- Department of Oncology, KU Leuven, Leuven, Belgium
| | | | - Jean-Claude Martinou
- Department of Cell Biology, Faculty of Sciences, University of Geneva, Geneva, Switzerland
| | - Pier G Mastroberardino
- Department of Molecular Genetics, Rotterdam, the Netherlands
- IFOM-ETS The AIRC Institute for Molecular Oncology, Milan, Italy
- Department of Life, Health, and Environmental Sciences, University of L'Aquila, L'Aquila, Italy
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
- Oncode Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Patrick Mehlen
- Apoptosis, Cancer, and Development Laboratory, Equipe labellisée 'La Ligue', LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Université Claude Bernard Lyon1, Lyon, France
| | - Pascal Meier
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK
| | - Gerry Melino
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Sonia Melino
- Department of Chemical Science and Technologies, University of Rome Tor Vergata, Rome, Italy
| | - Edward A Miao
- Department of Immunology, Duke University School of Medicine, Durham, NC, USA
| | - Ute M Moll
- Department of Pathology and Stony Brook Cancer Center, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, USA
| | - Cristina Muñoz-Pinedo
- Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
| | - Daniel J Murphy
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | | | - Flavia Novelli
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Gabriel Núñez
- Department of Pathology and Rogel Cancer Center, The University of Michigan, Ann Arbor, MI, USA
| | - Andrew Oberst
- Department of Immunology, University of Washington, Seattle, WA, USA
| | - Dimitry Ofengeim
- Rare and Neuroscience Therapeutic Area, Sanofi, Cambridge, MA, USA
| | - Joseph T Opferman
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA
| | - Moshe Oren
- Department of Molecular Cell Biology, The Weizmann Institute, Rehovot, Israel
| | - Michele Pagano
- Department of Biochemistry and Molecular Pharmacology, New York University Grossman School of Medicine and Howard Hughes Medical Institute, New York, NY, USA
| | - Theocharis Panaretakis
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Department of GU Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | | | - Josef M Penninger
- IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria
- Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, Canada
| | | | - David M Pereira
- REQUIMTE/LAQV, Laboratório de Farmacognosia, Departamento de Química, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
| | - Shazib Pervaiz
- Department of Physiology, YLL School of Medicine, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research (N2CR), National University of Singapore, Singapore, Singapore
- National University Cancer Institute, NUHS, Singapore, Singapore
- ISEP, NUS Graduate School, National University of Singapore, Singapore, Singapore
| | - Marcus E Peter
- Department of Medicine, Division Hematology/Oncology, Northwestern University, Chicago, IL, USA
| | - Paolo Pinton
- Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Giovanni Porta
- Center of Genomic Medicine, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Jochen H M Prehn
- Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland (RCSI) University of Medicine and Health Sciences, Dublin 2, Ireland
| | - Hamsa Puthalakath
- Department of Biochemistry and Chemistry, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
| | - Gabriel A Rabinovich
- Laboratorio de Glicomedicina. Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Buenos Aires, Argentina
| | | | - Kodi S Ravichandran
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Division of Immunobiology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA
- Center for Cell Clearance, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA
| | - Markus Rehm
- Institute of Cell Biology and Immunology, University of Stuttgart, Stuttgart, Germany
| | - Jean-Ehrland Ricci
- Université Côte d'Azur, INSERM, C3M, Equipe labellisée Ligue Contre le Cancer, Nice, France
| | - Rosario Rizzuto
- Department of Biomedical Sciences, University of Padua, Padua, Italy
| | - Nirmal Robinson
- Centre for Cancer Biology, University of South Australia, Adelaide, SA, Australia
| | - Cecilia M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Barak Rotblat
- Department of Life sciences, Ben Gurion University of the Negev, Beer Sheva, Israel
- The NIBN, Beer Sheva, Israel
| | - Carla V Rothlin
- Department of Immunobiology and Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA
| | - David C Rubinsztein
- Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge, UK
- UK Dementia Research Institute, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, UK
| | - Thomas Rudel
- Microbiology Biocentre, University of Würzburg, Würzburg, Germany
| | - Alessandro Rufini
- Dipartimento di Bioscienze, Università degli Studi di Milano, Milano, Italy
- University of Leicester, Leicester Cancer Research Centre, Leicester, UK
| | - Kevin M Ryan
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Kristopher A Sarosiek
- John B. Little Center for Radiation Sciences, Harvard School of Public Health, Boston, MA, USA
- Department of Systems Biology, Lab of Systems Pharmacology, Harvard Program in Therapeutics Science, Harvard Medical School, Boston, MA, USA
- Department of Environmental Health, Molecular and Integrative Physiological Sciences Program, Harvard School of Public Health, Boston, MA, USA
| | - Akira Sawa
- Johns Hopkins Schizophrenia Center, Johns Hopkins University, Baltimore, MD, USA
| | - Emre Sayan
- Faculty of Medicine, Cancer Sciences Unit, University of Southampton, Southampton, UK
| | - Kate Schroder
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia
| | - Luca Scorrano
- Department of Biology, University of Padua, Padua, Italy
- Veneto Institute of Molecular Medicine, Padua, Italy
| | - Federico Sesti
- Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, NJ, USA
| | - Feng Shao
- National Institute of Biological Sciences, Beijing, PR China
| | - Yufang Shi
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
- The Third Affiliated Hospital of Soochow University and State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Soochow University, Suzhou, Jiangsu, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Giuseppe S Sica
- Department of Surgical Science, University Tor Vergata, Rome, Italy
| | - John Silke
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Hans-Uwe Simon
- Institute of Pharmacology, University of Bern, Bern, Switzerland
- Institute of Biochemistry, Brandenburg Medical School, Neuruppin, Germany
| | - Antonella Sistigu
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | | | - Brent R Stockwell
- Department of Biological Sciences and Department of Chemistry, Columbia University, New York, NY, USA
| | - Flavie Strapazzon
- IRCCS Fondazione Santa Lucia, Rome, Italy
- Univ Lyon, Univ Lyon 1, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyogène CNRS, INSERM, Lyon, France
| | - Andreas Strasser
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Liming Sun
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China
| | - Erwei Sun
- Department of Rheumatology and Immunology, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China
| | - Qiang Sun
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Gyorgy Szabadkai
- Department of Biomedical Sciences, University of Padua, Padua, Italy
- Department of Cell and Developmental Biology, Consortium for Mitochondrial Research, University College London, London, UK
| | - Stephen W G Tait
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Beatson Institute, Glasgow, UK
| | - Daolin Tang
- Department of Surgery, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA
| | - Nektarios Tavernarakis
- Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology-Hellas, Heraklion, Crete, Greece
- Department of Basic Sciences, School of Medicine, University of Crete, Heraklion, Crete, Greece
| | - Carol M Troy
- Departments of Pathology & Cell Biology and Neurology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, NY, USA
| | - Boris Turk
- Department of Biochemistry and Molecular and Structural Biology, J. Stefan Institute, Ljubljana, Slovenia
- Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, Slovenia
| | - Nicoletta Urbano
- Department of Oncohaematology, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Peter Vandenabeele
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Methusalem Program, Ghent University, Ghent, Belgium
| | - Tom Vanden Berghe
- VIB-UGent Center for Inflammation Research, Ghent, Belgium
- Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
- Infla-Med Centre of Excellence, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Matthew G Vander Heiden
- Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
- Dana-Farber Cancer Institute, Boston, MA, USA
| | | | - Alexei Verkhratsky
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- Achucarro Center for Neuroscience, IKERBASQUE, Bilbao, Spain
- School of Forensic Medicine, China Medical University, Shenyang, China
- State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania
| | - Andreas Villunger
- Institute for Developmental Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria
- The Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences (OeAW), Vienna, Austria
- The Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases (LBI-RUD), Vienna, Austria
| | - Silvia von Karstedt
- Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, Cologne, Germany
| | - Anne K Voss
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, Australia
| | | | - Domagoj Vucic
- Department of Early Discovery Biochemistry, Genentech, South San Francisco, CA, USA
| | - Daniela Vuri
- Department of Experimental Medicine, University of Rome Tor Vergata, TOR, Rome, Italy
| | - Erwin F Wagner
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Henning Walczak
- Center for Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany
- CECAD Cluster of Excellence, University of Cologne, Cologne, Germany
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, London, UK
| | - David Wallach
- Department of Biomolecular Sciences, The Weizmann Institute of Science, Rehovot, Israel
| | - Ruoning Wang
- Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA
| | - Ying Wang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Achim Weber
- University of Zurich and University Hospital Zurich, Department of Pathology and Molecular Pathology, Zurich, Switzerland
- University of Zurich, Institute of Molecular Cancer Research, Zurich, Switzerland
| | - Will Wood
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK
| | - Takahiro Yamazaki
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA
| | - Huang-Tian Yang
- Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Zahra Zakeri
- Queens College and Graduate Center, City University of New York, Flushing, NY, USA
| | - Joanna E Zawacka-Pankau
- Department of Medicine Huddinge, Karolinska Institute, Stockholm, Sweden
- Department of Biochemistry, Laboratory of Biophysics and p53 protein biology, Medical University of Warsaw, Warsaw, Poland
| | - Lin Zhang
- Department of Pharmacology & Chemical Biology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Haibing Zhang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China
| | - Boris Zhivotovsky
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
- Faculty of Medicine, Lomonosov Moscow State University, Moscow, Russia
| | - Wenzhao Zhou
- Laboratory of Cell Engineering, Institute of Biotechnology, Beijing, China
- Research Unit of Cell Death Mechanism, 2021RU008, Chinese Academy of Medical Science, Beijing, China
| | - Mauro Piacentini
- Department of Biology, University of Rome Tor Vergata, Rome, Italy
- National Institute for Infectious Diseases IRCCS "Lazzaro Spallanzani", Rome, Italy
| | - Guido Kroemer
- Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France
- Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire de France, Paris, France
- Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
| | - Lorenzo Galluzzi
- Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, New York, NY, USA.
- Caryl and Israel Englander Institute for Precision Medicine, New York, NY, USA.
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10
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Abstract
Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts. Other conditions, such as acquired cystic disease and kidney cancer, are characterized by excess numbers of cyst wall and malignant cells, respectively. Cell death modalities act to clear unwanted cells, but disproportionate responses can contribute to the detrimental loss of kidney cells. Indeed, pathways of regulated cell death - including apoptosis and necrosis - have emerged as central events in the pathogenesis of various kidney diseases that may be amenable to therapeutic intervention. Modes of regulated necrosis, such as ferroptosis, necroptosis and pyroptosis may cause kidney injury directly or through the recruitment of immune cells and stimulation of inflammatory responses. Importantly, multiple layers of interconnections exist between different modalities of regulated cell death, including shared triggers, molecular components and protective mechanisms.
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Affiliation(s)
- Ana B Sanz
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain
- RICORS2040, Madrid, Spain
| | - Maria Dolores Sanchez-Niño
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain
- RICORS2040, Madrid, Spain
- Departamento de Medicina, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
| | - Adrian M Ramos
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain
- RICORS2040, Madrid, Spain
| | - Alberto Ortiz
- Department of Nephrology and Hypertension, IIS-Fundacion Jimenez Diaz UAM, Madrid, Spain.
- RICORS2040, Madrid, Spain.
- Departamento de Farmacología, Universidad Autonoma de Madrid, Madrid, Spain.
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11
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Costa F, Beltrami E, Mellone S, Sacchetti S, Boggio E, Gigliotti CL, Stoppa I, Dianzani U, Rolla R, Giordano M. Genes and Microbiota Interaction in Monogenic Autoimmune Disorders. Biomedicines 2023; 11:1127. [PMID: 37189745 PMCID: PMC10135656 DOI: 10.3390/biomedicines11041127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 03/30/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023] Open
Abstract
Monogenic autoimmune disorders represent an important tool to understand the mechanisms behind central and peripheral immune tolerance. Multiple factors, both genetic and environmental, are known to be involved in the alteration of the immune activation/immune tolerance homeostasis typical of these disorders, making it difficult to control the disease. The latest advances in genetic analysis have contributed to a better and more rapid diagnosis, although the management remains confined to the treatment of clinical manifestations, as there are limited studies on rare diseases. Recently, the correlation between microbiota composition and the onset of autoimmune disorders has been investigated, thus opening up new perspectives on the cure of monogenic autoimmune diseases. In this review, we will summarize the main genetic features of both organ-specific and systemic monogenic autoimmune diseases, reporting on the available literature data on microbiota alterations in these patients.
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Affiliation(s)
- Federica Costa
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
| | - Eleonora Beltrami
- Maggiore della Carità University Hospital, 28100 Novara, Italy; (E.B.); (S.M.)
| | - Simona Mellone
- Maggiore della Carità University Hospital, 28100 Novara, Italy; (E.B.); (S.M.)
| | - Sara Sacchetti
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
| | - Elena Boggio
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
| | - Casimiro Luca Gigliotti
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
| | - Ian Stoppa
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
| | - Umberto Dianzani
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
- Maggiore della Carità University Hospital, 28100 Novara, Italy; (E.B.); (S.M.)
| | - Roberta Rolla
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
- Maggiore della Carità University Hospital, 28100 Novara, Italy; (E.B.); (S.M.)
| | - Mara Giordano
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
- Maggiore della Carità University Hospital, 28100 Novara, Italy; (E.B.); (S.M.)
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12
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Liu L, Wu Y, Ye K, Cai M, Zhuang G, Wang J. Antibody-Targeted TNFRSF Activation for Cancer Immunotherapy: The Role of FcγRIIB Cross-Linking. Front Pharmacol 2022; 13:924197. [PMID: 35865955 PMCID: PMC9295861 DOI: 10.3389/fphar.2022.924197] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 05/30/2022] [Indexed: 12/19/2022] Open
Abstract
Co-stimulation signaling in various types of immune cells modulates immune responses in physiology and disease. Tumor necrosis factor receptor superfamily (TNFRSF) members such as CD40, OX40 and CD137/4-1BB are expressed on myeloid cells and/or lymphocytes, and they regulate antigen presentation and adaptive immune activities. TNFRSF agonistic antibodies have been evaluated extensively in preclinical models, and the robust antitumor immune responses and efficacy have encouraged continued clinical investigations for the last two decades. However, balancing the toxicities and efficacy of TNFRSF agonistic antibodies remains a major challenge in the clinical development. Insights into the co-stimulation signaling biology, antibody structural roles and their functionality in immuno-oncology are guiding new advancement of this field. Leveraging the interactions between antibodies and the inhibitory Fc receptor FcγRIIB to optimize co-stimulation agonistic activities dependent on FcγRIIB cross-linking selectively in tumor microenvironment represents the current frontier, which also includes cross-linking through tumor antigen binding with bispecific antibodies. In this review, we will summarize the immunological roles of TNFRSF members and current clinical studies of TNFRSF agonistic antibodies. We will also cover the contribution of different IgG structure domains to these agonistic activities, with a focus on the role of FcγRIIB in TNFRSF cross-linking and clustering bridged by agonistic antibodies. We will review and discuss several Fc-engineering approaches to optimize Fc binding ability to FcγRIIB in the context of proper Fab and the epitope, including a cross-linking antibody (xLinkAb) model and its application in developing TNFRSF agonistic antibodies with improved efficacy and safety for cancer immunotherapy.
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Affiliation(s)
| | - Yi Wu
- Lyvgen Biopharma, Shanghai, China
| | - Kaiyan Ye
- State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Meichun Cai
- State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guanglei Zhuang
- State Key Laboratory of Oncogenes and Related Genes, Department of Obstetrics and Gynecology, Ren Ji Hospital, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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13
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Akama-Garren EH, Carroll MC. T Cell Help in the Autoreactive Germinal Center. Scand J Immunol 2022; 95:e13192. [PMID: 35587582 DOI: 10.1111/sji.13192] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 05/10/2022] [Accepted: 05/13/2022] [Indexed: 11/29/2022]
Abstract
The germinal center serves as a site of B cell selection and affinity maturation, critical processes for productive adaptive immunity. In autoimmune disease tolerance is broken in the germinal center reaction, leading to production of autoreactive B cells that may propagate disease. Follicular T cells are crucial regulators of this process, providing signals necessary for B cell survival in the germinal center. Here we review the emerging roles of follicular T cells in the autoreactive germinal center. Recent advances in immunological techniques have allowed study of the gene expression profiles and repertoire of follicular T cells at unprecedented resolution. These studies provide insight into the potential role follicular T cells play in preventing or facilitating germinal center loss of tolerance. Improved understanding of the mechanisms of T cell help in autoreactive germinal centers provides novel therapeutic targets for diseases of germinal center dysfunction.
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Affiliation(s)
- Elliot H Akama-Garren
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.,Harvard-MIT Health Sciences and Technology, Harvard Medical School, Boston, MA, USA
| | - Michael C Carroll
- Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
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14
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Regulation of activated T cell survival in rheumatic autoimmune diseases. Nat Rev Rheumatol 2022; 18:232-244. [PMID: 35075294 DOI: 10.1038/s41584-021-00741-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/16/2021] [Indexed: 12/29/2022]
Abstract
Adaptive immune responses rely on the proliferation of T lymphocytes able to recognize and eliminate pathogens. The magnitude and duration of the expansion of activated T cell clones are finely regulated to minimize immunopathology and avoid autoimmunity. In patients with rheumatic autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, activated lymphocytes survive and exert effector functions for prolonged periods, defying the mechanisms that normally curb their capacities during acute and chronic infections. Here, we review the molecular mechanisms that limit the duration of immune responses in health and discuss the factors that alter such regulation in the setting of systemic lupus erythematosus and rheumatoid arthritis. We highlight defects that could contribute to the development and progression of autoimmune disease and describe how chronic inflammation can alter the regulation of activated lymphocyte survival, promoting its perpetuation. These concepts might contribute to the understanding of the mechanisms that underlie the chronicity of inflammation in the context of autoimmunity.
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15
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Risso V, Lafont E, Le Gallo M. Therapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases. Cell Death Dis 2022; 13:248. [PMID: 35301281 PMCID: PMC8931059 DOI: 10.1038/s41419-022-04688-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 02/09/2022] [Accepted: 02/24/2022] [Indexed: 12/14/2022]
Abstract
Cell death plays a pivotal role in the maintenance of tissue homeostasis. Key players in the controlled induction of cell death are the Death Receptors (DR). CD95 is a prototypic DR activated by its cognate ligand CD95L triggering programmed cell death. As a consequence, alterations in the CD95/CD95L pathway have been involved in several disease conditions ranging from autoimmune diseases to inflammation and cancer. CD95L-induced cell death has multiple roles in the immune response since it constitutes one of the mechanisms by which cytotoxic lymphocytes kill their targets, but it is also involved in the process of turning off the immune response. Furthermore, beyond the canonical pro-death signals, CD95L, which can be membrane-bound or soluble, also induces non-apoptotic signaling that contributes to its tumor-promoting and pro-inflammatory roles. The intent of this review is to describe the role of CD95/CD95L in the pathophysiology of cancers, autoimmune diseases and chronic inflammation and to discuss recently patented and emerging therapeutic strategies that exploit/block the CD95/CD95L system in these diseases.
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Affiliation(s)
- Vesna Risso
- INSERM U1242, Oncogenesis Stress Signaling, University of Rennes, Rennes, France
- Centre de lutte contre le cancer Eugène Marquis, Rennes, France
| | - Elodie Lafont
- INSERM U1242, Oncogenesis Stress Signaling, University of Rennes, Rennes, France
- Centre de lutte contre le cancer Eugène Marquis, Rennes, France
| | - Matthieu Le Gallo
- INSERM U1242, Oncogenesis Stress Signaling, University of Rennes, Rennes, France.
- Centre de lutte contre le cancer Eugène Marquis, Rennes, France.
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16
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Huang X, Zhang Q, Zhang H, Lu Q. A Contemporary Update on the Diagnosis of Systemic Lupus Erythematosus. Clin Rev Allergy Immunol 2022; 63:311-329. [DOI: 10.1007/s12016-021-08917-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/23/2021] [Indexed: 12/11/2022]
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17
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Aki T, Uemura K. Cell Death and Survival Pathways Involving ATM Protein Kinase. Genes (Basel) 2021; 12:1581. [PMID: 34680975 PMCID: PMC8535589 DOI: 10.3390/genes12101581] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/28/2021] [Accepted: 10/04/2021] [Indexed: 12/15/2022] Open
Abstract
Cell death is the ultimate form of cellular dysfunction, and is induced by a wide range of stresses including genotoxic stresses. During genotoxic stress, two opposite cellular reactions, cellular protection through DNA repair and elimination of damaged cells by the induction of cell death, can occur in both separate and simultaneous manners. ATM (ataxia telangiectasia mutated) kinase (hereafter referred to as ATM) is a protein kinase that plays central roles in the induction of cell death during genotoxic stresses. It has long been considered that ATM mediates DNA damage-induced cell death through inducing apoptosis. However, recent research progress in cell death modality is now revealing ATM-dependent cell death pathways that consist of not only apoptosis but also necroptosis, ferroptosis, and dysfunction of autophagy, a cellular survival mechanism. In this short review, we intend to provide a brief outline of cell death mechanisms in which ATM is involved, with emphasis on pathways other than apoptosis.
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Affiliation(s)
- Toshihiko Aki
- Department of Forensic Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
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18
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Abstract
In the last decade, the role of apoptosis in the pathophysiology of acute kidney injury (AKI) and AKI to chronic kidney disease (CKD) progression has been revisited as our understanding of ferroptosis and necroptosis has emerged. A growing body of evidence, reviewed here, ascribes a central pathophysiological role for ferroptosis and necroptosis to AKI, nephron loss, and acute tubular necrosis. We will introduce concepts to the non-cell-autonomous manner of kidney tubular injury during ferroptosis, a phenomenon that we refer to as a "wave of death." We hypothesize that necroptosis might initiate cell death propagation through ferroptosis. The remaining necrotic debris requires effective removal processes to prevent a secondary inflammatory response, referred to as necroinflammation. Open questions include the differences in the immunogenicity of ferroptosis and necroptosis, and the specificity of necrostatins and ferrostatins to therapeutically target these processes to prevent AKI-to-CKD progression and end-stage renal disease.
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19
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Vincent FB, Kandane-Rathnayake R, Koelmeyer R, Harris J, Hoi AY, Mackay F, Morand EF. Associations of serum soluble Fas and Fas ligand (FasL) with outcomes in systemic lupus erythematosus. Lupus Sci Med 2021; 7:7/1/e000375. [PMID: 32546562 PMCID: PMC7299016 DOI: 10.1136/lupus-2019-000375] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/24/2020] [Accepted: 05/13/2020] [Indexed: 01/11/2023]
Abstract
Objective Fas/Fas ligand (FasL) and B cell-activating factor (BAFF) signalling have pivotal roles in SLE pathogenesis. We investigated the clinical associations of serum concentrations of soluble Fas (sFas) and soluble FasL (sFasL) in SLE and their relationship with BAFF. Methods Serum sFas and sFasL were quantified by multiplex assay, and BAFF by ELISA, in 118 patients with SLE and 17 healthy controls (HC). SLE disease activity and organ damage were assessed using the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) and the Systemic Lupus International Collaborating Clinics Damage Index. Results sFas, sFasL and BAFF were detectable in all samples. Serum sFas and sFasL were significantly higher in SLE compared with HC. In univariable regression analyses, patients with active renal disease and those with flare had significantly higher levels of sFas compared with those without. High serum BAFF in patients with SLE was associated with increased sFas but not sFasL. The association between sFas and renal disease remained significant after adjusting for BAFF, but the association with flare attenuated. High sFas levels were associated with increased time-adjusted mean SLEDAI-2K, even after adjusting for BAFF, and with higher odds of flare over time. In contrast, high sFasL was associated with reduced organ damage over time. Serum sFasL/sFas ratio was negatively associated with active overall disease, flare and organ damage. Conclusions Serum sFas is associated with active renal SLE, and active disease and flare over time, while sFasL/sFas ratio is negatively associated with disease activity and organ damage accrual. Treatments correcting abnormal levels of sFas/FasL may be worthy of evaluation in SLE.
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Affiliation(s)
- Fabien B Vincent
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Rangi Kandane-Rathnayake
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Rachel Koelmeyer
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - James Harris
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Alberta Y Hoi
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Fabienne Mackay
- Department of Immunology and Pathology, Monash University, Central Clinical School, Alfred Medical Research and Education Precinct (AMREP), Melbourne, Victoria, Australia.,Department of Microbiology and Immunology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
| | - Eric F Morand
- Centre for Inflammatory Diseases, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
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20
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Hughes LD, Wang Y, Meli AP, Rothlin CV, Ghosh S. Decoding Cell Death: From a Veritable Library of Babel to Vade Mecum? Annu Rev Immunol 2021; 39:791-817. [PMID: 33902311 DOI: 10.1146/annurev-immunol-102819-072601] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Programmed cell death (PCD) is a requisite feature of development and homeostasis but can also be indicative of infections, injuries, and pathologies. In concordance with these heterogeneous contexts, an array of disparate effector responses occur downstream of cell death and its clearance-spanning tissue morphogenesis, homeostatic turnover, host defense, active dampening of inflammation, and tissue repair. This raises a fundamental question of how a single contextually appropriate response ensues after an event of PCD. To explore how complex inputs may together tailor the specificity of the resulting effector response, here we consider (a) the varying contexts during which different cell death modalities are observed, (b) the nature of the information that can be passed on by cell corpses, and (c) the ways by which efferocyte populations synthesize signals from dying cells with those from the surrounding microenvironment.
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Affiliation(s)
- Lindsey D Hughes
- Department of Immunobiology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA; , , ,
| | - Yaqiu Wang
- Department of Immunobiology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA; , , ,
| | - Alexandre P Meli
- Department of Immunobiology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA; , , ,
| | - Carla V Rothlin
- Department of Immunobiology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA; , , , .,Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA;
| | - Sourav Ghosh
- Department of Pharmacology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA; .,Department of Neurology, School of Medicine, Yale University, New Haven, Connecticut 06520, USA
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21
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Lundy SK, Taitano SH, van der Vlugt LEPM. Characterization and Activation of Fas Ligand-Producing Mouse B Cells and Their Killer Exosomes. Methods Mol Biol 2021; 2270:149-178. [PMID: 33479898 DOI: 10.1007/978-1-0716-1237-8_9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
B lymphocytes make several contributions to immune regulation including production of antibodies with regulatory properties, release of immune suppressive cytokines, and expression of death-inducing ligands. A role for Fas ligand (FasL)-expressing "killer" B cells in regulating T helper (TH) cell survival and chronic inflammation has been demonstrated in animal models of schistosome worm and other infections, asthma, autoimmune arthritis, and type 1 diabetes. FasL+ B cells were also capable of inducing immune tolerance in a male-to-female transplantation model. Interestingly, populations of B cells found in the spleen and lungs of naïve mice constitutively expresses FasL and have potent killer function against TH cells that is antigen-specific and FasL-dependent. Epstein-Barr virus-transformed human B cells constitutively express FasL and package it into exosomes that co-express MHC Class II molecules and have killer function against antigen-specific TH cells. FasL+ exosomes with markers of B-cell lineage are abundant in the spleen of naïve mice. Killer B cells therefore represent a novel target for immune modulation in many disease settings. Our laboratory has published methods of characterizing FasL+ B cells and inducing their proliferation in vitro. This updated chapter will describe methods of identifying and expanding killer B cells from mice, detecting FasL expression in B cells, extracting FasL+ exosomes from spleen and culture supernatants, and performing functional killing assays against antigen-specific TH cells.
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Affiliation(s)
- Steven K Lundy
- Graduate Program in Immunology, Program in Biomedical Sciences and Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
| | - Sophina H Taitano
- Graduate Program in Immunology, Program in Biomedical Sciences and Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Luciën E P M van der Vlugt
- Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA
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22
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Flores-Mendoza G, Rodríguez-Rodríguez N, Rubio RM, Madera-Salcedo IK, Rosetti F, Crispín JC. Fas/FasL Signaling Regulates CD8 Expression During Exposure to Self-Antigens. Front Immunol 2021; 12:635862. [PMID: 33841416 PMCID: PMC8024570 DOI: 10.3389/fimmu.2021.635862] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 03/04/2021] [Indexed: 11/13/2022] Open
Abstract
Activation of self-reactive CD8+ T cells induces a peripheral tolerance mechanism that involves loss of CD8 expression. Because genetic deficiency of Fas and Fasl causes the accumulation of double-negative (DN; CD3+ TCR-αβ+ CD4- CD8-) T cells that have been proposed to derive from CD8+ cells, we decided to explore the role of Fas and FasL in self-antigen-induced CD8 downregulation. To this end, we quantified Fas and FasL induction by different stimuli and analyzed the effects of Fas/FasL deficiency during a protective immune response and after exposure to self-antigens. Our data describes how Fas and FasL upregulation differs depending on the setting of CD8 T cell activation and demonstrates that Fas/FasL signaling maintains CD8 expression during repetitive antigen stimulation and following self-antigen encounter. Together, our results reveal an unexpected role of Fas/FasL signaling and offer a new insight into the role of these molecules in the regulation of immune tolerance.
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Affiliation(s)
- Giovanna Flores-Mendoza
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Noé Rodríguez-Rodríguez
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Rosa M. Rubio
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Iris K. Madera-Salcedo
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - Florencia Rosetti
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - José C. Crispín
- Departamento de Inmunología y Reumatología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Escuela de Medicina y Ciencias de la Salud, Tecnologico de Monterrey, Monterrey, Mexico
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23
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Neonatal Autoimmune Lymphoproliferative Syndrome: A Case Report and A Brief Review. J Pediatr Hematol Oncol 2021; 43:e227-e229. [PMID: 32149866 DOI: 10.1097/mph.0000000000001777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 02/10/2020] [Indexed: 11/27/2022]
Abstract
The authors are reporting a case of autoimmune lymphoproliferative syndrome in a newborn who presented with massive hepatosplenomegaly, thrombocytopenia, and anemia at birth. Antenatal ultrasound revealed a fetus with hepatosplenomegaly. The infant was treated with steroids and sirolimus and is doing well at 4 years of age. This is the first case report of autoimmune lymphoproliferative syndrome presenting as hepatosplenomegaly during fetal life.
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24
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Gregory-Ksander M, Marshak-Rothstein A. The FasLane to ocular pathology-metalloproteinase cleavage of membrane-bound FasL determines FasL function. J Leukoc Biol 2021; 110:965-977. [PMID: 33565149 DOI: 10.1002/jlb.3ri1220-834r] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 12/26/2022] Open
Abstract
Fas ligand (FasL) is best known for its ability to induce cell death in a wide range of Fas-expressing targets and to limit inflammation in immunoprivileged sites such as the eye. In addition, the ability of FasL to induce a much more extensive list of outcomes is being increasingly explored and accepted. These outcomes include the induction of proinflammatory cytokine production, T cell activation, and cell motility. However, the distinct and opposing functions of membrane-associated FasL (mFasL) and the C-terminal soluble FasL fragment (sFasL) released by metalloproteinase cleavage is less well documented and understood. Both mFasL and sFasL can form trimers that engage the trimeric Fas receptor, but only mFasL can form a multimeric complex in lipid rafts to trigger apoptosis and inflammation. By contrast, a number of reports have now documented the anti-apoptotic and anti-inflammatory activity of sFasL, pointing to a critical regulatory function of the soluble molecule. The immunomodulatory activity of FasL is particularly evident in ocular pathology where elimination of the metalloproteinase cleavage site and the ensuing increased expression of mFasL can severely exacerbate the extent of inflammation and cell death. By contrast, both homeostatic and increased expression of sFasL can limit inflammation and cell death. The mechanism(s) responsible for the protective activity of sFasL are discussed but remain controversial. Nevertheless, it will be important to consider therapeutic applications of sFasL for the treatment of ocular diseases such as glaucoma.
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Affiliation(s)
- Meredith Gregory-Ksander
- Schepens Eye Research Institute of Mass Eye and Ear, Harvard Medical School, Boston, Massachusetts, USA
| | - Ann Marshak-Rothstein
- Department of Medicine/Rheumatology, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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25
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ALG2 Influences T cell apoptosis by regulating FASLG intracellular transportation. Biochem J 2021; 477:3105-3121. [PMID: 32766719 DOI: 10.1042/bcj20200028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Revised: 08/06/2020] [Accepted: 08/06/2020] [Indexed: 12/16/2022]
Abstract
In the immune system, T lymphocytes undergo rapid clonal expansion upon pathogen infection. Following pathogen clearance, most of proliferated T cells will be eliminated by the apoptosis pathway to keep the balance of immune cells. FASLG, by interacting with its cognate receptor FAS, plays a major role in controlling the T cell death. FASLG is a type II transmembrane protein, with its C-terminal extracellular domain responsible for interacting with FAS. The N-terminal cytosolic region, despite short and intrinsically disordered, plays critical roles on the protein stability and transportation. The correct localization, either on the plasma membrane or secreted with exosome, or shed into the extracellular region after protease cleavage, has a great impact on the proper function of FASLG. Following synthesis, FASLG is transported by intracellular vesicle transportation system to the final destination. In this report, ALG2, a molecule identified in the T cell apoptosis and shown to be involved in vesicle trafficking previously, was found to interact with FASLG and regulate FASLG transportation. Therefore, we identified a new regulating factor for FASLG function within T cells and also revealed a new pathway for ALG2 involvement in T cell apoptosis.
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26
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Casamayor-Polo L, López-Nevado M, Paz-Artal E, Anel A, Rieux-Laucat F, Allende LM. Immunologic evaluation and genetic defects of apoptosis in patients with autoimmune lymphoproliferative syndrome (ALPS). Crit Rev Clin Lab Sci 2020; 58:253-274. [PMID: 33356695 DOI: 10.1080/10408363.2020.1855623] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Apoptosis plays an important role in controlling the adaptive immune response and general homeostasis of the immune cells, and impaired apoptosis in the immune system results in autoimmunity and immune dysregulation. In the last 25 years, inherited human diseases of the Fas-FasL pathway have been recognized. Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity, characterized clinically by nonmalignant and noninfectious lymphoproliferation, autoimmunity, and increased risk of lymphoma due to a defect in lymphocyte apoptosis. The laboratory hallmarks of ALPS are an elevated percentage of T-cell receptor αβ double negative T cells (DNTs), elevated levels of vitamin B12, soluble FasL, IL-10, IL-18 and IgG, and defective in vitro Fas-mediated apoptosis. In order of frequency, the genetic defects associated with ALPS are germinal and somatic ALPS-FAS, ALPS-FASLG, ALPS-CASP10, ALPS-FADD, and ALPS-CASP8. Partial disease penetrance and severity suggest the combination of germline and somatic FAS mutations as well as other risk factor genes. In this report, we summarize human defects of apoptosis leading to ALPS and defects that are known as ALPS-like syndromes that can be clinically similar to, but are genetically distinct from, ALPS. An efficient genetic and immunological diagnostic approach to patients suspected of having ALPS or ALPS-like syndromes is essential because this enables the establishment of specific therapeutic strategies for improving the prognosis and quality of life of patients.
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Affiliation(s)
- Laura Casamayor-Polo
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Marta López-Nevado
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain
| | - Estela Paz-Artal
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.,Immunology Department, University Hospital 12 de Octubre, Madrid, Spain.,School of Medicine, University Hospital 12 de Octubre, Complutense University of Madrid, Madrid, Spain
| | - Alberto Anel
- Apoptosis, Immunity and Cancer Group, University of Zaragoza/Aragón Health Research Institute (IIS-Aragón), Zaragoza, Spain
| | - Frederic Rieux-Laucat
- Laboratory of Immunogenetics of Pediatric Autoimmune Diseases, Université de Paris, Imagine Institute, INSERM UMR 1163, Paris, France
| | - Luis M Allende
- Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain.,Immunology Department, University Hospital 12 de Octubre, Madrid, Spain.,School of Medicine, University Hospital 12 de Octubre, Complutense University of Madrid, Madrid, Spain
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27
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Xiao B, Li X, Feng XY, Gong S, Li ZB, Zhang J, Yuan HJ, Tan JH. Restraint stress of male mice induces apoptosis in spermatozoa and spermatogenic cells: role of the FasL/Fas system†. Biol Reprod 2020; 101:235-247. [PMID: 31066896 DOI: 10.1093/biolre/ioz057] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/28/2018] [Accepted: 04/05/2019] [Indexed: 12/23/2022] Open
Abstract
The mechanisms by which psychological stress impairs semen quality are largely unknown. By using a restraint-stressed mouse model, we studied the role of the FasL/Fas system in psychological stress-induced apoptosis of spermatozoa and spermatogenic cells. Male mice were restrained for 48 h before examination for sperm fertilizing potential and for apoptosis and FasL/Fas expression in spermatozoa, spermatogenetic cells/seminiferous tubules, and caudae epididymides. The results showed that the male restraint reduced motility, fertilization rates, and mitochondrial membrane potential while increasing apoptosis and Fas expression in spermatozoa. Restraint also facilitated apoptosis and FasL/Fas expression in spermatogenic cells/seminiferous tubules and caudae epididymides. The restraint-induced apoptosis in spermatozoa and spermatogenic cells was significantly ameliorated in gld mice that harbor a loss-of-function mutation in FasL. However, incubation with FasL did not affect sperm motility and apoptosis, while incubation with tumor necrosis factor (TNF)-α did. The epididymis of the gld mice produced significantly less TNF-α and TNF-related apoptosis-inducing ligand (TRAIL) than that of wild-type mice did after male restraint. Thus, the results confirmed that the FasL/Fas system played an important role in the psychological stress-induced apoptosis of spermatozoa and spermatogenic cells and that FasL triggered sperm apoptosis in epididymis dependently through promoting TNF-α and TRAIL secretion.
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Affiliation(s)
- Bin Xiao
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Xiao Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Xiu-Yun Feng
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Shuai Gong
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Zhi-Bin Li
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Jie Zhang
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Hong-Jie Yuan
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
| | - Jing-He Tan
- Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, College of Animal Science and Veterinary Medicine, Shandong Agricultural University, Tai'an City, P. R. China
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28
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Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease. Nat Rev Rheumatol 2020; 16:496-513. [PMID: 32641743 DOI: 10.1038/s41584-020-0455-8] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/08/2020] [Indexed: 02/08/2023]
Abstract
Cell death is a vital process that occurs in billions of cells in the human body every day. This process helps maintain tissue homeostasis, supports recovery from acute injury, deals with infection and regulates immunity. Cell death can also provoke inflammatory responses, and lytic forms of cell death can incite inflammation. Loss of cell membrane integrity leads to the uncontrolled release of damage-associated molecular patterns (DAMPs), which are normally sequestered inside cells. Such DAMPs increase local inflammation and promote the production of cytokines and chemokines that modulate the innate immune response. Cell death can be both a consequence and a cause of inflammation, which can be difficult to distinguish in chronic diseases. Despite this caveat, excessive or poorly regulated cell death is increasingly recognized as a contributor to chronic inflammation in rheumatic disease and other inflammatory conditions. Drugs that inhibit cell death could, therefore, be used therapeutically for the treatment of these diseases, and programmes to develop such inhibitors are already underway. In this Review, we outline pathways for the major cell death programmes (apoptosis, necroptosis, pyroptosis and NETosis) and their potential roles in chronic inflammation. We also discuss current and developing therapies that target the cell death machinery.
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29
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Abstract
Laboratory animal models are beneficial when they recapitulate all or just some of the clinical and immunological manifestations of the disease. Various animals such as cats, rats, dogs, hamsters, guinea pigs, rabbits, horses, minks, pigs, and primates have been described lupus-like phenotype. However, a mouse has remained the preferable animal for scientific investigations as a result of their reduced lifespan, easy reproduction, markedly low costs, public acceptance, ease of genetic management, and the probability to stay under standardized conditions. It is highly challenging to establish a mouse model with all features of lupus because of the difficulty and the heterogeneity of the clinical features in systemic lupus erythematous (SLE). Additionally, due to the multiple differences between the mouse and human immune system, the direct translation usually fails. Each mouse model has specific characteristics and shares many subsets of aspects with the disease observed in humans, which gives researchers a tool to select their particular needs. Over 50 years, many mice models have been developed and used to dissect the pathogenesis of lupus, also to test novel drugs and therapies. In general, mice models that contribute considerably in SLE understanding can be divided into four groups: Spontaneous models, induced models, genetically modified models, along with humanizing mouse models that are the link between the mouse and human immune system. In this updated review, we will present what has been learned from different lupus mice models and how these models have contributed to a better understanding of lupus pathogenesis and treatment.
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Affiliation(s)
- Alya Halkom
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Haijing Wu
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qianjin Lu
- Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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30
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Meghil MM, Cutler CW. Oral Microbes and Mucosal Dendritic Cells, "Spark and Flame" of Local and Distant Inflammatory Diseases. Int J Mol Sci 2020; 21:E1643. [PMID: 32121251 PMCID: PMC7084622 DOI: 10.3390/ijms21051643] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 02/24/2020] [Accepted: 02/25/2020] [Indexed: 12/20/2022] Open
Abstract
Mucosal health and disease is mediated by a complex interplay between the microbiota ("spark") and the inflammatory response ("flame"). Pathobionts, a specific class of microbes, exemplified by the oral microbe Porphyromonas gingivalis, live mostly "under the radar" in their human hosts, in a cooperative relationship with the indigenous microbiota. Dendritic cells (DCs), mucosal immune sentinels, often remain undisturbed by such microbes and do not alert adaptive immunity to danger. At a certain tipping point of inflammation, an "awakening" of pathobionts occurs, wherein their active growth and virulence are stimulated, leading to a dysbiosis. Pathobiont becomes pathogen, and commensal becomes accessory pathogen. The local inflammatory outcome is the Th17-mediated degenerative bone disease, periodontitis (PD). In systemic circulation of PD subjects, inflammatory DCs expand, carrying an oral microbiome and promoting Treg and Th17 responses. At distant peripheral sites, comorbid diseases including atherosclerosis, Alzheimer's disease, macular degeneration, chronic kidney disease, and others are reportedly induced. This review will review the immunobiology of DCs, examine the complex interplay of microbes and DCs in the pathogenesis of PD and its comorbid inflammatory diseases, and discuss the role of apoptosis and autophagy in this regard. Overall, the pathophysiological mechanisms of DC-mediated chronic inflammation and tissue destruction will be summarized.
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Affiliation(s)
| | - Christopher W. Cutler
- Department of Periodontics, The Dental College of Georgia at Augusta University, Augusta, GA 30912, USA;
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31
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Guégan JP, Ginestier C, Charafe-Jauffret E, Ducret T, Quignard JF, Vacher P, Legembre P. CD95/Fas and metastatic disease: What does not kill you makes you stronger. Semin Cancer Biol 2020; 60:121-131. [PMID: 31176682 DOI: 10.1016/j.semcancer.2019.06.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 06/05/2019] [Accepted: 06/05/2019] [Indexed: 12/14/2022]
Abstract
CD95 (also known as Fas) is the prototype of death receptors; however, evidence suggests that this receptor mainly implements non-apoptotic signaling pathways such as NF-κB, MAPK, and PI3K that are involved in cell migration, differentiation, survival, and cytokine secretion. At least two different forms of CD95 L exist. The multi-aggregated transmembrane ligand (m-CD95 L) is cleaved by metalloproteases to release a homotrimeric soluble ligand (s-CD95 L). Unlike m-CD95 L, the interaction between s-CD95 L and its receptor CD95 fails to trigger apoptosis, but instead promotes calcium-dependent cell migration, which contributes to the accumulation of inflammatory Th17 cells in damaged organs of lupus patients and favors cancer cell invasiveness. Novel inhibitors targeting the pro-inflammatory roles of CD95/CD95 L may provide attractive therapeutic options for patients with chronic inflammatory disorders or cancer. This review discusses the roles of the CD95/CD95 L pair in cell migration and metastasis.
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Affiliation(s)
- Jean Philippe Guégan
- CLCC Eugène Marquis, Équipe Ligue Contre Le Cancer, Rennes, France; Université Rennes, INSERM U1242, Rennes, France
| | - Christophe Ginestier
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, Marseille, France
| | - Emmanuelle Charafe-Jauffret
- Aix-Marseille Univ, Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Epithelial Stem Cells and Cancer Lab, Marseille, France
| | - Thomas Ducret
- Université de Bordeaux, Bordeaux, France; Centre de Recherche Cardio Thoracique de Bordeaux, INSERM U1045, Bordeaux, France
| | - Jean-François Quignard
- Université de Bordeaux, Bordeaux, France; Centre de Recherche Cardio Thoracique de Bordeaux, INSERM U1045, Bordeaux, France
| | - Pierre Vacher
- Université de Bordeaux, Bordeaux, France; INSERM U1218, Bordeaux, France
| | - Patrick Legembre
- CLCC Eugène Marquis, Équipe Ligue Contre Le Cancer, Rennes, France; Université Rennes, INSERM U1242, Rennes, France.
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Olia A, Shimokawa C, Imai T, Suzue K, Hisaeda H. Suppression of systemic lupus erythematosus in NZBWF1 mice infected with Hymenolepis microstoma. Parasitol Int 2020; 76:102057. [PMID: 31954872 DOI: 10.1016/j.parint.2020.102057] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 01/13/2020] [Accepted: 01/14/2020] [Indexed: 12/15/2022]
Abstract
Intestinal helminths induce immune suppressive responses thought to regulate inflammatory diseases including allergies and autoimmune diseases. This study was designed to evaluate whether helminthic infections suppress the natural development of systemic lupus erythematosus (SLE) in NZBWF1 mice. Infection of NZBWF1 SLE-prone mice with two nematodes failed to establish long-lasting settlement. However, the Hymenolepis microstoma (Hm) rodent tapeworm successfully established long-term parasitization of NZBWF1 mice and was used to evaluate the suppressive effects of helminth infection. Ten-month-old NZBWF1 mice developed symptoms including autoantibody generation, proteinuria, glomerular histopathology, and splenomegaly, but mice infected with Hm at 2 months of age did not show any clinical signs. Furthermore, infection with Hm reduced lymphocyte activation and increased regulatory T cells in the spleen and mesenteric lymph nodes. These results indicate that infection with Hm protects NZBWF1 mice from naturally developing SLE and suggest that pathological immunity is attenuated, presumably because of the induction of regulatory T cells.
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Affiliation(s)
- Alex Olia
- Department of Parasitology, Graduate School of Medicine, Gunma University, Gunma, Japan; Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Chikako Shimokawa
- Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan
| | - Takashi Imai
- Department of Parasitology, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Kazutomo Suzue
- Department of Parasitology, Graduate School of Medicine, Gunma University, Gunma, Japan
| | - Hajime Hisaeda
- Department of Parasitology, Graduate School of Medicine, Gunma University, Gunma, Japan; Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan.
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Radaelli E, Santagostino SF, Sellers RS, Brayton CF. Immune Relevant and Immune Deficient Mice: Options and Opportunities in Translational Research. ILAR J 2019; 59:211-246. [PMID: 31197363 PMCID: PMC7114723 DOI: 10.1093/ilar/ily026] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/03/2018] [Indexed: 12/29/2022] Open
Abstract
In 1989 ILAR published a list and description of immunodeficient rodents used in research. Since then, advances in understanding of molecular mechanisms; recognition of genetic, epigenetic microbial, and other influences on immunity; and capabilities in manipulating genomes and microbiomes have increased options and opportunities for selecting mice and designing studies to answer important mechanistic and therapeutic questions. Despite numerous scientific breakthroughs that have benefitted from research in mice, there is debate about the relevance and predictive or translational value of research in mice. Reproducibility of results obtained from mice and other research models also is a well-publicized concern. This review summarizes resources to inform the selection and use of immune relevant mouse strains and stocks, aiming to improve the utility, validity, and reproducibility of research in mice. Immune sufficient genetic variations, immune relevant spontaneous mutations, immunodeficient and autoimmune phenotypes, and selected induced conditions are emphasized.
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Affiliation(s)
- Enrico Radaelli
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Sara F Santagostino
- Department of Safety Assessment, Genentech, Inc., South San Francisco, California
| | | | - Cory F Brayton
- Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland
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Ban T, Sato GR, Tamura T. Regulation and role of the transcription factor IRF5 in innate immune responses and systemic lupus erythematosus. Int Immunol 2019; 30:529-536. [PMID: 29860420 DOI: 10.1093/intimm/dxy032] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 05/29/2018] [Indexed: 02/07/2023] Open
Abstract
The transcription factor interferon regulatory factor-5 (IRF5) plays an important role in innate immune responses via the TLR-MyD88 (Toll-like receptor - myeloid differentiation primary response 88) pathway. IRF5 is also involved in the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE). Recent studies have identified new regulators, both positive and negative, which act on IRF5 activation events in the TLR-MyD88 pathway such as post-translational modifications, dimerization and nuclear translocation. A model of the causal relationship between IRF5 activation and SLE pathogenesis proposes that a loss of the negative regulation of IRF5 causes its hyperactivation, resulting in hyperproduction of type I interferons and other cytokines, and ultimately in the development of SLE. Importantly, to our knowledge, all murine models of SLE studied thus far have shown that IRF5 is required for the pathogenesis of SLE-like diseases. During the development of SLE-like diseases, IRF5 plays key roles in various cell types, including dendritic cells and B cells. It is noteworthy that the onset of SLE-like diseases can be inhibited by reducing the activity or amount of IRF5 by half. Therefore, IRF5 is an important therapeutic target of SLE, and selective suppression of its activity and expression may potentially lead to the development of new therapies.
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Affiliation(s)
- Tatsuma Ban
- Department of Immunology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan
| | - Go R Sato
- Department of Immunology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan
| | - Tomohiko Tamura
- Department of Immunology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan
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Jung KT, Oh SH. Polyubiquitination of p62/SQSTM1 is a prerequisite for Fas/CD95 aggregation to promote caspase-dependent apoptosis in cadmium-exposed mouse monocyte RAW264.7 cells. Sci Rep 2019; 9:12240. [PMID: 31439879 PMCID: PMC6706394 DOI: 10.1038/s41598-019-48684-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 08/01/2019] [Indexed: 12/19/2022] Open
Abstract
Cadmium(Cd) induces cytotoxicity via autophagy-induced apoptosis in non-activated mouse monocytes; however, the molecular mechanism remains unclear. Here, we show that autophagy induces Fas (CD95/APO-1)-mediated apoptosis by promoting accumulation of p62/SQSTM1 in response to Cd. Cd produced tumor necrosis factor (TNF)-α, peaking at 6 h, and exhibiting a concentration-dependent increase. Immunoblot analysis revealed polyubiquitinated (polyUb) full-length Fas (antibody clone G-9) and reduced cytosolic Fas (antibody clone M-20) in Cd-exposed RAW264.7 cells. The accumulation of polyUb-Fas was transient and positively correlated with polyUb-p62 and polyUb-proteins. Autophagy inhibition via chemical and genetic modulation suppressed Cd-induced polyUb-p62, polyUb-Fas, and polyUb-protein levels, whereas the level of cytosolic Fas recovered to that of the control. Immunofluorescence (IF) staining for full-length Fas, p62, and ubiquitin revealed an aggregated pattern in Cd-induced apoptotic cells, which was inhibited by blocking autophagy. Fas colocalized with microtubule-associated protein 1 light chain (LC)-3B. IF staining and immunoprecipitation assays revealed colocalization and interaction among p62, Ub, and Fas. Knockdown of p62 reduced the binding of Ub and Fas. Together, these data suggest that polyUb-p62 targets Fas and recruits it to autophagosomes, where Fas transiently aggregates to promote apoptosis and is degraded with polyUb-p62. In conclusion, autophagy regulates C-terminal cytosolic Fas aggregation via p62 polyubiquitination, which is required for apoptosis and may play a critical role in the production of select cytokines.
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Affiliation(s)
- Ki-Tae Jung
- Department of Anesthesiology and Pain Medicine, School of Medicine, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju, 501-759, Korea
| | - Seon-Hee Oh
- School of Medicine, Chosun University, 309 Pilmundaero, Dong-gu, Gwangju, 501-759, Korea.
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Moore DK, Loxton AG. Regulatory B lymphocytes: development and modulation of the host immune response during disease. Immunotherapy 2019; 11:691-704. [DOI: 10.2217/imt-2018-0185] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The role of B lymphocytes (B cells) in immunogenic responses has become increasingly important over the past decade, focusing on a new B-cell subtype: regulatory B-cells (Bregs). These Bregs have been shown to possess potent immunosuppressive activities and have identified as key players in disease control and immune tolerance. In this review, the occurrence of Breg type in various conditions, along with evidence supporting discovered functions and proposed purposes will be explored. An example of such regulatory functions includes the induction or suppression of various T lymphocyte phenotypes in response to a particular stimulus. Should Bregs prove effective in mediating immune responses, and correlate with favorable disease outcome, they may serve as a novel therapeutic to combat disease and prevent infection. However, the induction, function and stability of these cells remain unclear and further investigation is needed to better understand their role and therapeutic efficacy.
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Affiliation(s)
- Dannielle K Moore
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Cape Town, South Africa, 8000
- South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa, 8000
- Faculty of Medicine & Health Sciences, Division of Molecular Biology & Human Genetics, Stellenbosch University, Cape Town, South Africa, 8000
| | - Andre G Loxton
- DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Cape Town, South Africa, 8000
- South African Medical Research Council Centre for Tuberculosis Research, Stellenbosch University, Cape Town, South Africa, 8000
- Faculty of Medicine & Health Sciences, Division of Molecular Biology & Human Genetics, Stellenbosch University, Cape Town, South Africa, 8000
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Caspase-8-dependent control of NK- and T cell responses during cytomegalovirus infection. Med Microbiol Immunol 2019; 208:555-571. [PMID: 31098689 DOI: 10.1007/s00430-019-00616-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Accepted: 04/17/2019] [Indexed: 12/26/2022]
Abstract
Caspase-8 (CASP8) impacts antiviral immunity in expected as well as unexpected ways. Mice with combined deficiency in CASP8 and RIPK3 cannot support extrinsic apoptosis or RIPK3-dependent programmed necrosis, enabling studies of CASP8 function without complications of unleashed necroptosis. These extrinsic cell death pathways are naturally targeted by murine cytomegalovirus (MCMV)-encoded cell death suppressors, showing they are key to cell-autonomous host defense. Remarkably, Casp8-/-Ripk3-/-, Ripk1-/-Casp8-/-Ripk3-/- and Casp8-/-Ripk3K51A/K51A mice mount robust antiviral T cell responses to control MCMV infection. Studies in Casp8-/-Ripk3-/- mice show that CASP8 restrains expansion of MCMV-specific natural killer (NK) and CD8 T cells without compromising contraction or immune memory. Infected Casp8-/-Ripk3-/- or Casp8-/-Ripk3K51A/K51A mice have higher levels of virus-specific NK cells and CD8 T cells compared to matched RIPK3-deficient littermates or WT mice. CASP8, likely acting downstream of Fas death receptor, dampens proliferation of CD8 T cells during expansion. Importantly, contraction proceeds unimpaired in the absence of extrinsic death pathways owing to intact Bim-dependent (intrinsic) apoptosis. CD8 T cell memory develops in Casp8-/-Ripk3-/- mice, but memory inflation characteristic of MCMV infection is not sustained in the absence of CASP8 function. Despite this, Casp8-/-Ripk3-/- mice are immune to secondary challenge. Interferon (IFN)γ is recognized as a key cytokine for adaptive immune control of MCMV. Ifngr-/-Casp8-/-Ripk3-/- mice exhibit increased lifelong persistence in salivary glands as well as lungs compared to Ifngr-/- and Casp8-/-Ripk3-/- mice. Thus, mice deficient in CASP8 and RIPK3 are more dependent on IFNγ mechanisms for sustained T cell immune control of MCMV. Overall, appropriate NK- and T cell immunity to MCMV is dependent on host CASP8 function independent of RIPK3-regulated pathways.
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Rossin A, Miloro G, Hueber AO. TRAIL and FasL Functions in Cancer and Autoimmune Diseases: Towards an Increasing Complexity. Cancers (Basel) 2019; 11:cancers11050639. [PMID: 31072029 PMCID: PMC6563024 DOI: 10.3390/cancers11050639] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 04/26/2019] [Accepted: 04/28/2019] [Indexed: 12/31/2022] Open
Abstract
Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) and Fas Ligand (FasL/TNFSF6), two major cytokines of the TNF (Tumor Necrosis Factor) superfamily, exert their main functions from the immune system compartment. Mice model studies revealed that TRAIL and FasL-mediated signalling both control the homeostasis of the immune cells, mainly from the lymphoid lineage, and function on cytotoxic cells as effector proteins to eliminate the compromised cells. The first clues in the physiological functions of TRAIL arose from the analysis of TRAIL deficient mice, which, even though they are viable and fertile, are prone to cancer and autoimmune diseases development, revealing TRAIL as an important safeguard against autoimmunity and cancer. The naturally occurring gld (generalized lymphoproliferative disease) and lpr (lymphoproliferation) mutant mice develop lymphadenopathy and lupus-like autoimmune disease. The discovery that they are mutated in the fasl and the fas receptor gene, respectively, demonstrates the critical role of the FasL/Fas system in lymphocyte homeostasis and autoimmunity. This review summarizes the state of current knowledge regarding the key death and non-death immune functions that TRAIL and FasL play in the initiation and progression of cancer and autoimmune diseases.
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Affiliation(s)
- Aurélie Rossin
- Université Côte d'Azur, CNRS, Inserm, iBV, 06108 Nice, France.
| | - Giorgia Miloro
- Université Côte d'Azur, CNRS, Inserm, iBV, 06108 Nice, France.
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Sagrillo-Fagundes L, Bienvenue-Pariseault J, Legembre P, Vaillancourt C. An insight into the role of the death receptor CD95 throughout pregnancy: Guardian, facilitator, or foe. Birth Defects Res 2019; 111:197-211. [PMID: 30702213 DOI: 10.1002/bdr2.1470] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2018] [Accepted: 01/16/2019] [Indexed: 12/24/2022]
Abstract
The prototype death receptor CD95 (Fas) and its ligand, CD95L (FasL), have been thoroughly studied due to their role in immune homeostasis and elimination of infected and transformed cells. The fact that CD95 is present in female reproductive cells and modulated during embryogenesis and pregnancy has raised interest in its role in immune tolerance to the fetoplacental unit. CD95 has been shown to be critical for proper embryonic formation and survival. Moreover, altered expression of CD95 or its ligand causes autoimmunity and has also been directly involved in recurrent pregnancy losses and pregnancy disorders. The objective of this review is to summarize studies that evaluate the mechanisms involved in the activation of CD95 to provide an updated global view of its effect on the regulation of the maternal immune system. Modulation of the CD95 system components may be the immune basis of several common pregnancy disorders.
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Affiliation(s)
- Lucas Sagrillo-Fagundes
- Department of Environmental toxicology and Chemical Pharmacology, INRS - Institut Armand-Frappier and Center for Interdisciplinary Research on Well-Being, Health, Society and Environment, Laval, Quebec, Canada
| | - Josianne Bienvenue-Pariseault
- Department of Environmental toxicology and Chemical Pharmacology, INRS - Institut Armand-Frappier and Center for Interdisciplinary Research on Well-Being, Health, Society and Environment, Laval, Quebec, Canada
| | - Patrick Legembre
- Oncogenesis, Stress & Signaling Laboratory INSERM ERL440, Centre Eugène Marquis, Inserm U1242, Equipe Ligue Contre Le Cancer, Rennes, France
| | - Cathy Vaillancourt
- Department of Environmental toxicology and Chemical Pharmacology, INRS - Institut Armand-Frappier and Center for Interdisciplinary Research on Well-Being, Health, Society and Environment, Laval, Quebec, Canada
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Hahn BH, Kono DH. Animal Models in Lupus. DUBOIS' LUPUS ERYTHEMATOSUS AND RELATED SYNDROMES 2019:164-215. [DOI: 10.1016/b978-0-323-47927-1.00014-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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41
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Du W, Cao X. Cytotoxic Pathways in Allogeneic Hematopoietic Cell Transplantation. Front Immunol 2018; 9:2979. [PMID: 30631325 PMCID: PMC6315278 DOI: 10.3389/fimmu.2018.02979] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 12/04/2018] [Indexed: 12/11/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for hematologic malignancies, and other hematologic and immunologic diseases. Donor-derived immune cells identify and attack cancer cells in the patient producing a unique graft-vs.-tumor (GVT) effect. This beneficial response renders allo-HCT one of the most effective forms of tumor immunotherapy. However, alloreactive donor T cells can damage normal host cells thereby causing graft-vs.-host disease (GVHD), which results in substantial morbidity and mortality. To date, GVHD remains as the major obstacle for more successful application of allo-HCT. Of special significance in this context are a number of cytotoxic pathways that are involved in GVHD and GVT response as well as donor cell engraftment. In this review, we summarize progress in the investigation of these cytotoxic pathways, including Fas/Fas ligand (FasL), perforin/granzyme, and cytokine pathways. Many studies have delineated their distinct operating mechanisms and how they are involved in the complex cellular interactions amongst donor, host, tumor, and infectious pathogens. Driven by progressing elucidation of their contributions in immune reconstitution and regulation, various interventional strategies targeting these pathways have entered translational stages with aims to improve the effectiveness of allo-HCT.
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Affiliation(s)
- Wei Du
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States
| | - Xuefang Cao
- Department of Immunology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.,Department of Microbiology and Immunology, Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, MD, United States
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Bönelt P, Wöhner M, Minnich M, Tagoh H, Fischer M, Jaritz M, Kavirayani A, Garimella M, Karlsson MC, Busslinger M. Precocious expression of Blimp1 in B cells causes autoimmune disease with increased self-reactive plasma cells. EMBO J 2018; 38:embj.2018100010. [PMID: 30498131 PMCID: PMC6331720 DOI: 10.15252/embj.2018100010] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 10/29/2018] [Accepted: 11/02/2018] [Indexed: 11/25/2022] Open
Abstract
The transcription factor Blimp1 is not only an essential regulator of plasma cells, but also a risk factor for the development of autoimmune disease in humans. Here, we demonstrate in the mouse that the Prdm1 (Blimp1) gene was partially activated at the chromatin and transcription level in early B cell development, although mature Prdm1 mRNA did not accumulate due to posttranscriptional regulation. By analyzing a mouse model that facilitated ectopic Blimp1 protein expression throughout B lymphopoiesis, we could demonstrate that Blimp1 impaired B cell development by interfering with the B cell gene expression program, while leading to an increased abundance of plasma cells by promoting premature plasmablast differentiation of immature and mature B cells. With progressing age, these mice developed an autoimmune disease characterized by the presence of autoantibodies and glomerulonephritis. Hence, these data identified ectopic Blimp1 expression as a novel mechanism, through which Blimp1 can act as a risk factor in the development of autoimmune disease.
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Affiliation(s)
- Peter Bönelt
- Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
| | - Miriam Wöhner
- Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
| | - Martina Minnich
- Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
| | - Hiromi Tagoh
- Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
| | - Maria Fischer
- Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
| | - Markus Jaritz
- Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
| | - Anoop Kavirayani
- Vienna Biocenter Core Facilities (VBCF), Vienna Biocenter (VBC), Vienna, Austria
| | - Manasa Garimella
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
| | - Mikael Ci Karlsson
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
| | - Meinrad Busslinger
- Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
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Meyer Zu Horste G, Przybylski D, Schramm MA, Wang C, Schnell A, Lee Y, Sobel R, Regev A, Kuchroo VK. Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1. Immunity 2018; 48:556-569.e7. [PMID: 29562202 DOI: 10.1016/j.immuni.2018.03.008] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 02/28/2018] [Accepted: 03/02/2018] [Indexed: 12/21/2022]
Abstract
The death receptor Fas removes activated lymphocytes through apoptosis. Previous transcriptional profiling predicted that Fas positively regulates interleukin-17 (IL-17)-producing T helper 17 (Th17) cells. Here, we demonstrate that Fas promoted the generation and stability of Th17 cells and prevented their differentiation into Th1 cells. Mice with T-cell- and Th17-cell-specific deletion of Fas were protected from induced autoimmunity, and Th17 cell differentiation and stability were impaired. Fas-deficient Th17 cells instead developed a Th1-cell-like transcriptional profile, which a new algorithm predicted to depend on STAT1. Experimentally, Fas indeed bound and sequestered STAT1, and Fas deficiency enhanced IL-6-induced STAT1 activation and nuclear translocation, whereas deficiency of STAT1 reversed the transcriptional changes induced by Fas deficiency. Thus, our computational and experimental approach identified Fas as a regulator of the Th17-to-Th1 cell balance by controlling the availability of opposing STAT1 and STAT3 to have a direct impact on autoimmunity.
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Affiliation(s)
- Gerd Meyer Zu Horste
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Department of Neurology, University Hospital Münster, Münster, Germany
| | | | - Markus A Schramm
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA
| | - Chao Wang
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA
| | - Alexandra Schnell
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA
| | - Youjin Lee
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA
| | - Raymond Sobel
- Palo Alto Veteran's Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
| | - Aviv Regev
- Broad Institute of MIT and Harvard, Cambridge, MA, USA.
| | - Vijay K Kuchroo
- Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA, USA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
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Murine DX5 +NKT Cells Display Their Cytotoxic and Proapoptotic Potentials against Colitis-Inducing CD4 +CD62L high T Cells through Fas Ligand. J Immunol Res 2018; 2018:8175810. [PMID: 30364054 PMCID: PMC6186349 DOI: 10.1155/2018/8175810] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 08/20/2018] [Accepted: 09/04/2018] [Indexed: 12/18/2022] Open
Abstract
Introduction It has been previously shown that immunoregulatory DX5+NKT cells are able to prevent colitis induced by CD4+CD62Lhigh T lymphocytes in a SCID mouse model. The aim of this study was to further investigate the underlying mechanism in vitro. Methods CD4+CD62Lhigh and DX5+NKT cells from the spleen of Balb/c mice were isolated first by MACS, followed by FACS sorting and cocultured for up to 96 h. After polyclonal stimulation with anti-CD3, anti-CD28, and IL-2, proliferation of CD4+CD62Lhigh cells was assessed using a CFSE assay and activity of proapoptotic caspase-3 was determined by intracellular staining and flow cytometry. Extrinsic apoptotic pathway was blocked using an unconjugated antibody against FasL, and activation of caspase-3 was measured. Results As previously shown in vivo, DX5+NKT cells inhibit proliferation of CD4+CD62Lhigh cells in vitro after 96 h coculture compared to a CD4+CD62Lhigh monoculture (proliferation index: 1.39 ± 0.07 vs. 1.76 ± 0.12; P = 0.0079). The antiproliferative effect of DX5+NKT cells was likely due to an induction of apoptosis in CD4+CD62Lhigh cells as evidenced by increased activation of the proapoptotic caspase-3 after 48 h (38 ± 3% vs. 28 ± 3%; P = 0.0451). Furthermore, DX5+NKT cells after polyclonal stimulation showed an upregulation of FasL on their cell surface (15 ± 2% vs. 2 ± 1%; P = 0.0286). Finally, FasL was blocked on DX5+NKT cells, and therefore, the extrinsic apoptotic pathway abrogated the activation of caspase-3 in CD4+CD62Lhigh cells. Conclusion Collectively, these data confirmed that DX5+NKT cells inhibit proliferation of colitis-inducing CD4+CD62Lhigh cells by induction of apoptosis. Furthermore, DX5+NKT cells likely mediate their cytotoxic and proapoptotic potentials via FasL, confirming recent reports about iNKT cells. Further studies will be necessary to evaluate the therapeutical potential of these immunoregulatory cells in patients with colitis.
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Soloviova K, Puliaiev M, Puliaev R, Puliaeva I, Via CS. Both perforin and FasL are required for optimal CD8 T cell control of autoreactive B cells and autoantibody production in parent-into-F1 lupus mice. Clin Immunol 2018; 194:34-42. [PMID: 29940333 PMCID: PMC6089648 DOI: 10.1016/j.clim.2018.06.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 06/18/2018] [Accepted: 06/19/2018] [Indexed: 11/29/2022]
Abstract
To test the relative roles of perforin (pfp) vs. FasL in CTL control of autoreactive B cell expansion, we used the parent-into-F1 model of murine graft-vs.-host disease in which donor CD8 CTL prevent lupus like disease by eliminating activated autoreactive B cells. F1 mice receiving either pfp or FasL defective donor T cells exhibited an intermediate short-term phenotype. Pairing of purified normal CD4 T cells with either pfp or FasL defective CD8 T cell subsets resulted in impaired host B cell elimination and mild lupus like disease that was roughly equivalent in the two experimental groups. Thus, in addition to major roles in tumor and intracellular pathogen control, pfp mediated CD8 CTL killing plays a significant role in controlling autoreactive B cell expansion and lupus downregulation that is comparable to that mediated by FasL killing. Importantly, both pathways are required for optimal elimination of activated autoreactive B cells.
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Affiliation(s)
- Kateryna Soloviova
- Pathology Department, Uniformed Services University of Health Sciences, Bethesda, MD 20815, United States
| | - Maksym Puliaiev
- Pathology Department, Uniformed Services University of Health Sciences, Bethesda, MD 20815, United States
| | - Roman Puliaev
- Pathology Department, Uniformed Services University of Health Sciences, Bethesda, MD 20815, United States
| | - Irina Puliaeva
- Pathology Department, Uniformed Services University of Health Sciences, Bethesda, MD 20815, United States
| | - Charles S Via
- Pathology Department, Uniformed Services University of Health Sciences, Bethesda, MD 20815, United States.
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Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren's Syndrome. Int J Mol Sci 2018; 19:ijms19082369. [PMID: 30103522 PMCID: PMC6121505 DOI: 10.3390/ijms19082369] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 08/08/2018] [Accepted: 08/10/2018] [Indexed: 12/11/2022] Open
Abstract
The pathogenesis of Sjögren’s syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas ligand system is a leading player with activation of the death domain and caspase 8/3 cleavage, the role of soluble Fas/FasL (including its polymorphism) in apoptosis is controversial. The tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of salivary gland epithelial cells (SGECs) involves a mitochondrial pathway that includes caspase 9 cleavage. The involvement of innate immunity cells such as toll-like receptors (TLRs) has been investigated; TLR2-4 and TLR7-9 are associated with the induction of inflammation in exocrine glands of SS patients. TLR3 has the potential to induce the apoptosis of SS patients’ SGECs. Linkage of epidermal growth factor (EGF) was shown in exocrine glands in SS, and it inhibited the Fas/FasL system with the help of cell-survival factors. TLR3 has dual actions to cause inflammation as well as apoptosis, which are inhibited by EGF. In conclusion, apoptosis in exocrine glands of SS patients is tightly controlled by balance of pro-apoptotic signals and growth factor.
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Montalvão F, Nascimento DO, Nunes MP, Koeller CM, Morrot A, Lery LMS, Bisch PM, Teixeira SMR, Vasconcellos R, Freire-de-Lima L, Lopes MF, Heise N, DosReis GA, Freire-de-Lima CG. Antibody Repertoires Identify β-Tubulin as a Host Protective Parasite Antigen in Mice Infected With Trypanosoma cruzi. Front Immunol 2018; 9:671. [PMID: 29706955 PMCID: PMC5909033 DOI: 10.3389/fimmu.2018.00671] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Accepted: 03/19/2018] [Indexed: 12/17/2022] Open
Abstract
Few studies investigate the major protein antigens targeted by the antibody diversity of infected mice with Trypanosoma cruzi. To detect global IgG antibody specificities, sera from infected mice were immunoblotted against whole T. cruzi extracts. By proteomic analysis, we were able to identify the most immunogenic T. cruzi proteins. We identified three major antigens as pyruvate phosphate dikinase, Hsp-85, and β-tubulin. The major protein band recognized by host IgG was T. cruzi β-tubulin. The T. cruzi β-tubulin gene was cloned, expressed in E. coli, and recombinant T. cruzi β-tubulin was obtained. Infection increased IgG reactivity against recombinant T. cruzi β-tubulin. A single immunization of mice with recombinant T. cruzi β-tubulin increased specific IgG reactivity and induced protection against T. cruzi infection. These results indicate that repertoire analysis is a valid approach to identify antigens for vaccines against Chagas disease.
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Affiliation(s)
- Fabricio Montalvão
- Faculdade de Medicina de Petrópolis (FMP-FASE), Petrópolis, Brazil.,Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Marise P Nunes
- Laboratório de Imunoparasitologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Carolina M Koeller
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alexandre Morrot
- Laboratório de Imunoparasitologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.,Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Leticia Miranda S Lery
- Laboratório de Microbiologia Celular, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
| | - Paulo M Bisch
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Santuza M R Teixeira
- Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Rita Vasconcellos
- Instituto de Biologia, Universidade Federal Fluminense, Niterói, Brazil
| | - Leonardo Freire-de-Lima
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Marcela F Lopes
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Norton Heise
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - George A DosReis
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
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Lee J, Dieckmann NMG, Edgar JR, Griffiths GM, Siegel RM. Fas Ligand localizes to intraluminal vesicles within NK cell cytolytic granules and is enriched at the immune synapse. IMMUNITY INFLAMMATION AND DISEASE 2018; 6:312-321. [PMID: 29642281 PMCID: PMC5946154 DOI: 10.1002/iid3.219] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Revised: 01/16/2018] [Accepted: 02/06/2018] [Indexed: 11/06/2022]
Abstract
INTRODUCTION T cell and NK cell cytotoxicity can be mediated via the perforin/granzyme system and Fas Ligand (FasL, CD178). FasL is synthesized as a type II transmembrane protein that binds its cognate receptor Fas (CD95). Membrane-bound FasL is expressed on the plasma membrane of activated lymphocytes and is the main form of FasL with cytotoxic activity, but whether FasL is delivered to the immune synapse along with granzyme and perforin-containing granules is unclear. METHODS We stably expressed FasL-fluorescent fusion proteins into human NK cells and examined the localization of FasL relative to other intracellular markers by confocal and immunoelectron microscopy, and examined the trafficking of FasL during formation of immune synapses with HLA-deficient B cells. RESULTS FasL co-localized with CD63 more strongly than perforin or Lamp1+ in cytolytic granules. Electron microscopy revealed that FasL is enriched on intraluminal vesicles (ILVs) adjacent to the dense-core within cytolytic granules. In NK cells forming immune synapses with HLA-deficient B cells, a portion of FasL-containing granules re-localize toward the immune synapse, while a distinct pool of FasL remains at the distal pole of the cell. CONCLUSIONS Localization of FasL to intra-luminal vesicles within cytolytic granules facilitates FasL trafficking to immune synapses and cytotoxic function in NK cells.
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Affiliation(s)
- Jeansun Lee
- CIMR, Department of Medicine, Cambridge University, Cambridge, UK.,Immunoregulation Section, Autoimmunity Branch, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | | | - James R Edgar
- CIMR, Department of Medicine, Cambridge University, Cambridge, UK
| | | | - Richard M Siegel
- Immunoregulation Section, Autoimmunity Branch, National Institutes of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Abstract
Necrosis is a hallmark of several widespread diseases or their direct complications. In the past decade, we learned that necrosis can be a regulated process that is potentially druggable. RIPK3- and MLKL-mediated necroptosis represents by far the best studied pathway of regulated necrosis. During necroptosis, the release of damage-associated molecular patterns (DAMPs) drives a phenomenon referred to as necroinflammation, a common consequence of necrosis. However, most studies of regulated necrosis investigated cell lines in vitro in a cell autonomous manner, which represents a non-physiological situation. Conclusions based on such work might not necessarily be transferrable to disease states in which synchronized, non-cell autonomous effects occur. Here, we summarize the current knowledge of the pathophysiological relevance of necroptosis in vivo, and in light of this understanding, we reassess the morphological classification of necrosis that is generally used by pathologists. Along these lines, we discuss the paucity of data implicating necroptosis in human disease. Finally, the in vivo relevance of non-necroptotic forms of necrosis, such as ferroptosis, is addressed.
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Affiliation(s)
- Wulf Tonnus
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine III, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
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Brandt D, Hedrich CM. TCRαβ +CD3 +CD4 -CD8 - (double negative) T cells in autoimmunity. Autoimmun Rev 2018; 17:422-430. [PMID: 29428806 DOI: 10.1016/j.autrev.2018.02.001] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2017] [Accepted: 12/07/2017] [Indexed: 12/14/2022]
Abstract
TCRαβ+CD3+CD4-CD8- "double negative" (DN) T cells comprise a small subset of mature peripheral T cells. The origin and function of DN T cells are somewhat unclear and discussed controversially. While DN T cells resemble a rare and heterogeneous T cell subpopulation in healthy individuals, numbers of TCRαβ+ DN T cells are expanded in several inflammatory conditions, where they also exhibit distinct effector phenotypes and infiltrate inflamed tissues. Thus, DN T cells may be involved in systemic inflammation and tissue damage in autoimmune/inflammatory conditions, including SLE, Sjögren's syndrome, and psoriasis. Here, the current understanding of the origin and phenotype of DN T cells, and their role in the instruction of immune responses, autoimmunity and inflammation will be discussed in health and disease.
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Affiliation(s)
- D Brandt
- Division of Pediatric Rheumatology and Immunology, Children's Hospital Dresden, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - C M Hedrich
- Division of Pediatric Rheumatology and Immunology, Children's Hospital Dresden, Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany; Department of Women's & Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, UK.
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