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.
Key points
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Programmed cell death pathways can become pathological and promote chronic inflammation and rheumatic disease.
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Damage-associated molecular patterns, which are associated with various rheumatic diseases, are host-derived molecules that might be released from dying cells and then function as danger signals, enhancing local inflammation.
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Lytic forms of cell death, such as necroptosis, pyroptosis and NETosis, are highly pro-inflammatory owing to the release of cell contents, which can contribute to inflammation.
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Even apoptotic cell death, which is typically non-inflammatory, can cause pathology when upregulated or when cell debris is improperly cleared, resulting in the release of inflammatory mediators.
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Accumulating data, particularly in mouse models, suggest that targeting cell death has therapeutic potential in chronic inflammatory diseases.
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References
Mistry, P. & Kaplan, M. J. Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis. Clin. Immunol. 185, 59–73 (2017).
Chen, G. Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837 (2010).
Arango Duque, G. & Descoteaux, A. Macrophage cytokines: involvement in immunity and infectious diseases. Front. Immunol. 5, 491 (2014).
Turner, M. D., Nedjai, B., Hurst, T. & Pennington, D. J. Cytokines and chemokines: at the crossroads of cell signalling and inflammatory disease. Biochim. Biophys. Acta 1843, 2563–2582 (2014).
Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805–820 (2010).
Venereau, E., Ceriotti, C. & Bianchi, M. E. DAMPs from cell death to new life. Front. Immunol. 6, 422 (2015).
Gilroy, D. & De Maeyer, R. New insights into the resolution of inflammation. Semin. Immunol. 27, 161–168 (2015).
Roh, J. S. & Sohn, D. H. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 18, e27 (2018).
Cho, J. H. The genetics and immunopathogenesis of inflammatory bowel disease. Nat. Rev. Immunol. 8, 458–466 (2008).
Guttman-Yassky, E., Nograles, K. E. & Krueger, J. G. Contrasting pathogenesis of atopic dermatitis and psoriasis–part I: clinical and pathologic concepts. J. Allergy Clin. Immunol. 127, 1110–1118 (2011).
Guttman-Yassky, E., Nograles, K. E. & Krueger, J. G. Contrasting pathogenesis of atopic dermatitis and psoriasis–part II: immune cell subsets and therapeutic concepts. J. Allergy Clin. Immunol. 127, 1420–1432 (2011).
Gottschalk, T. A., Tsantikos, E. & Hibbs, M. L. Pathogenic inflammation and its therapeutic targeting in systemic lupus erythematosus. Front. Immunol. 6, 550 (2015).
Noack, M. & Miossec, P. Selected cytokine pathways in rheumatoid arthritis. Semin. Immunopathol. 39, 365–383 (2017).
Haroon, M. & FitzGerald, O. Psoriatic arthritis: complexities, comorbidities and implications for the clinic. Expert. Rev. Clin. Immunol. 12, 405–416 (2016).
Robinson, W. H. et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 580–592 (2016).
Zhu, W. et al. Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Res. 7, 22 (2019).
Ragab, G., Elshahaly, M. & Bardin, T. Gout: an old disease in new perspective – a review. J. Adv. Res. 8, 495–511 (2017).
Lis, K., Kuzawinska, O. & Balkowiec-Iskra, E. Tumor necrosis factor inhibitors – state of knowledge. Arch. Med. Sci. 10, 1175–1185 (2014).
Vandenabeele, P., Galluzzi, L., Vanden Berghe, T. & Kroemer, G. Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat. Rev. Mol. Cell Biol. 11, 700–714 (2010).
Wallach, D., Kang, T. B. & Kovalenko, A. Concepts of tissue injury and cell death in inflammation: a historical perspective. Nat. Rev. Immunol. 14, 51–59 (2014).
Kawane, K., Motani, K. & Nagata, S. DNA degradation and its defects. Cold Spring Harb. Perspect. Biol. 6, a016394 (2014).
Sachet, M., Liang, Y. Y. & Oehler, R. The immune response to secondary necrotic cells. Apoptosis 22, 1189–1204 (2017).
Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).
Green, D. R., Ferguson, T., Zitvogel, L. & Kroemer, G. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9, 353–363 (2009).
Orozco, S. L. et al. RIPK3 activation leads to cytokine synthesis that continues after loss of cell membrane integrity. Cell Rep. 28, 2275–2287.e5 (2019).
Martin, S. J., Henry, C. M. & Cullen, S. P. A perspective on mammalian caspases as positive and negative regulators of inflammation. Mol. Cell 46, 387–397 (2012).
Cayrol, C. & Girard, J. P. The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. Proc. Natl Acad. Sci. USA 106, 9021–9026 (2009).
Luthi, A. U. et al. Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31, 84–98 (2009).
O’Reilly, S. Pound the alarm: danger signals in rheumatic diseases. Clin. Sci. 128, 297–305 (2015).
White, M. J. et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549–1562 (2014).
Berthelot, J. M., Le Goff, B., Neel, A., Maugars, Y. & Hamidou, M. NETosis: at the crossroads of rheumatoid arthritis, lupus, and vasculitis. Jt. Bone Spine 84, 255–262 (2017).
Magna, M. & Pisetsky, D. S. The role of cell death in the pathogenesis of SLE: is pyroptosis the missing link? Scand. J. Immunol. 82, 218–224 (2015).
So, A. K. & Martinon, F. Inflammation in gout: mechanisms and therapeutic targets. Nat. Rev. Rheumatol. 13, 639–647 (2017).
Amarante-Mendes, G. P. et al. Pattern recognition receptors and the host cell death molecular machinery. Front. Immunol. 9, 2379 (2018).
Czabotar, P. E., Lessene, G., Strasser, A. & Adams, J. M. Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy. Nat. Rev. Mol. Cell Biol. 15, 49–63 (2014).
Delbridge, A. R., Grabow, S., Strasser, A. & Vaux, D. L. Thirty years of BCL-2: translating cell death discoveries into novel cancer therapies. Nat. Rev. Cancer 16, 99–109 (2016).
McArthur, K. et al. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 359, eaao6047 (2018).
Sugiura, R., Satoh, R., Ishiwata, S., Umeda, N. & Kita, A. Role of RNA-binding proteins in MAPK signal transduction pathway. J. Signal. Transduct. 2011, 109746 (2011).
Tiedje, C., Holtmann, H. & Gaestel, M. The role of mammalian MAPK signaling in regulation of cytokine mRNA stability and translation. J. Interferon Cytokine Res. 34, 220–232 (2014).
Silke, J. & Meier, P. Inhibitor of apoptosis (IAP) proteins–modulators of cell death and inflammation. Cold Spring Harb. Perspect. Biol. 5, a008730 (2013).
Vince, J. E. et al. TRAF2 must bind to cellular inhibitors of apoptosis for tumor necrosis factor (TNF) to efficiently activate NF-κB and to prevent TNF-induced apoptosis. J. Biol. Chem. 284, 35906–35915 (2009).
Dynek, J. N. et al. c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1 in TNF signalling. EMBO J. 29, 4198–4209 (2010).
Varfolomeev, E. et al. c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor α (TNFα)-induced NF-κB activation. J. Biol. Chem. 283, 24295–24299 (2008).
Ting, A. T. & Bertrand, M. J. M. More to life than NF-κB in TNFR1 signaling. Trends Immunol. 37, 535–545 (2016).
Silke, J. & Vince, J. IAPs and cell death. Curr. Top. Microbiol. Immunol. 403, 95–117 (2017).
Gerlach, B. et al. Linear ubiquitination prevents inflammation and regulates immune signalling. Nature 471, 591–596 (2011).
Dondelinger, Y. et al. NF-κB-independent role of IKKα/IKKβ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol. Cell 60, 63–76 (2015).
Geng, J. et al. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat. Commun. 8, 359 (2017).
Silke, J. The regulation of TNF signalling: what a tangled web we weave. Curr. Opin. Immunol. 23, 620–626 (2011).
Wong, W. W. et al. RIPK1 is not essential for TNFR1-induced activation of NF-κB. Cell Death Differ. 17, 482–487 (2010).
Anderton, H. et al. RIPK1 prevents TRADD-driven, but TNFR1 independent, apoptosis during development. Cell Death Differ. 26, 877–889 (2019).
Dowling, J. P., Alsabbagh, M., Del Casale, C., Liu, Z. G. & Zhang, J. TRADD regulates perinatal development and adulthood survival in mice lacking RIPK1 and RIPK3. Nat. Commun. 10, 705 (2019).
Takahashi, N. et al. RIPK1 ensures intestinal homeostasis by protecting the epithelium against apoptosis. Nature 513, 95–99 (2014).
Dannappel, M. et al. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90–94 (2014).
Kelliher, M. A. et al. The death domain kinase RIP mediates the TNF-induced NF-κB signal. Immunity 8, 297–303 (1998).
Dondelinger, Y., Darding, M., Bertrand, M. J. & Walczak, H. Poly-ubiquitination in TNFR1-mediated necroptosis. Cell Mol. Life Sci. 73, 2165–2176 (2016).
Tsuchiya, Y., Nakabayashi, O. & Nakano, H. FLIP the switch: regulation of apoptosis and necroptosis by cFLIP. Int. J. Mol. Sci. 16, 30321–30341 (2015).
Degterev, A., Ofengeim, D. & Yuan, J. Targeting RIPK1 for the treatment of human diseases. Proc. Natl Acad. Sci. USA 116, 9714–9722 (2019).
Jaco, I. et al. MK2 phosphorylates RIPK1 to prevent TNF-induced cell death. Mol. Cell 66, 698–710.e5 (2017).
Annibaldi, A. et al. Ubiquitin-mediated regulation of RIPK1 kinase activity independent of IKK and MK2. Mol. Cell 69, 566–580.e5 (2018).
Dondelinger, Y. et al. Serine 25 phosphorylation inhibits RIPK1 kinase-dependent cell death in models of infection and inflammation. Nat. Commun. 10, 1729 (2019).
Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).
Fox, S., Leitch, A. E., Duffin, R., Haslett, C. & Rossi, A. G. Neutrophil apoptosis: relevance to the innate immune response and inflammatory disease. J. Innate Immun. 2, 216–227 (2010).
Saas, P., Bonnefoy, F., Toussirot, E. & Perruche, S. Harnessing apoptotic cell clearance to treat autoimmune arthritis. Front. Immunol. 8, 1191 (2017).
Raza, K. et al. Synovial fluid leukocyte apoptosis is inhibited in patients with very early rheumatoid arthritis. Arthritis Res. Ther. 8, R120 (2006).
Wright, H. L., Moots, R. J., Bucknall, R. C. & Edwards, S. W. Neutrophil function in inflammation and inflammatory diseases. Rheumatology 49, 1618–1631 (2010).
Dzhagalov, I. L., Chen, K. G., Herzmark, P. & Robey, E. A. Elimination of self-reactive T cells in the thymus: a timeline for negative selection. PLoS Biol. 11, e1001566 (2013).
Nemazee, D. Mechanisms of central tolerance for B cells. Nat. Rev. Immunol. 17, 281–294 (2017).
Rieux-Laucat, F., Magerus-Chatinet, A. & Neven, B. The autoimmune lymphoproliferative syndrome with defective FAS or FAS-ligand functions. J. Clin. Immunol. 38, 558–568 (2018).
Watanabe-Fukunaga, R., Brannant, C. I., Copelandt, N. G., Jenkinst, N. A. & Nagata, S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356, 314–317 (1992).
Takahashi, T. et al. Generalized lymphoproliferative disease in mice, caused by a point mutation in the Fas ligand. Cell 76, 969–976 (1994).
O’ Reilly, L. et al. Membrane-bound Fas ligand only is essential for Fas-induced apoptosis. Nature 461, 659–663 (2009).
Peter, C., Wesselborg, S., Herrmann, M. & Lauber, K. Dangerous attraction: phagocyte recruitment and danger signals of apoptotic and necrotic cells. Apoptosis 15, 1007–1028 (2010).
Silva, M. T. Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Lett. 584, 4491–4499 (2010).
Munoz, L. E., Leppkes, M., Fuchs, T. A., Hoffmann, M. & Herrmann, M. Missing in action–the meaning of cell death in tissue damage and inflammation. Immunol. Rev. 280, 26–40 (2017).
Barton, D., HogenEsch, H. & Weih, F. Mice lacking the transcription factor RelB develop T cell-dependent skin lesions similar to human atopic dermatitis. Eur. J. Immunol. 30, 2323–2332 (2000).
Pasparakis, M. et al. TNF-mediated inflammatory skin disease in mice with epidermis-specific deletion of IKK2. Nature 417, 861–866 (2002).
Nenci, A. et al. Skin lesion development in a mouse model of incontinentia pigmenti is triggered by NEMO deficiency in epidermal keratinocytes and requires TNF signaling. Hum. Mol. Genet. 15, 531–542 (2006).
Anderton, H., Rickard, J. A., Varigos, G. A., Lalaoui, N. & Silke, J. Inhibitor of apoptosis proteins (IAPs) limit RIPK1-mediated skin inflammation. J. Invest. Dermatol. 137, 2371–2379 (2017).
Panayotova-Dimitrova, D. et al. cFLIP regulates skin homeostasis and protects against TNF-induced keratinocyte apoptosis. Cell Rep. 5, 397–408 (2013).
Rickard, J. A. et al. TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice. eLife 3, 1–23 (2014).
Berger, S. B. et al. Cutting edge: RIP1 kinase activity is dispensable for normal development but is a key regulator of inflammation in SHARPIN-deficient mice. J. Immunol. 192, 5476–5480 (2014).
Taraborrelli, L. et al. LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L. Nat. Commun. 9, 3910 (2018).
Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).
Steinbrecher, K. A., Harmel-Laws, E., Sitcheran, R. & Baldwin, A. S. Loss of epithelial RelA results in deregulated intestinal proliferative/apoptotic homeostasis and susceptibility to inflammation. J. Immunol. 180, 2588–2599 (2008).
Kajino-Sakamoto, R. et al. Enterocyte-derived TAK1 signaling prevents epithelium apoptosis and the development of ileitis and colitis. J. Immunol. 181, 1143–1152 (2008).
Gunther, C., Neumann, H., Neurath, M. F. & Becker, C. Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epithelium. Gut 62, 1062–1071 (2013).
Conrad, M. A., Carreon, C. K., Dawany, N., Russo, P. & Kelsen, J. R. Distinct histopathological features at diagnosis of very early onset inflammatory bowel disease. J. Crohns Colitis 13, 615–625 (2019).
Hagiwara, C., Tanaka, M. & Kudo, H. Increase in colorectal epithelial apoptotic cells in patients with ulcerative colitis ultimately requiring surgery. J. Gastroenterol. Hepatol. 17, 758–764 (2002).
Santoro, A. et al. Cytotoxic molecule expression and epithelial cell apoptosis in oral and cutaneous lichen planus. Am. J. Clin. Pathol. 121, 758–764 (2004).
Trautmann, A. et al. T cell-mediated Fas-induced keratinocyte apoptosis plays a key pathogenetic role in eczematous dermatitis. J. Clin. Invest. 106, 25–35 (2000).
Hofmeister, C. C. et al. Graft-versus-host disease of the skin: life and death on the epidermal edge. Biol. Blood Marrow Transpl. 10, 366–372 (2004).
Liu, Y. et al. TWEAK/Fn14 activation contributes to the pathogenesis of bullous pemphigoid. J. Invest. Dermatol. 137, 1512–1522 (2017).
Arya, A. K., Tripathi, R., Kumar, S. & Tripathi, K. Recent advances on the association of apoptosis in chronic non healing diabetic wound. World J. Diabetes 5, 756–762 (2014).
Zamli, Z. & Sharif, M. Chondrocyte apoptosis: a cause or consequence of osteoarthritis? Int. J. Rheum. Dis. 14, 159–166 (2011).
Hwang, H. S. & Kim, H. A. Chondrocyte apoptosis in the pathogenesis of osteoarthritis. Int. J. Mol. Sci. 16, 26035–26054 (2015).
Dharmapatni, A. A. et al. Elevated expression of caspase-3 inhibitors, survivin and xIAP correlates with low levels of apoptosis in active rheumatoid synovium. Arthritis Res. Ther. 11, R13 (2009).
Catrina, A. I., Ulfgren, A. K., Lindblad, S., Grondal, L. & Klareskog, L. Low levels of apoptosis and high FLIP expression in early rheumatoid arthritis synovium. Ann. Rheum. Dis. 61, 934–936 (2002).
Ottonello, L. et al. Synovial fluid from patients with rheumatoid arthritis inhibits neutrophil apoptosis: role of adenosine and proinflammatory cytokines. Rheumatology 41, 1249–1260 (2002).
Salmon, M. et al. Inhibition of T cell apoptosis in the rheumatoid synovium. J. Clin. Invest. 99, 439–446 (1997).
Pilling, D. et al. Interferon-β mediates stromal cell rescue of T cells from apoptosis. Eur. J. Immunol. 29, 1041–1050 (1999).
Glesse, N. et al. Evaluation of polymorphic variants in apoptotic genes and their role in susceptibility and clinical progression to systemic lupus erythematosus. Lupus 26, 746–755 (2017).
Murphy, J. M. et al. The pseudokinase MLKL mediates necroptosis via a molecular switch mechanism. Immunity 39, 443–453 (2013).
Zhang, L. et al. RIP1 cleavage in the kinase domain regulates TRAIL-induced NF-κB activation and lymphoma survival. Mol. Cell Biol. 35, 3324–3338 (2015).
Lin, Y., Devin, A., Rodriguez, Y. & Liu, Z. G. Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev. 13, 2514–2526 (1999).
Feng, S. et al. Cleavage of RIP3 inactivates its caspase-independent apoptosis pathway by removal of kinase domain. Cell Signal. 19, 2056–2067 (2007).
Lalaoui, N. et al. Mutations that prevent caspase cleavage of RIPK1 cause autoinflammatory disease. Nature 577, 103–108 (2020).
Newton, K. et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature 574, 428–431 (2019).
Zhang, X., Dowling, J. P. & Zhang, J. RIPK1 can mediate apoptosis in addition to necroptosis during embryonic development. Cell Death Dis. 10, 245 (2019).
Giogha, C., Lung, T. W., Pearson, J. S. & Hartland, E. L. Inhibition of death receptor signaling by bacterial gut pathogens. Cytokine Growth Factor. Rev. 25, 235–243 (2014).
Pearson, J. S. et al. EspL is a bacterial cysteine protease effector that cleaves RHIM proteins to block necroptosis and inflammation. Nat. Microbiol. 2, 16258 (2017).
Huang, D. et al. The MLKL channel in necroptosis is an octamer formed by tetramers in a dyadic process. Mol. Cell. Biol. 37, e00497–16 (2017).
Kaczmarek, A., Vandenabeele, P. & Krysko, D. V. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209–223 (2013).
Festjens, N., Vanden Berghe, T., Cornelis, S. & Vandenabeele, P. RIP1, a kinase on the crossroads of a cell’s decision to live or die. Cell Death Differ. 14, 400–410 (2007).
Pasparakis, M. & Vandenabeele, P. Necroptosis and its role in inflammation. Nature 517, 311–320 (2015).
Lawlor, K. E. et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat. Commun. 6, 6282 (2015).
Feoktistova, M. et al. cIAPs block ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol. Cell 43, 449–463 (2011).
Lin, J. et al. RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature 540, 124–128 (2016).
Newton, K. et al. RIPK1 inhibits ZBP1-driven necroptosis during development. Nature 540, 129–133 (2016).
Grootjans, S., Vanden Berghe, T. & Vandenabeele, P. Initiation and execution mechanisms of necroptosis: an overview. Cell Death Differ. 24, 1184–1195 (2017).
Ingram, J. P. et al. ZBP1/DAI drives RIPK3-mediated cell death induced by IFNs in the absence of RIPK1. J. Immunol. 203, 1348–1355 (2019).
Jiao, H. et al. Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation. Nature 580, 391–395 (2020).
Kuriakose, T. et al. ZBP1/DAI is an innate sensor of influenza virus triggering the NLRP3 inflammasome and programmed cell death pathways. Sci. Immunol. 1, aag2045 (2016).
Maelfait, J. et al. Sensing of viral and endogenous RNA by ZBP1/DAI induces necroptosis. EMBO J. 36, 2529–2543 (2017).
Daley-Bauer, L. P. et al. Mouse cytomegalovirus M36 and M45 death suppressors cooperate to prevent inflammation resulting from antiviral programmed cell death pathways. Proc. Natl Acad. Sci. USA 114, E2786–E2795 (2017).
Newton, K. & Manning, G. Necroptosis and inflammation. Annu. Rev. Biochem. 85, 743–763 (2016).
Dondelinger, Y., Hulpiau, P., Saeys, Y., Bertrand, M. J. M. & Vandenabeele, P. An evolutionary perspective on the necroptotic pathway. Trends Cell Biol. 26, 721–732 (2016).
Gunther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).
Rickard, J. A. et al. RIPK1 regulates RIPK3-MLKL-driven systemic inflammation and emergency hematopoiesis. Cell 157, 1175–1188 (2014).
Dillon, C. P. et al. RIPK1 blocks early postnatal lethality mediated by caspase-8 and RIPK3. Cell 157, 1189–1202 (2014).
Kaiser, W. J. et al. RIP1 suppresses innate immune necrotic as well as apoptotic cell death during mammalian parturition. Proc. Natl Acad. Sci. USA 111, 7753–7758 (2014).
Ito, Y. et al. RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353, 603–608 (2016).
Lin, J. et al. A role of RIP3-mediated macrophage necrosis in atherosclerosis development. Cell Rep. 3, 200–210 (2013).
Meng, L. et al. RIP3-dependent necrosis induced inflammation exacerbates atherosclerosis. Biochem. Biophys. Res. Commun. 473, 497–502 (2016).
Wang, X., Yousefi, S. & Simon, H. U. Necroptosis and neutrophil-associated disorders. Cell Death Dis. 9, 111 (2018).
Desai, J. et al. PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling. Eur. J. Immunol. 46, 223–229 (2016).
Alvarez-Diaz, S. et al. The pseudokinase MLKL and the kinase RIPK3 have distinct roles in autoimmune disease caused by loss of death-receptor-induced apoptosis. Immunity 45, 513–526 (2016).
Newton, K. et al. RIPK3 deficiency or catalytically inactive RIPK1 provides greater benefit than MLKL deficiency in mouse models of inflammation and tissue injury. Cell Death Differ. 23, 1565–1576 (2016).
Cuchet-Lourenco, D. et al. Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation. Science 361, 810–813 (2018).
Li, Y. et al. Human RIPK1 deficiency causes combined immunodeficiency and inflammatory bowel diseases. Proc. Natl Acad. Sci. USA 116, 970–975 (2019).
Miao, E. A. et al. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat. Immunol. 11, 1136–1142 (2010).
Bergsbaken, T., Fink, S. L. & Cookson, B. T. Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol. 7, 99–109 (2009).
Prochnicki, T., Mangan, M. S. & Latz, E. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. F1000Res 5, 1469 (2016).
Guo, H., Callaway, J. B. & Ting, J. P. Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21, 677–687 (2015).
Schroder, K. & Tschopp, J. The inflammasomes. Cell 140, 821–832 (2010).
Jo, E. K., Kim, J. K., Shin, D. M. & Sasakawa, C. Molecular mechanisms regulating NLRP3 inflammasome activation. Cell Mol. Immunol. 13, 148–159 (2016).
Latz, E., Xiao, T. S. & Stutz, A. Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397–411 (2013).
Tschopp, J., Martinon, F. & Burns, K. NALPs: a novel protein family involved in inflammation. Nat. Rev. Mol. Cell Biol. 4, 95–104 (2003).
Shimada, K. et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36, 401–414 (2012).
Tao, L. et al. The kinase receptor-interacting protein 1 is required for inflammasome activation induced by endoplasmic reticulum stress. Cell Death Dis. 9, 641 (2018).
Broz, P. & Dixit, V. M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Zhang, Z. et al. Protein kinase D at the Golgi controls NLRP3 inflammasome activation. J. Exp. Med. 214, 2671–2693 (2017).
Chen, J. & Chen, Z. J. PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation. Nature 564, 71–76 (2018).
Huang, X. et al. Caspase-11, a specific sensor for intracellular lipopolysaccharide recognition, mediates the non-canonical inflammatory pathway of pyroptosis. Cell Biosci. 9, 31 (2019).
Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187–192 (2014).
Sborgi, L. et al. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 35, 1766–1778 (2016).
He, W. T. et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 25, 1285–1298 (2015).
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).
Shi, J., Gao, W. & Shao, F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem. Sci. 42, 245–254 (2017).
Frank, D. & Vince, J. E. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 26, 99–114 (2019).
Ruan, J., Xia, S., Liu, X., Lieberman, J. & Wu, H. Cryo-EM structure of the gasdermin A3 membrane pore. Nature 557, 62–67 (2018).
Kesavardhana, S., Malireddi, R. K. S. & Kanneganti, T. D. Caspases in cell death, inflammation, and pyroptosis. Annu. Rev. Immunol. 38, 567–595 (2020).
Conos, S. A., Lawlor, K. E., Vaux, D. L., Vince, J. E. & Lindqvist, L. M. Cell death is not essential for caspase-1-mediated interleukin-1β activation and secretion. Cell Death Differ. 23, 1827–1838 (2016).
Martin-Sanchez, F. et al. Inflammasome-dependent IL-1β release depends upon membrane permeabilisation. Cell Death Differ. 23, 1219–1231 (2016).
Rashidi, M. et al. The pyroptotic cell death effector gasdermin D is activated by gout-associated uric acid crystals but is dispensable for cell death and IL-1β release. J. Immunol. 203, 736–748 (2019).
Park, Y. H., Wood, G., Kastner, D. L. & Chae, J. J. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat. Immunol. 17, 914–921 (2016).
Kuemmerle-Deschner, J. B. CAPS–pathogenesis, presentation and treatment of an autoinflammatory disease. Semin. Immunopathol. 37, 377–385 (2015).
Hoffman, H. M. & Broderick, L. The role of the inflammasome in patients with autoinflammatory diseases. J. Allergy Clin. Immunol. 138, 3–14 (2016).
Brydges, S. D. et al. Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. J. Clin. Invest. 123, 4695–4705 (2013).
Kanneganti, A. et al. GSDMD is critical for autoinflammatory pathology in a mouse model of familial Mediterranean fever. J. Exp. Med. 215, 1519–1529 (2018).
Xiao, J. et al. Gasdermin D mediates the pathogenesis of neonatal-onset multisystem inflammatory disease in mice. PLoS Biol. 16, e3000047 (2018).
Chen, C. J. et al. MyD88-dependent IL-1 receptor signaling is essential for gouty inflammation stimulated by monosodium urate crystals. J. Clin. Invest. 116, 2262–2271 (2006).
Reber, L. L. et al. Contribution of mast cell-derived interleukin-1β to uric acid crystal-induced acute arthritis in mice. Arthritis Rheumatol. 66, 2881–2891 (2014).
Kelly, G. et al. Dysregulated cytokine expression in lesional and nonlesional skin in hidradenitis suppurativa. Br. J. Dermatol. 173, 1431–1439 (2015).
Campbell, L., Raheem, I., Malemud, C. J. & Askari, A. D. The relationship between NALP3 and autoinflammatory syndromes. Int. J. Mol. Sci. 17, 725 (2016).
Yin, Y. et al. Early hyperlipidemia promotes endothelial activation via a caspase-1-sirtuin 1 pathway. Arterioscler. Thromb. Vasc. Biol. 35, 804–816 (2015).
Zhang, Y. et al. Coronary endothelial dysfunction induced by nucleotide oligomerization domain-like receptor protein with pyrin domain containing 3 inflammasome activation during hypercholesterolemia: beyond inflammation. Antioxid. Redox Signal. 22, 1084–1096 (2015).
England, B. R., Thiele, G. M., Anderson, D. R. & Mikuls, T. R. Increased cardiovascular risk in rheumatoid arthritis: mechanisms and implications. BMJ 361, k1036 (2018).
Blum, A. & Adawi, M. Rheumatoid arthritis (RA) and cardiovascular disease. Autoimmun. Rev. 18, 679–690 (2019).
Liew, J. W., Ramiro, S. & Gensler, L. S. Cardiovascular morbidity and mortality in ankylosing spondylitis and psoriatic arthritis. Best Pract. Res. Clin. Rheumatol. 32, 369–389 (2018).
Giannelou, M. & Mavragani, C. P. Cardiovascular disease in systemic lupus erythematosus: a comprehensive update. J. Autoimmun. 82, 1–12 (2017).
Bartoloni, E. et al. Targeting inflammation to prevent cardiovascular disease in chronic rheumatic diseases: myth or reality? Front. Cardiovasc. Med. 5, 177 (2018).
Nurmohamed, M. T., Heslinga, M. & Kitas, G. D. Cardiovascular comorbidity in rheumatic diseases. Nat. Rev. Rheumatol. 11, 693–704 (2015).
Lee, K. H. et al. Neutrophil extracellular traps (NETs) in autoimmune diseases: a comprehensive review. Autoimmun. Rev. 16, 1160–1173 (2017).
Morshed, M. et al. NADPH oxidase-independent formation of extracellular DNA traps by basophils. J. Immunol. 192, 5314–5323 (2014).
Yousefi, S. et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat. Med. 14, 949–953 (2008).
Goldmann, O. & Medina, E. The expanding world of extracellular traps: not only neutrophils but much more. Front. Immunol. 3, 420 (2012).
Yousefi, S., Mihalache, C., Kozlowski, E., Schmid, I. & Simon, H. U. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ. 16, 1438–1444 (2009).
Sollberger, G. et al. Gasdermin D plays a vital role in the generation of neutrophil extracellular traps. Sci. Immunol. 3, eaar6689 (2018).
Chen, K. W. et al. Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps. Sci. Immunol. 3, eaar6676 (2018).
Kaplan, M. J. & Radic, M. Neutrophil extracellular traps: double-edged swords of innate immunity. J. Immunol. 189, 2689–2695 (2012).
Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).
Remijsen, Q. et al. Dying for a cause: NETosis, mechanisms behind an antimicrobial cell death modality. Cell Death Differ. 18, 581–588 (2011).
Branzk, N. et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat. Immunol. 15, 1017–1025 (2014).
Malireddi, R. K. S. et al. TAK1 restricts spontaneous NLRP3 activation and cell death to control myeloid proliferation. J. Exp. Med. 215, 1023–1034 (2018).
Pierini, R. et al. AIM2/ASC triggers caspase-8-dependent apoptosis in Francisella-infected caspase-1-deficient macrophages. Cell Death Differ. 19, 1709–1721 (2012).
Sagulenko, V. et al. AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death Differ. 20, 1149–1160 (2013).
Vince, J. E. et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36, 215–227 (2012).
Orning, P. et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science 362, 1064–1069 (2018).
Lawlor, K. E. et al. XIAP loss triggers RIPK3- and caspase-8-driven IL-1β activation and cell death as a consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation. Cell Rep. 20, 668–682 (2017).
Wicki, S. et al. Loss of XIAP facilitates switch to TNFα-induced necroptosis in mouse neutrophils. Cell Death Dis. 7, e2422 (2016).
Yabal, M. et al. XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell Rep. 7, 1796–1808 (2014).
Gutierrez, K. D. et al. MLKL activation triggers NLRP3-mediated processing and release of IL-1β independently of gasdermin-D. J. Immunol. 198, 2156–2164 (2017).
Amini, P. et al. NET formation can occur independently of RIPK3 and MLKL signaling. Eur. J. Immunol. 46, 178–184 (2016).
Desai, J., Mulay, S. R., Nakazawa, D. & Anders, H. J. Matters of life and death. How neutrophils die or survive along NET release and is “NETosis”=necroptosis? Cell Mol. Life Sci. 73, 2211–2219 (2016).
Yousefi, S. et al. Untangling “NETosis” from NETs. Eur. J. Immunol. 49, 221–227 (2019).
Radner, H. & Aletaha, D. Anti-TNF in rheumatoid arthritis: an overview. Wien. Med. Wochenschr. 165, 3–9 (2015).
Maxwell, L. J. et al. TNF-alpha inhibitors for ankylosing spondylitis. Cochrane Database Syst. Rev. 4, CD005468 (2015).
Lubrano, E., Scriffignano, S. & Perrotta, F. M. TNF-alpha inhibitors for the six treatment targets of psoriatic arthritis. Expert. Rev. Clin. Immunol. 15, 1303–1312 (2019).
Danese, S., Vuitton, L. & Peyrin-Biroulet, L. Biologic agents for IBD: practical insights. Nat. Rev. Gastroenterol. Hepatol. 12, 537–545 (2015).
Narazaki, M., Tanaka, T. & Kishimoto, T. The role and therapeutic targeting of IL-6 in rheumatoid arthritis. Expert. Rev. Clin. Immunol. 13, 535–551 (2017).
Sakkas, L. I., Zafiriou, E. & Bogdanos, D. P. Mini review: new treatments in psoriatic arthritis. Focus on the IL-23/17 axis. Front. Pharmacol. 10, 872 (2019).
Sieper, J., Poddubnyy, D. & Miossec, P. The IL-23–IL-17 pathway as a therapeutic target in axial spondyloarthritis. Nat. Rev. Rheumatol. 15, 747–757 (2019).
Zwicky, P., Unger, S. & Becher, B. Targeting interleukin-17 in chronic inflammatory disease: a clinical perspective. J. Exp. Med. 217, e20191123 (2020).
Place, D. E. & Kanneganti, T. D. Cell death-mediated cytokine release and its therapeutic implications. J. Exp. Med. 216, 1474–1486 (2019).
Bae, J. M., Kwon, H. S., Kim, G. M., Park, K. S. & Kim, K. J. Paradoxical psoriasis following anti-TNF therapy in ankylosing spondylitis: a population-based cohort study. J. Allergy Clin. Immunol. 142, 1001–1003.e2 (2018).
Pugliese, D. et al. Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study. Aliment. Pharmacol. Ther. 42, 880–888 (2015).
Yamauchi, P. S., Bissonnette, R., Teixeira, H. D. & Valdecantos, W. C. Systematic review of efficacy of anti-tumor necrosis factor (TNF) therapy in patients with psoriasis previously treated with a different anti-TNF agent. J. Am. Acad. Dermatol. 75, 612–618.e6 (2016).
Conrad, C. et al. TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis. Nat. Commun. 9, 25 (2018).
Poreba, M. et al. Unnatural amino acids increase sensitivity and provide for the design of highly selective caspase substrates. Cell Death Differ. 21, 1482–1492 (2014).
Brumatti, G. et al. The caspase-8 inhibitor emricasan combines with the SMAC mimetic birinapant to induce necroptosis and treat acute myeloid leukemia. Sci. Transl Med. 8, 339ra369 (2016).
Smith, C. E. et al. Non-steroidal anti-inflammatory drugs are caspase inhibitors. Cell Chem. Biol. 24, 281–292 (2017).
Harris, P. A. et al. Discovery of a first-in-class receptor interacting protein 1 (RIP1) kinase specific clinical candidate (GSK2982772) for the treatment of inflammatory diseases. J. Med. Chem. 60, 1247–1261 (2017).
Martens, S., Hofmans, S., Declercq, W., Augustyns, K. & Vandenabeele, P. Inhibitors targeting RIPK1/RIPK3: old and new drugs. Trends Pharmacol. Sci. 41, 209–224 (2020).
Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014).
Mandal, P. et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol. Cell 56, 481–495 (2014).
Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012).
Yan, B. et al. Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein. Chem. Commun. 53, 3637–3640 (2017).
Mangan, M. S. J. et al. Targeting the NLRP3 inflammasome in inflammatory diseases. Nat. Rev. Drug. Discov. 17, 588–606 (2018).
Pandeya, A., Li, L., Li, Z. & Wei, Y. Gasdermin D (GSDMD) as a new target for the treatment of infection. Medchemcomm 10, 660–667 (2019).
Rathkey, J. K. et al. Chemical disruption of the pyroptotic pore-forming protein gasdermin D inhibits inflammatory cell death and sepsis. Sci. Immunol. 3, eaat2738 (2018).
Heneka, M. T. et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493, 674–678 (2013).
Flores, J. et al. Caspase-1 inhibition alleviates cognitive impairment and neuropathology in an Alzheimer’s disease mouse model. Nat. Commun. 9, 3916 (2018).
Tan, M. S. et al. Amyloid-β induces NLRP1-dependent neuronal pyroptosis in models of Alzheimer’s disease. Cell Death Dis. 5, e1382 (2014).
Pontillo, A., Catamo, E., Arosio, B., Mari, D. & Crovella, S. NALP1/NLRP1 genetic variants are associated with Alzheimer disease. Alzheimer Dis. Assoc. Disord. 26, 277–281 (2012).
Acknowledgements
The work of the authors is supported by the Walter and Eliza Hall Institute of Medical Research Indigenous Fund; Reid Charitable Trusts, the National Health and Medical Research Council of Australia (fellowships 1107149 to J.S. and 1023407 to I.P.W.); and the Victorian State Government (Operational Infrastructure Grant).
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Anderton, H., Wicks, I.P. & Silke, J. Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease. Nat Rev Rheumatol 16, 496–513 (2020). https://doi.org/10.1038/s41584-020-0455-8
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DOI: https://doi.org/10.1038/s41584-020-0455-8
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