Abstract
One of the pathological changes frequently observed in tissues injured as a result of inflammation is death of cells. Whereas apoptotic cell death in such lesions is clearly identifiable, and we have a reasonably clear notion of its functional significance, our knowledge of the exact nature of the non-apoptotic forms of cell death accompanying inflammation and of their functional significance is still limited. Emerging evidence indicates that necrotic cell death can be both induced and counteracted by a specific set of signaling molecules. Studies showing that the same signaling molecules also trigger inflammation in vivo and that when cells die necrotically some of the molecules they release can facilitate inflammation raised the possibility that the death induced by these signaling molecules (“necroptosis”) serves to trigger inflammation. Attempts have been made to probe this hypothesis by genetic modulation of the signaling proteins that control induction of necrotic cell death. Here we briefly discuss the work done on the in vivo function of caspase-8, an enzyme crucially involved in regulating the induction of necroptosis. The studies to date imply that caspase-8 and the other proximal signaling proteins known to participate in the induction of necroptosis might be too pleiotropic to serve as reliable molecular probes for determining the in vivo occurrence and significance of this death process. Only by identifying molecular events further downstream of and more specific to necroptosis might we be able to reliably monitor the occurrence of this particular form of death in inflammation and define its causal role in the inflammatory process.
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References
Arends MJ, Morris RG, Wyllie AH (1990) Apoptosis. The role of the endonuclease. Am J Pathol 136:593–608
Ben Moshe T, Barash H, Kang TB, Kim JC, Kovalenko A, Gross E, Schuchmann M, Abramovitch R, Galun E, Wallach D (2007) Role of caspase-8 in hepatocyte response to infection and injury in mice. Hepatology 45:1014–1024
Biton S, Ashkenazi A (2011) NEMO and RIP1 control cell fate in response to extensive DNA damage via TNF-alpha feedforward signaling. Cell 145:92–103
Boldin MP, Goncharov TM, Goltsev YV, Wallach D (1996) Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 85:803–815
Bonnet MC, Preukschat D, Welz PS, van Loo G, Ermolaeva MA, Bloch W, Haase I, Pasparakis M (2011) The adaptor protein FADD protects epidermal keratinocytes from necroptosis in vivo and prevents skin inflammation. Immunity 35:572–582
Bossaller L, Chiang PI, Schmidt-Lauber C, Ganesan S, Kaiser WJ, Rathinam VA, Mocarski ES, Subramanian D, Green DR, Silverman N, Fitzgerald KA, Marshak-Rothstein A, Latz E (2012) Cutting edge: FAS (CD95) mediates noncanonical IL-1beta and IL-18 maturation via caspase-8 in an RIP3-independent manner. J Immunol 189:5508–5512
Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, Chan FK (2009) Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137:1112–1123
Clarke PG, Clarke S (1996) Nineteenth century research on naturally occurring cell death and related phenomena. Anat Embryol 193:81–99
Degterev A, Hitomi J, Germscheid M, Ch’en IL, Korkina O, Teng X, Abbott D, Cuny GD, Yuan C, Wagner G, Hedrick SM, Gerber SA, Lugovskoy A, Yuan J (2008) Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol 4:313–321
Devin A, Lin Y, Liu ZG (2003) The role of the death-domain kinase RIP in tumour-necrosis-factor-induced activation of mitogen-activated protein kinases. EMBO Rep 4:623–627
Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43–50
Fadok VA, Bratton DL, Konowal A, Freed PW, Westcott JY, Henson PM (1998) 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
Frelin C, Imbert V, Bottero V, Gonthier N, Samraj AK, Schulze-Osthoff K, Auberger P, Courtois G, Peyron JF (2008) Inhibition of the NF-kappaB survival pathway via caspase-dependent cleavage of the IKK complex scaffold protein and NF-kappaB essential modulator NEMO. Cell Death Differ 15:152–160
Green DR, Oberst A, Dillon CP, Weinlich R, Salvesen GS (2011) RIPK-dependent necrosis and its regulation by caspases: a mystery in five acts. Mol Cell 44:9–16
Gringhuis SI, Kaptein TM, Wevers BA, Theelen B, van der Vlist M, Boekhout T, Geijtenbeek TB (2012) Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1beta via a noncanonical caspase-8 inflammasome. Nat Immunol 13:246
Gunther C, Martini E, Wittkopf N, Amann K, Weigmann B, Neumann H, Waldner MJ, Hedrick SM, Tenzer S, Neurath MF, Becker C (2011) Caspase-8 regulates TNF-alpha-induced epithelial necroptosis and terminal ileitis. Nature 477:335–339
Haslett C, Savill JS, Whyte MK, Stern M, Dransfield I, Meagher LC (1994) Granulocyte apoptosis and the control of inflammation. Philos Trans R Soc Lond B Biol Sci 345:327–333
He S, Wang L, Miao L, Wang T, Du F, Zhao L, Wang X (2009) Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137:1100–1111
Henkler F, Baumann B, Fotin-Mleczek M, Weingartner M, Schwenzer R, Peters N, Graness A, Wirth T, Scheurich P, Schmid JA, Wajant H (2003) Caspase-mediated cleavage converts the tumor necrosis factor (TNF) receptor-associated factor (TRAF)-1 from a selective modulator of TNF receptor signaling to a general inhibitor of NF-kappaB activation. J Biol Chem 278:29216–29230
Henson PM, Johnston RB Jr (1987) Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J Clin Invest 79:669–674
Holler N, Zaru R, Micheau O, Thome M, Attinger A, Valitutti S, Bodmer JL, Schneider P, Seed B, Tschopp J (2000) Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat Immunol 1:489–495
Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T, Mocarski ES (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471:368–372
Kang TB, Oh G-S, Scandella E, Bolinger B, Ludewig B, Kovalenko A, Wallach D (2008) Mutation of a self-processing site in caspase-8 compromises its apoptotic but not its nonapoptotic functions in bacterial artificial chromosome-transgenic mice. J Immunol 181:2522–2532
Kang TB, Yang SH, Toth B, Kovalenko A, Wallach D (2013) Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38:27–40
Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257
Kovalenko A, Kim JC, Kang TB, Rajput A, Bogdanov K, Dittrich-Breiholz O, Kracht M, Brenner O, Wallach D (2009) Caspase-8 deficiency in epidermal keratinocytes triggers an inflammatory skin disease. J Exp Med 206:2161–2177
Levkau B, Scatena M, Giachelli CM, Ross R, Raines EW (1999) Apoptosis overrides survival signals through a caspase-mediated dominant-negative NF-kappa B loop. Nat Cell Biol 1:227–233
Li C, Lasse S, Lee P, Nakasaki M, Chen SW, Yamasaki K, Gallo RL, Jamora C (2010) Development of atopic dermatitis-like skin disease from the chronic loss of epidermal caspase-8. Proc Natl Acad Sci U S A 107:22249–22254
Lin Y, Devin A, Rodriguez Y, Liu ZG (1999) Cleavage of the death domain kinase RIP by caspase-8 prompts TNF-induced apoptosis. Genes Dev 13:2514–2526
Lukens JR, Vogel P, Johnson GR, Kelliher MA, Iwakura Y, Lamkanfi M, Kanneganti TD (2013) RIP1-driven autoinflammation targets IL-1alpha independently of inflammasomes and RIP3. Nature 498:224–227
Majno G, La Gattuta M, Thompson TE (1960) Cellular death and necrosis: chemical, physical and morphologic changes in rat liver. Virchows Arch Pathol Anat Physiol Klin Med 333:421–465
Matzinger P (1994) Tolerance, danger, and the extended family. Annu Rev Immunol 12:991–1045
Menkin V (1948) Newer concepts of inflammation. Charles C Thomas, Springfield, IL
Muzio M, Chinnaiyan AM, Kischkel FC, O’Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 85:817–827
O’Donnell MA, Perez-Jimenez E, Oberst A, Ng A, Massoumi R, Xavier R, Green DR, Ting AT (2011) Caspase 8 inhibits programmed necrosis by processing CYLD. Nat Cell Biol 13:1437–1442
Rajput A, Kovalenko A, Bogdanov K, Yang SH, Kang TB, Kim JC, Du J, Wallach D (2011) RIG-I RNA helicase activation of IRF3 transcription factor is negatively regulated by caspase-8-mediated cleavage of the RIP1 protein. Immunity 34:340–351
Rock KL, Kono H (2008) The inflammatory response to cell death. Annu Rev Pathol 3:99–126
Sakahira H, Enari M, Nagata S (1998) Cleavage of CAD inhibitor in CAD activation and DNA degradation during apoptosis. Nature 391:96–99
Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X (2012) Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148:213–227
Vandenabeele P, Galluzzi L, Vanden Berghe T, Kroemer G (2010) Molecular mechanisms of necroptosis: an ordered cellular explosion. Nat Rev Mol Cell Biol 11:700–714
Varfolomeev EE, Schuchmann M, Luria V, Chiannilkulchai N, Beckmann JS, Mett IL, Rebrikov D, Brodianski VM, Kemper OC, Kollet O, Lapidot T, Soffer D, Sobe T, Avraham KB, Goncharov T, Holtmann H, Lonai P, Wallach D (1998) Targeted disruption of the mouse Caspase 8 gene ablates cell death induction by the TNF receptors, Fas/Apo1, and DR3 and is lethal prenatally. Immunity 9:267–276
Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R, O’Reilly L, Mason K, Gross O, Ma S, Guarda G, Anderton H, Castillo R, Hacker G, Silke J, Tschopp J (2012) Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36:215–227
Voll RE, Herrmann M, Roth EA, Stach C, Kalden JR, Girkontaite I (1997) Immunosuppressive effects of apoptotic cells. Nature 390:350–351
Wallach D, Kovalenko A, Kang TB (2011) ‘Necrosome’-induced inflammation: must cells die for it? Trends Immunol 32:505
Wallach D, Varfolomeev EE, Malinin NL, Goltsev YV, Kovalenko AV, Boldin MP (1999) Tumor necrosis factor receptor and Fas signaling mechanisms. Annu Rev Immunol 17:331–367
Wang Z, Jiang H, Chen S, Du F, Wang X (2012) The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways. Cell 148:228–243
Zhang DW, Shao J, Lin J, Zhang N, Lu BJ, Lin SC, Dong MQ, Han J (2009) RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325:332–336
Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, Liu ZG (2012) Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci U S A 109:5322–5327
Acknowledgments
D.W. is the incumbent of the Joseph and Bessie Feinberg Professorial Chair at The Weizmann Institute of Science.
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Wallach, D. et al. (2014). The In Vivo Significance of Necroptosis: Lessons from Exploration of Caspase-8 Function. In: Shen, HM., Vandenabeele, P. (eds) Necrotic Cell Death. Cell Death in Biology and Diseases. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-8220-8_7
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DOI: https://doi.org/10.1007/978-1-4614-8220-8_7
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