Abstract
The intestinal epithelium has one of the highest rates of cellular turnover in a process that is tightly regulated. As the transit-amplifying progenitors of the intestinal epithelium generate ~300 cells per crypt every day, regulated cell death and sloughing at the apical surface keeps the overall cell number in check. An aberrant increase in the rate of intestinal epithelial cell (IEC) death underlies instances of extensive epithelial erosion, which is characteristic of several intestinal diseases such as inflammatory bowel disease and infectious colitis. Emerging evidence points to a crucial role of necroptosis, autophagy and pyroptosis as important modes of programmed cell death in the intestine in addition to apoptosis. The mode of cell death affects tissue restitution responses and ultimately the long-term risks of intestinal fibrosis and colorectal cancer. A vicious cycle of intestinal barrier breach, misregulated cell death and subsequent inflammation is at the heart of chronic inflammatory and infectious gastrointestinal diseases. This Review discusses the underlying molecular and cellular underpinnings that control programmed cell death in IECs, which emerge during intestinal diseases. Translational aspects of cell death modulation for the development of novel therapeutic alternatives for inflammatory bowel diseases and colorectal cancer are also discussed.
Key points
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During active flare-ups, various programmed cell death modes are elevated in the intestine of patients with inflammatory bowel disease, compromising the gut barrier.
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Intestinal epithelial cells undergo programmed cell death through various modes including anoikis, apoptosis, necroptosis and pyroptosis.
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Pyroptosis and necroptosis are pro-inflammatory, leading to the spread of inflammation, whereas anoikis and apoptosis restrict the spread of inflammation.
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GSDMD and MLKL are two host proteins that execute pyroptosis and necroptosis, respectively, via the formation of membrane pores causing the leakage of intracellular contents and cell death.
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Depending on the mode of cell death, factors derived from dead cells can trigger compensatory proliferation to replace the cells lost during inflammation.
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There is an urgent need to characterize the proportion of various types of cell death that occur in different cellular compartments of the gut in patients with inflammatory bowel disease.
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References
Said, H. M. Physiology of the Gastrointestinal Tract (Elsevier, 2018).
Paul, W. E. Fundamental Immunology (Lippincott Williams & Wilkins, 2015).
Okumura, R. & Takeda, K. Roles of intestinal epithelial cells in the maintenance of gut homeostasis. Exp. Mol. Med. 49, e338 (2017).
Suzanne, M. & Steller, H. Shaping organisms with apoptosis. Cell Death Differ. 20, 669–675 (2013).
Jorgensen, I. & Miao, E. A. Pyroptotic cell death defends against intracellular pathogens. Immunol. Rev. 265, 130–142 (2015).
Christofferson, D. E. & Yuan, J. Necroptosis as an alternative form of programmed cell death. Curr. Opin. Cell Biol. 22, 263–268 (2010).
Iwamoto, M., Koji, T., Makiyama, K., Kobayashi, N. & Nakane, P. K. Apoptosis of crypt epithelial cells in ulcerative colitis. J. Pathol. 180, 152–159 (1996).
Gupta, K. H. et al. Apoptosis and compensatory proliferation signaling are coupled by CrkI-containing microvesicles. Dev. Cell 41, 674–684.e5 (2017).
Li, F. et al. Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration. Sci. Signal. 3, ra13 (2010).
Bosurgi, L., Hughes, L. D., Rothlin, C. V. & Ghosh, S. Death begets a new beginning. Immunol. Rev. 280, 8–25 (2017).
Chan, F. K., Luz, N. F. & Moriwaki, K. Programmed necrosis in the cross talk of cell death and inflammation. Annu. Rev. Immunol. 33, 79–106 (2015).
Chan, F. K. Fueling the flames: mammalian programmed necrosis in inflammatory diseases. Cold Spring Harb. Perspect Biol. 4, a008805 (2012).
Shibahara, T. et al. The fate of effete epithelial cells at the villus tips of the human small intestine. Arch. Histol. Cytol. 58, 205–219 (1995).
Baxt, L. A. & Xavier, R. J. Role of autophagy in the maintenance of intestinal homeostasis. Gastroenterology 149, 553–562 (2015).
Madara, J. L. Maintenance of the macromolecular barrier at cell extrusion sites in intestinal epithelium: physiological rearrangement of tight junctions. J. Membr. Biol. 116, 177–184 (1990).
Marchiando, A. M. et al. The epithelial barrier is maintained by in vivo tight junction expansion during pathologic intestinal epithelial shedding. Gastroenterology 140, 1208–1218.e1-2 (2011).
Sato, T. et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009).
Spit, M., Koo, B. K. & Maurice, M. M. Tales from the crypt: intestinal niche signals in tissue renewal, plasticity and cancer. Open Biol. 8, 180120 (2018).
Sellin, M. E. et al. Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. Cell Host Microbe 16, 237–248 (2014).
Ingram, J. P. et al. A nonpyroptotic IFN-γ-triggered cell death mechanism in nonphagocytic cells promotes salmonella clearance in vivo. J. Immunol. 200, 3626–3634 (2018).
Talmon, G., Manasek, T., Miller, R., Muirhead, D. & Lazenby, A. The apoptotic crypt abscess: an underappreciated histologic finding in gastrointestinal pathology. Am. J. Clin. Pathol. 148, 538–544 (2017).
Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117–121 (2011).
Wang, S. et al. Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell 92, 501–509 (1998).
Demers, M. J. et al. Intestinal epithelial cancer cell anoikis resistance: EGFR-mediated sustained activation of Src overrides Fak-dependent signaling to MEK/Erk and/or PI3-K/Akt-1. J. Cell Biochem. 107, 639–654 (2009).
Windham, T. C. et al. Src activation regulates anoikis in human colon tumor cell lines. Oncogene 21, 7797–7807 (2002).
Liu, J. Z. et al. Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations. Nat. Genet. 47, 979–986 (2015).
Jostins, L. et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 491, 119–124 (2012).
Hyoh, Y. et al. Activation of caspases in intestinal villus epithelial cells of normal and nematode infected rats. Gut 50, 71–77 (2002).
Iwakiri, R. et al. Programmed cell death in rat intestine: effect of feeding and fasting. Scand. J. Gastroenterol. 36, 39–47 (2001).
Barker, N. et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007).
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).
Moss, S. F., Attia, L., Scholes, J. V., Walters, J. R. & Holt, P. R. Increased small intestinal apoptosis in coeliac disease. Gut 39, 811–817 (1996).
Adolph, T. E. et al. Paneth cells as a site of origin for intestinal inflammation. Nature 503, 272–276 (2013).
Kaser, A. & Blumberg, R. S. ATG16L1 Crohn’s disease risk stresses the endoplasmic reticulum of Paneth cells. Gut 63, 1038–1039 (2014).
Kaser, A. et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell 134, 743–756 (2008).
Nenci, A. et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446, 557–561 (2007).
Tanaka, H. et al. Intestinal deletion of claudin-7 enhances paracellular organic solute flux and initiates colonic inflammation in mice. Gut 64, 1529–1538 (2015).
Ye, P. et al. Tankyrases maintain homeostasis of intestinal epithelium by preventing cell death. PLoS Genet. 14, e1007697 (2018).
Zhang, H. S. et al. The endoplasmic reticulum stress sensor IRE1α in intestinal epithelial cells is essential for protecting against colitis. J. Biol. Chem. 290, 15327–15336 (2015).
Vlantis, K. et al. NEMO prevents RIP kinase 1-mediated epithelial cell death and chronic intestinal inflammation by NF-κB-dependent and -independent functions. Immunity 44, 553–567 (2016).
Souza, H. S. et al. Apoptosis in the intestinal mucosa of patients with inflammatory bowel disease: evidence of altered expression of FasL and perforin cytotoxic pathways. Int. J. Colorectal Dis. 20, 277–286 (2005).
Tanaka, M. & Riddell, R. H. The pathological diagnosis and differential diagnosis of Crohn’s disease. Hepatogastroenterology 37, 18–31 (1990).
Soucy, G. et al. Clinical and pathological analysis of colonic Crohn’s disease, including a subgroup with ulcerative colitis-like features. Mod. Pathol. 25, 295–307 (2012).
Odze, R. Diagnostic problems and advances in inflammatory bowel disease. Mod. Pathol. 16, 347–358 (2003).
Farin, H. F. et al. Paneth cell extrusion and release of antimicrobial products is directly controlled by immune cell-derived IFN-γ. J. Exp. Med. 211, 1393–1405 (2014).
Ginzberg, H. H. et al. Leukocyte elastase induces epithelial apoptosis: role of mitochondial permeability changes and Akt. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G286–G298 (2004).
Gunther, C. et al. Caspase-8 controls the gut response to microbial challenges by Tnf-α-dependent and independent pathways. Gut 64, 601–610 (2015).
Simmons, A. N., Kajino-Sakamoto, R. & Ninomiya-Tsuji, J. TAK1 regulates Paneth cell integrity partly through blocking necroptosis. Cell Death Dis. 7, e2196 (2016).
Cario, E., Gerken, G. & Podolsky, D. K. Toll-like receptor 2 controls mucosal inflammation by regulating epithelial barrier function. Gastroenterology 132, 1359–1374 (2007).
Cario, E. & Podolsky, D. K. Differential alteration in intestinal epithelial cell expression of toll-like receptor 3 (TLR3) and TLR4 in inflammatory bowel disease. Infect. Immun. 68, 7010–7017 (2000).
Gourbeyre, P. et al. Pattern recognition receptors in the gut: analysis of their expression along the intestinal tract and the crypt/villus axis. Physiol. Rep. 3, e12225 (2015).
Abreu, M. T. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat. Rev. Immunol. 10, 131–144 (2010).
Middendorp, S. et al. Adult stem cells in the small intestine are intrinsically programmed with their location-specific function. Stem Cell 32, 1083–1091 (2014).
Hill, A. A. & Diehl, G. E. Identifying the patterns of pattern recognition receptors. Immunity 49, 389–391 (2018).
Price, A. E. et al. A map of toll-like receptor expression in the intestinal epithelium reveals distinct spatial, cell type-specific, and temporal patterns. Immunity 49, 560–575 e566 (2018).
Haber, A. L. et al. A single-cell survey of the small intestinal epithelium. Nature 551, 333–339 (2017).
Zushi, S. et al. Role of heparin-binding EGF-related peptides in proliferation and apoptosis of activated ras-stimulated intestinal epithelial cells. Int. J. Cancer 73, 917–923 (1997).
Miguel, J. C. et al. Epidermal growth factor suppresses intestinal epithelial cell shedding through a MAPK-dependent pathway. J. Cell Sci. 130, 90–96 (2017).
Koren, E. et al. ARTS mediates apoptosis and regeneration of the intestinal stem cell niche. Nat. Commun. 9, 4582 (2018).
Wang, R. et al. Gut stem cell necroptosis by genome instability triggers bowel inflammation. Nature 580, 386–390 (2020).
Pull, S. L., Doherty, J. M., Mills, J. C., Gordon, J. I. & Stappenbeck, T. S. Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury. Proc. Natl Acad. Sci. USA 102, 99–104 (2005).
D’Angelo, F. et al. Macrophages promote epithelial repair through hepatocyte growth factor secretion. Clin. Exp. Immunol. 174, 60–72 (2013).
Ruemmele, F. M. et al. Butyrate mediates Caco-2 cell apoptosis via up-regulation of pro-apoptotic BAK and inducing caspase-3 mediated cleavage of poly-(ADP-ribose) polymerase (PARP). Cell Death Differ. 6, 729–735 (1999).
Tessner, T. G., Muhale, F., Riehl, T. E., Anant, S. & Stenson, W. F. Prostaglandin E2 reduces radiation-induced epithelial apoptosis through a mechanism involving AKT activation and bax translocation. J. Clin. Invest. 114, 1676–1685 (2004).
Chen, D. et al. PUMA amplifies necroptosis signaling by activating cytosolic DNA sensors. Proc. Natl Acad. Sci. USA 115, 3930–3935 (2018).
Moriwaki, K. et al. The necroptosis adaptor RIPK3 promotes injury-induced cytokine expression and tissue repair. Immunity 41, 567–578 (2014).
Shamas-Din, A., Kale, J., Leber, B. & Andrews, D. W. Mechanisms of action of Bcl-2 family proteins. Cold Spring Harb. Perspect. Biol. 5, a008714 (2013).
Sidi, S. et al. Chk1 suppresses a caspase-2 apoptotic response to DNA damage that bypasses p53, Bcl-2, and caspase-3. Cell 133, 864–877 (2008).
Greenow, K. R., Clarke, A. R. & Jones, R. H. Chk1 deficiency in the mouse small intestine results in p53-independent crypt death and subsequent intestinal compensation. Oncogene 28, 1443–1453 (2009).
Watari, A., Hasegawa, M., Yagi, K. & Kondoh, M. Checkpoint kinase 1 activation enhances intestinal epithelial barrier function via regulation of claudin-5 expression. PLoS One 11, e0145631 (2016).
Strater, J. & Moller, P. Expression and function of death receptors and their natural ligands in the intestine. Ann. N. Y. Acad. Sci. 915, 162–170 (2000).
Moller, P., Walczak, H., Reidl, S., Strater, J. & Krammer, P. H. Paneth cells express high levels of CD95 ligand transcripts: a unique property among gastrointestinal epithelia. Am. J. Pathol. 149, 9–13 (1996).
Strater, J. et al. CD95 (APO-1/Fas)-mediated apoptosis in colon epithelial cells: a possible role in ulcerative colitis. Gastroenterology 113, 160–167 (1997).
Kischkel, F. C. et al. Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO J. 14, 5579–5588 (1995).
Hsu, H., Shu, H. B., Pan, M. G. & Goeddel, D. V. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNF receptor 1 signal transduction pathways. Cell 84, 299–308 (1996).
Grunert, M. et al. The adaptor protein FADD and the initiator caspase-8 mediate activation of NF-κB by TRAIL. Cell Death Dis. 3, e414 (2012).
Henry, C. M. & Martin, S. J. Caspase-8 acts in a non-enzymatic role as a scaffold for assembly of a pro-inflammatory “FADDosome” complex upon TRAIL stimulation. Mol. Cell 65, 715–729.e5 (2017).
Lehle, A. S. et al. Intestinal inflammation and dysregulated immunity in patients with inherited caspase-8 deficiency. Gastroenterology 156, 275–278 (2019).
Mahoney, D. J. et al. Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation. Proc. Natl Acad. Sci. USA 105, 11778–11783 (2008).
Petersen, S. L. et al. Autocrine TNFα signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 12, 445–456 (2007).
Wang, L., Du, F. & Wang, X. TNF-α induces two distinct caspase-8 activation pathways. Cell 133, 693–703 (2008).
Zarnegar, B. J. et al. Noncanonical NF-κB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat. Immunol. 9, 1371–1378 (2008).
Kreuz, S., Siegmund, D., Scheurich, P. & Wajant, H. NF-κB inducers upregulate cFLIP, a cycloheximide-sensitive inhibitor of death receptor signaling. Mol. Cell Biol. 21, 3964–3973 (2001).
Thome, M. et al. Viral FLICE-inhibitory proteins (FLIPs) prevent apoptosis induced by death receptors. Nature 386, 517–521 (1997).
Wittkopf, N. et al. Cellular FLICE-like inhibitory protein secures intestinal epithelial cell survival and immune homeostasis by regulating caspase-8. Gastroenterology 145, 1369–1379 (2013).
Shindo, R. et al. Necroptosis of intestinal epithelial cells induces type 3 innate lymphoid cell-dependent lethal ileitis. iScience 15, 536–551 (2019).
Cai, Z. et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16, 55–65 (2014).
Chen, X. et al. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 24, 105–121 (2014).
Dannappel, M. et al. RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513, 90–94 (2014).
Dondelinger, Y. et al. MLKL compromises plasma membrane integrity by binding to phosphatidylinositol phosphates. Cell Rep. 7, 971–981 (2014).
Gunther, C. et al. Caspase-8 regulates TNF-α-induced epithelial necroptosis and terminal ileitis. Nature 477, 335–339 (2011).
He, S., Liang, Y., Shao, F. & Wang, X. Toll-like receptors activate programmed necrosis in macrophages through a receptor-interacting kinase-3-mediated pathway. Proc. Natl Acad. Sci. USA 108, 20054–20059 (2011).
Rebsamen, M. et al. DAI/ZBP1 recruits RIP1 and RIP3 through RIP homotypic interaction motifs to activate NF-κB. EMBO Rep. 10, 916–922 (2009).
Pierdomenico, M. et al. Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation. Am. J. Gastroenterol. 109, 279–287 (2014).
Welz, P. S. et al. FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477, 330–334 (2011).
Garcia-Carbonell, R. et al. Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death. Proc. Natl Acad. Sci. USA 115, E9192–E9200 (2018).
Kattah, M. G. et al. A20 and ABIN-1 synergistically preserve intestinal epithelial cell survival. J. Exp. Med. 215, 1839–1852 (2018).
Zaidi, D., Huynh, H. Q., Carroll, M. W., Baksh, S. & Wine, E. Tumor necrosis factor α-induced protein 3 (A20) is dysregulated in pediatric Crohn disease. Clin. Exp. Gastroenterol. 11, 217–231 (2018).
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).
Geng, J. et al. Regulation of RIPK1 activation by TAK1-mediated phosphorylation dictates apoptosis and necroptosis. Nat. Commun. 8, 359 (2017).
Guo, X. et al. TAK1 regulates caspase 8 activation and necroptotic signaling via multiple cell death checkpoints. Cell Death Dis. 7, e2381 (2016).
Singh, A. et al. TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers. Cell 148, 639–650 (2012).
Totzke, J. et al. Takinib, a selective TAK1 inhibitor, broadens the therapeutic efficacy of TNF-α inhibition for cancer and autoimmune disease. Cell Chem. Biol. 24, 1029–1039.e7 (2017).
Dondelinger, Y. et al. NF-κB-independent role of IKKα/IKKκ in preventing RIPK1 kinase-dependent apoptotic and necroptotic cell death during TNF signaling. Mol. Cell 60, 63–76 (2015).
Ruder, B. et al. Chronic intestinal inflammation in mice expressing viral Flip in epithelial cells. Mucosal Immunol. 11, 1621–1629 (2018).
Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016).
Liu, Z. et al. Role of inflammasomes in host defense against Citrobacter rodentium infection. J. Biol. Chem. 287, 16955–16964 (2012).
Nowarski, R. et al. Epithelial IL-18 equilibrium controls barrier function in colitis. Cell 163, 1444–1456 (2015).
Shi, J. et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature 526, 660–665 (2015).
Van Opdenbosch, N. et al. Caspase-1 engagement and TLR-induced c-FLIP expression suppress ASC/caspase-8-dependent apoptosis by inflammasome sensors NLRP1b and NLRC4. Cell Rep. 21, 3427–3444 (2017).
Rauch, I. et al. NAIP-NLRC4 inflammasomes coordinate intestinal epithelial cell expulsion with eicosanoid and IL-18 release via activation of caspase-1 and -8. Immunity 46, 649–659 (2017).
Fritsch, M. et al. Caspase-8 is the molecular switch for apoptosis, necroptosis and pyroptosis. Nature 575, 683–687 (2019).
Newton, K. et al. Activity of caspase-8 determines plasticity between cell death pathways. Nature 575, 679–682 (2019).
Saavedra, P. H. V. et al. Apoptosis of intestinal epithelial cells restricts Clostridium difficile infection in a model of pseudomembranous colitis. Nat. Commun. 9, 4846 (2018).
Aglietti, R. A. et al. GsdmD p30 elicited by caspase-11 during pyroptosis forms pores in membranes. Proc. Natl Acad. Sci. USA 113, 7858–7863 (2016).
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).
Demon, D. et al. Caspase-11 is expressed in the colonic mucosa and protects against dextran sodium sulfate-induced colitis. Mucosal Immunol. 7, 1480–1491 (2014).
Mandal, P. et al. Caspase-8 collaborates with caspase-11 to drive tissue damage and execution of endotoxic shock. Immunity 49, 42–55.e6 (2018).
Hefele, M. et al. Intestinal epithelial caspase-8 signaling is essential to prevent necroptosis during Salmonella typhimurium induced enteritis. Mucosal Immunol. 11, 1191–1202 (2018).
Progatzky, F. et al. Dietary cholesterol directly induces acute inflammasome-dependent intestinal inflammation. Nat. Commun. 5, 5864 (2014).
Kang, S. et al. Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3. Nat. Commun. 6, 7515 (2015).
Kang, T. B., Yang, S. H., Toth, B., Kovalenko, A. & Wallach, D. Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38, 27–40 (2013).
Lawlor, K. E. et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat. Commun. 6, 6282 (2015).
Liu, L. et al. The pathogenic role of NLRP3 inflammasome activation in inflammatory bowel diseases of both mice and humans. J. Crohns Colitis 11, 737–750 (2017).
Perera, A. P. et al. MCC950, a specific small molecule inhibitor of NLRP3 inflammasome attenuates colonic inflammation in spontaneous colitis mice. Sci. Rep. 8, 8618 (2018).
US National Library of Medicine. ClinicalTrials.gov https://www.clinicaltrials.gov/ct2/show/NCT03681067?term=GSK1070806&recrs=a&draw=2&rank=1 (2009).
Trump, B. F., Berezesky, I. K., Chang, S. H. & Phelps, P. C. The pathways of cell death: oncosis, apoptosis, and necrosis. Toxicol. Pathol. 25, 82–88 (1997).
de Vasconcelos, N. M., Van Opdenbosch, N., Van Gorp, H., Parthoens, E. & Lamkanfi, M. Single-cell analysis of pyroptosis dynamics reveals conserved GSDMD-mediated subcellular events that precede plasma membrane rupture. Cell Death Differ. 26, 146–161 (2019).
Chen, X. et al. Pyroptosis is driven by non-selective gasdermin-D pore and its morphology is different from MLKL channel-mediated necroptosis. Cell Res. 26, 1007–1020 (2016).
Kerr, J. F. Shrinkage necrosis: a distinct mode of cellular death. J. Pathol. 105, 13–20 (1971).
Bortner, C. D. & Cidlowski, J. A. A necessary role for cell shrinkage in apoptosis. Biochem. Pharmacol. 56, 1549–1559 (1998).
Gulbins, E., Welsch, J., Lepple-Wienhuis, A., Heinle, H. & Lang, F. Inhibition of Fas-induced apoptotic cell death by osmotic cell shrinkage. Biochem. Biophys. Res. Commun. 236, 517–521 (1997).
Orlov, S. N., Platonova, A. A., Hamet, P. & Grygorczyk, R. Cell volume and monovalent ion transporters: their role in cell death machinery triggering and progression. Am. J. Physiol. Cell Physiol. 305, C361–C372 (2013).
Grauso, M., Lan, A., Andriamihaja, M., Bouillaud, F. & Blachier, F. Hyperosmolar environment and intestinal epithelial cells: impact on mitochondrial oxygen consumption, proliferation, and barrier function in vitro. Sci. Rep. 9, 11360 (2019).
Field, M. Intestinal ion transport and the pathophysiology of diarrhea. J. Clin. Invest. 111, 931–943 (2003).
Lim, C. H., Bot, A. G., de Jonge, H. R. & Tilly, B. C. Osmosignaling and volume regulation in intestinal epithelial cells. Methods Enzymol. 428, 325–342 (2007).
van der Wijk, T., Tomassen, S. F., de Jonge, H. R. & Tilly, B. C. Signalling mechanisms involved in volume regulation of intestinal epithelial cells. Cell Physiol. Biochem. 10, 289–296 (2000).
Lang, F. et al. Functional significance of cell volume regulatory mechanisms. Physiol. Rev. 78, 247–306 (1998).
Eisenhoffer, G. T. et al. Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia. Nature 484, 546–549 (2012).
Kunzelmann, K. Ion channels in regulated cell death. Cell Mol. Life Sci. 73, 2387–2403 (2016).
Schreiber, R. et al. Expression and function of epithelial anoctamins. J. Biol. Chem. 285, 7838–7845 (2010).
Kunzelmann, K. et al. Expression and function of epithelial anoctamins. Exp. Physiol. 97, 184–192 (2012).
Ousingsawat, J. et al. Anoctamin 6 mediates effects essential for innate immunity downstream of P2X7 receptors in macrophages. Nat. Commun. 6, 6245 (2015).
Bao, J. et al. Deficient LRRC8A-dependent volume-regulated anion channel activity is associated with male infertility in mice. JCI Insight 3, e99767 (2018).
Wang, R. et al. The volume-regulated anion channel (LRRC8) in nodose neurons is sensitive to acidic pH. JCI Insight 2, e90632 (2017).
Olivan-Viguera, A. et al. Pharmacological activation of TRPV4 produces immediate cell damage and induction of apoptosis in human melanoma cells and HaCaT keratinocytes. PLoS One 13, e0190307 (2018).
Peters, A. A. et al. Oncosis and apoptosis induction by activation of an overexpressed ion channel in breast cancer cells. Oncogene 36, 6490–6500 (2017).
Hernandez, A. M. et al. Anti-NeuGcGM3 antibodies, actively elicited by idiotypic vaccination in nonsmall cell lung cancer patients, induce tumor cell death by an oncosis-like mechanism. J. Immunol. 186, 3735–3744 (2011).
Loo, D. et al. The glycotope-specific RAV12 monoclonal antibody induces oncosis in vitro and has antitumor activity against gastrointestinal adenocarcinoma tumor xenografts in vivo. Mol. Cancer Ther. 6, 856–865 (2007).
Sun, Y. et al. Oncosis-like cell death is induced by berberine through ERK1/2-mediated impairment of mitochondrial aerobic respiration in gliomas. Biomed. Pharmacother. 102, 699–710 (2018).
Schroeder, M. E. et al. Pro-inflammatory Ca++-activated K+ channels are inhibited by hydroxychloroquine. Sci. Rep. 7, 1892 (2017).
Di, L. et al. Inhibition of the K+ channel KCa3.1 ameliorates T cell-mediated colitis. Proc. Natl Acad. Sci. USA 107, 1541–1546 (2010).
Martin, S. J. & Henry, C. M. Distinguishing between apoptosis, necrosis, necroptosis and other cell death modalities. Methods 61, 87–89 (2013).
Zhang, Y., Chen, X., Gueydan, C. & Han, J. Plasma membrane changes during programmed cell deaths. Cell Res. 28, 9–21 (2018).
Xia, B. et al. MLKL forms cation channels. Cell Res. 26, 517–528 (2016).
Wulff, H., Christophersen, P., Colussi, P., Chandy, K. G. & Yarov-Yarovoy, V. Antibodies and venom peptides: new modalities for ion channels. Nat. Rev. Drug. Discov. 18, 339–357 (2019).
Sun, G. et al. A molecular signature for anastasis, recovery from the brink of apoptotic cell death. J. Cell Biol. 216, 3355–3368 (2017).
Tang, H. L., Tang, H. M., Fung, M. C. & Hardwick, J. M. In vivo CaspaseTracker biosensor system for detecting anastasis and non-apoptotic caspase activity. Sci. Rep. 5, 9015 (2015).
Tang, H. L., Tang, H. M., Hardwick, J. M. & Fung, M. C. Strategies for tracking anastasis, a cell survival phenomenon that reverses apoptosis. J. Vis. Exp. 96, e51964 (2015).
Tang, H. L. et al. Cell survival, DNA damage, and oncogenic transformation after a transient and reversible apoptotic response. Mol. Biol. Cell 23, 2240–2252 (2012).
Tang, H. M., Fung, M. C. & Tang, H. L. Detecting anastasis In vivo by caspasetracker biosensor. J. Vis. Exp. 132, e54107 (2018).
Tang, H. M., Talbot, C. C. Jr, Fung, M. C. & Tang, H. L. Molecular signature of anastasis for reversal of apoptosis. F1000Res 6, 43 (2017).
Tang, H. M. & Tang, H. L. Correction to: ‘Anastasis: recovery from the brink of cell death’. R. Soc. Open. Sci. 5, 181629 (2018).
Galluzzi, L., Kepp, O. & Kroemer, G. MLKL regulates necrotic plasma membrane permeabilization. Cell Res. 24, 139–140 (2014).
Wang, H. et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol. Cell 54, 133–146 (2014).
Gong, Y. N. et al. ESCRT-III acts downstream of MLKL to regulate necroptotic cell death and its consequences. Cell 169, 286–300.e16 (2017).
Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).
Lucas, M., Stuart, L. M., Savill, J. & Lacy-Hulbert, A. Apoptotic cells and innate immune stimuli combine to regulate macrophage cytokine secretion. J. Immunol. 171, 2610–2615 (2003).
Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).
Voll, R. E. et al. Immunosuppressive effects of apoptotic cells. Nature 390, 350–351 (1997).
Bullen, T. F. et al. Characterization of epithelial cell shedding from human small intestine. Lab. Invest. 86, 1052–1063 (2006).
Mitsuhashi, S. et al. Luminal extracellular vesicles (EVs) in inflammatory bowel disease (IBD) exhibit proinflammatory effects on epithelial cells and macrophages. Inflamm. Bowel Dis. 22, 1587–1595 (2016).
Bounous, G. Acute necrosis of the intestinal mucosa. Gastroenterology 82, 1457–1467 (1982).
Bounous, G., Echave, V., Vobecky, S. J., Navert, H. & Wollin, A. Acute necrosis of the intestinal mucosa with high serum levels of diamine oxidase. Dig. Dis. Sci. 29, 872–874 (1984).
Song, H. L., Lv, S. & Liu, P. The roles of tumor necrosis factor-alpha in colon tight junction protein expression and intestinal mucosa structure in a mouse model of acute liver failure. BMC Gastroenterol. 9, 70 (2009).
Kaczmarek, A., Vandenabeele, P. & Krysko, D. V. Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209–223 (2013).
Sangiuliano, B., Perez, N. M., Moreira, D. F. & Belizario, J. E. Cell death-associated molecular-pattern molecules: inflammatory signaling and control. Mediators Inflamm. 2014, 821043 (2014).
Pentecost, M., Otto, G., Theriot, J. A. & Amieva, M. R. Listeria monocytogenes invades the epithelial junctions at sites of cell extrusion. PLoS Pathog. 2, e3 (2006).
Lee, K. Z. et al. Enterocyte purge and rapid recovery is a resilience reaction of the gut epithelium to pore-forming toxin attack. Cell Host Microbe 20, 716–730 (2016).
Knodler, L. A. et al. Noncanonical inflammasome activation of caspase-4/caspase-11 mediates epithelial defenses against enteric bacterial pathogens. Cell Host Microbe 16, 249–256 (2014).
Loetscher, Y. et al. Salmonella transiently reside in luminal neutrophils in the inflamed gut. PLoS One 7, e34812 (2012).
Brazil, J. C. & Parkos, C. A. Pathobiology of neutrophil-epithelial interactions. Immunol. Rev. 273, 94–111 (2016).
Lee, C. S. et al. Boosting apoptotic cell clearance by colonic epithelial cells attenuates inflammation in vivo. Immunity 44, 807–820 (2016).
Cummings, R. J. et al. Different tissue phagocytes sample apoptotic cells to direct distinct homeostasis programs. Nature 539, 565–569 (2016).
Hunter, M. M. et al. In vitro-derived alternatively activated macrophages reduce colonic inflammation in mice. Gastroenterology 138, 1395–1405 (2010).
Weisser, S. B. et al. SHIP-deficient, alternatively activated macrophages protect mice during DSS-induced colitis. J. Leukoc. Biol. 90, 483–492 (2011).
Yang, Z. et al. C-type lectin receptor LSECtin-mediated apoptotic cell clearance by macrophages directs intestinal repair in experimental colitis. Proc. Natl Acad. Sci. USA 115, 11054–11059 (2018).
Botto, M. & Walport, M. J. C1q, autoimmunity and apoptosis. Immunobiology 205, 395–406 (2002).
Poon, I. K., Lucas, C. D., Rossi, A. G. & Ravichandran, K. S. Apoptotic cell clearance: basic biology and therapeutic potential. Nat. Rev. Immunol. 14, 166–180 (2014).
Green, D. R., Oguin, T. H. & Martinez, J. The clearance of dying cells: table for two. Cell Death Differ. 23, 915–926 (2016).
Sachet, M., Liang, Y. Y. & Oehler, R. The immune response to secondary necrotic cells. Apoptosis 22, 1189–1204 (2017).
Silva, M. T. Secondary necrosis: the natural outcome of the complete apoptotic program. FEBS Lett. 584, 4491–4499 (2010).
Rogers, C. et al. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 8, 14128 (2017).
Krysko, D. V. et al. Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol. 32, 157–164 (2011).
Boyapati, R. K. et al. Mitochondrial DNA is a pro-inflammatory damage-associated molecular pattern released during active IBD. Inflamm. Bowel Dis. 24, 2113–2122 (2018).
Bertheloot, D. & Latz, E. HMGB1, IL-1α, IL-33 and S100 proteins: dual-function alarmins. Cell Mol. Immunol. 14, 43–64 (2017).
Scarpa, M. et al. The epithelial danger signal IL-1α is a potent activator of fibroblasts and reactivator of intestinal inflammation. Am. J. Pathol. 185, 1624–1637 (2015).
Dinarello, C. A., Simon, A. & van der Meer, J. W. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat. Rev. Drug. Discov. 11, 633–652 (2012).
Hugle, B., Speth, F. & Haas, J. P. Inflammatory bowel disease following anti-interleukin-1-treatment in systemic juvenile idiopathic arthritis. Pediatr. Rheumatol. Online J. 15, 16 (2017).
Mahapatro, M. et al. Programming of intestinal epithelial differentiation by IL-33 derived from pericryptal fibroblasts in response to systemic infection. Cell Rep. 15, 1743–1756 (2016).
Pastorelli, L. et al. Epithelial-derived IL-33 and its receptor ST2 are dysregulated in ulcerative colitis and in experimental Th1/Th2 driven enteritis. Proc. Natl Acad. Sci. USA 107, 8017–8022 (2010).
Lopetuso, L. R. et al. IL-33 promotes recovery from acute colitis by inducing miR-320 to stimulate epithelial restitution and repair. Proc. Natl Acad. Sci. USA 115, E9362–E9370 (2018).
Reed, K. R. et al. Secreted HMGB1 from Wnt activated intestinal cells is required to maintain a crypt progenitor phenotype. Oncotarget 7, 51665–51673 (2016).
Zhao, X. L. et al. High-mobility group Box 1 released by autophagic cancer-associated fibroblasts maintains the stemness of luminal breast cancer cells. J. Pathol. 243, 376–389 (2017).
Khoury, M. K., Gupta, K., Franco, S. R. & Liu, B. Necroptosis in the pathophysiology of disease. Am. J. Pathol. 190, 272–285 (2020).
Parker, A. et al. Elevated apoptosis impairs epithelial cell turnover and shortens villi in TNF-driven intestinal inflammation. Cell Death Dis. 10, 108 (2019).
Tang, D., Kang, R., Berghe, T. V., Vandenabeele, P. & Kroemer, G. The molecular machinery of regulated cell death. Cell Res. 29, 347–364 (2019).
Shi, J., Gao, W. & Shao, F. Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem. Sci. 42, 245–254 (2017).
Jiao, H. et al. Z-nucleic-acid sensing triggers ZBP1-dependent necroptosis and inflammation. Nature 580, 391–395 (2020).
Kim, J. M. et al. Apoptosis of human intestinal epithelial cells after bacterial invasion. J. Clin. Invest. 102, 1815–1823 (1998).
Zargarian, S. et al. Phosphatidylserine externalization, “necroptotic bodies” release, and phagocytosis during necroptosis. PLoS Biol. 15, e2002711 (2017).
Perez-Lopez, A. M., Soria-Gila, M. L., Marsden, E. R., Lilienkampf, A. & Bradley, M. Fluorogenic substrates for in situ monitoring of caspase-3 activity in live cells. PLoS One 11, e0153209 (2016).
Bast, A. et al. Caspase-1-dependent and -independent cell death pathways in Burkholderia pseudomallei infection of macrophages. PLoS Pathog. 10, e1003986 (2014).
Acknowledgements
This work received funding from the DFG projects TRR241 (A03), SFB1181 (C05) and FOR2438 (TP05) and individual grant BE3686/9, as well as the Interdisciplinary Center for Clinical Research (IZKF; J68, A76).
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Glossary
- Inflammasome
-
An oligomeric protein complex that is formed after various pattern recognition receptors are engaged and then binds to an adapter protein and pro-caspase 1, leading the maturation and activation of caspase 1 and pyroptotic cell death.
- Caspase
-
A conserved family of cysteine-dependent aspartate-directed proteases that initiate and execute different molecular cell death pathways.
- Apoptosome
-
A multimolecular protein complex with critical functions in apoptotic cell death; it is triggered by the release of cytochrome c from the mitochondria and consists of cytochrome c, apoptotic protease activating factor 1 and initiator caspases such as caspase 9.
- Ripoptosome
-
A multiprotein complex that has a crucial role in the necroptotic form of cell death; it consists of receptor-interacting serine/threonine-protein kinases RIPK1 and RIPK3 and forms when the TNF receptor is activated and the activity of the initiator caspase, caspase 8, is reduced or lacking.
- Necrosis
-
A term that was used to describe non-programmed cell death due to chemical or mechanical damage; it is now restricted to describing cell death where all identifiable modes of programmed cell death have been ruled out or cannot be investigated and therefore the exact mode of cell death is unclear.
- Oncosis
-
Also referred to as ischaemic cell death, oncosis is a process of cell death following cellular swelling involving disruption and swelling of intracellular organelles including the nucleus.
- Anastasis
-
A mode of cellular ‘resurrection’ in which cells survive even after well-established molecular milestones of cell death have been reached, such as cytochrome c release and effector caspase activation.
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Patankar, J.V., Becker, C. Cell death in the gut epithelium and implications for chronic inflammation. Nat Rev Gastroenterol Hepatol 17, 543–556 (2020). https://doi.org/10.1038/s41575-020-0326-4
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DOI: https://doi.org/10.1038/s41575-020-0326-4
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