Abstract
Microbial infection and tissue injury are well established as the two major drivers of inflammation. However, although it is widely accepted that necrotic cell death can trigger or potentiate inflammation, precisely how this is achieved still remains relatively obscure. Certain molecules, which have been dubbed ‘damage-associated molecular patterns’ (DAMPs) or alarmins, are thought to promote inflammation upon release from necrotic cells. However, the precise nature and relative potency of DAMPs, compared to conventional pro-inflammatory cytokines or pathogen-associated molecular patterns (PAMPs), remains unclear. How different modes of cell death impact on the immune system also requires further clarification. Apoptosis has long been regarded as a non-inflammatory or even anti-inflammatory mode of cell death, but recent studies suggest that this is not always the case. Necroptosis is a programmed form of necrosis that is engaged under certain conditions when caspase activation is blocked. Necroptosis is also regarded as a highly pro-inflammatory mode of cell death but there has been little explicit examination of this issue. Here we discuss the inflammatory implications of necrosis, necroptosis and apoptosis and some of the unresolved questions concerning how dead cells influence inflammatory responses.
Acknowledgments
This work was supported by grants of the Russian government for state support of scientific research, as well as Science Foundation Ireland.
References
Altemeier, W.A., Zhu, X., Berrington, W.R., Harlan, J.M., and Liles, W.C. (2007). Fas (CD95). induces macrophage proinflammatory chemokine production via a MyD88-dependent, caspase-independent pathway. J. Leukoc. Biol. 82, 721–718.Search in Google Scholar
Azijli, K., Yuvaraj, S., Peppelenbosch, M.P., Würdinger, T., Dekker, H., Joore, J., van Dijk, E., Quax, W.J., Peters, G.J., de Jong, S., et al. (2012). Kinome profiling of non-canonical TRAIL signaling reveals RIP1-Src-STAT3-dependent invasion in resistant non-small cell lung cancer cells. J. Cell Sci. 125, 4651–4661.Search in Google Scholar
Baader, E., Toloczko, A., Fuchs, U., Schmid, I., Beltinger, C., Ehrhardt, H., Debatin, K.M., and Jeremias, I. (2005). Tumor necrosis factor-related apoptosis-inducing ligand-mediated proliferation of tumor cells with receptor-proximal apoptosis defects. Cancer Res. 65, 7888–7895.Search in Google Scholar
Barnhart, B.C., Legembre, P., Pietras, E., Bubici, C., Franzoso, G., and Peter M.E. (2004). CD95 ligand induces motility and invasiveness of apoptosis-resistant tumor cells. EMBO J. 23, 3175–3185.Search in Google Scholar
Baroja-Mazo, A., Martín-Sánchez, F., Gomez, A.I., Martínez, C.M., Amores-Iniesta, J., Compan, V., Barberà-Cremades, M., Yagüe, J., Ruiz-Ortiz, E., Antón, J., et al. (2014). The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 15, 738–748.Search in Google Scholar
Berg, D., Stühmer, T., Siegmund, D., Müller, N., Giner, T., Dittrich-Breiholz, O., Kracht, M., Bargou, R., and Wajant, H. (2009). Oligomerized tumor necrosis factor-related apoptosis inducing ligand strongly induces cell death in myeloma cells, but also activates proinflammatory signaling pathways. FEBS J. 276, 6912–6927.Search in Google Scholar
Brennan, F.M. and McInnes, I.B. (2008). Evidence that cytokines play a role in rheumatoid arthritis. J. Clin. Invest. 118, 3537–3545.Search in Google Scholar
Cai, Z., Jitkaew, S., Zhao, J., Chiang, H.C., Choksi, S., Liu, J., Ward, Y., Wu, L.G, and Liu, Z.G. (2014). Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat. Cell Biol. 16, 55–65.Search in Google Scholar
Chen, G.Y. and Nuñez, G. (2010). Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826–837.Search in Google Scholar
Chen, L., Park, S.M, Tumanov, A.V., Hau, A., Sawada, K., Feig, C., Turner, J.R., Fu, Y.X., Romero, I.L., Lengyel, E., et al. (2010a). CD95 promotes tumour growth. Nature 465, 492–496.Search in Google Scholar
Chen, L., Park, S.M., Tumanov, A., Hau, A., Sawada, K., Feig, C., Turner, J., Fu, Y.X., Romeo, I., Lengyel, E., et al. (2010b). CD95 promotes tumour growth. Nature 465, 492–496.Search in Google Scholar
Chen, X., Li, W., Ren, J., Huang, D., He, W.T., Song, Y., Yang, C., Li, W., Zheng, X., Chen, P., et al. (2014). Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 24, 105–121.Search in Google Scholar
Cho, Y.S., Challa, S., Moquin, D., Genga, R., Ray, T.D., Guildford, M., and Chan, F.K. (2009). Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123.Search in Google Scholar
Choi, C., Xu, X., Oh, J.W., Lee, S.J., Gillespie, G.Y., Park, H., Jo, H., and Benveniste, E.N. (2001). Fas-induced expression of chemokines in human glioma cells: involvement of extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase. Cancer Res. 61, 3084–3091.Search in Google Scholar
Cohen, I., Rider, P., Carmi, Y., Braiman, A., Dotan, S., White, M.R., Voronov, E., Martin, M.U., Dinarello, C.A., and Aptea, R.N. (2010). Differential release of chromatin-bound IL-1α discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc. Natl. Acad. Sci. USA 107, 2574–2579.Search in Google Scholar
Croft, M., Duan, W., Choi, H., Eun, S.Y., Madireddi, S., and Mehta, A. (2011). TNF superfamily in inflammatory disease: translating basic insights. Trends Immunol. Trends Immunol. 33, 144–152.Search in Google Scholar
Cullen, S.P., Henry, C.M., Kearney, C.J., Logue, S.E., Feoktistova, M., Tynan, G.A., Lavelle, E.C., Leverkus, M., and Martin S.J. (2013). Fas/CD95-induced chemokines can serve as “find-me” signals for apoptotic cells. Mol. Cell 49, 1034–1048.Search in Google Scholar
Dickens, L.S., Boyd, R.S., Jukes-Jones, R., Hughes, M.A., Robinson, G.L., Fairall, L., Schwabe, J.W., Cain, K., and Macfarlane, M. (2012). A death effector domain chain DISC model reveals a crucial role for caspase-8 chain assembly in mediating apoptotic cell death. Mol. Cell 47, 291–305.Search in Google Scholar
Duprez, L., Takahashi, N., Van Hauwermeiren, F., Vandendriessche, B., Goossens, V., Vanden Berghe, T., Declercq, W., Libert, C., Cauwels, A., and Vandenabeele, P. (2011). RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity. 35, 908–918.Search in Google Scholar
Ehrhardt, H., Fulda, S., Schmid, I., Hiscott, J., Debatin, K.M., and Jeremias, I. (2003). TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-κB. Oncogene 22, 3842–3852.Search in Google Scholar
Esche, C., Stellato, C., and Beck, L.A. (2005). Chemokines: Key Players in Innate and Adaptive Immunity. J. Inv. Derm. 125, 615–628.Search in Google Scholar
Falschlehner, C., Schaefer, U., and Walczak, H. (2009). Following TRAIL’s path in the immune system. Immunology 127, 145–154.Search in Google Scholar
Farley, S.M., Dotson, A.D., Purdy, D.E., Sundholm, A.J., Schneider, P., Magun, B.E., and Iordanov, M.S. (2006). Fas ligand elicits a caspase-independent proinflammatory response in human keratinocytes: implications for dermatitis. J. Invest. Dermatol. 126, 2438–2451.Search in Google Scholar
Franklin, B.S., Bossaller, L., De Nardo, D., Ratter, J.M., Stutz, A., Engels, G., Brenker, C., Nordhoff, M., Mirandola, S.R., Al-Amoudi, A., et al. (2014). The adaptor ASC has extracellular and ‘prionoid’ activities that propagate inflammation. Nat. Immunol. 15, 727–737.Search in Google Scholar
Gallucci, S., Lolkema, M., and Matzinger, P. (1999). Natural adjuvants: endogenous activators of dendritic cells. Nat. Med. 5, 1249–1255.Search in Google Scholar
Garlanda, C., Dinarello, C.A., and Mantovani, A. (2013). The interleukin-1 family: back to the future. Immunity 39, 1003–1018.Search in Google Scholar
Gonzalvez, F., Lawrence, D., Yang, B., Yee, S., Pitti, R., Marsters, S., Pham, V.C., Stephan, J.P., Lill, J., and Ashkenazi, A. (2012). TRAF2 Sets a threshold for extrinsic apoptosis by tagging caspase-8 with a ubiquitin shutoff timer. Mol. Cell 48, 888–899.Search in Google Scholar
He, S., Wang, L., Miao, L., Wang, T., Du, F., Zhao, L., and Wang, X. (2009). Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α. Cell 137, 1100–1111.Search in Google Scholar
Hoogwater, F.J., Nijkamp, M.W., Smakman, N., Steller, E.J, Emmink, B.L., Westendorp, B.F., Raats, D.A., Sprick, M.R., Schaefer, U., Van Houdt, W.J., et al. (2010). Oncogenic K-Ras turns death receptors into metastasis-promoting receptors in human and mouse colorectal cancer cells. Gastroenterology 138, 2357–2367.Search in Google Scholar
Kaczmarek, A., Vandenabeele, P., and Krysko D.V. (2013). Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity 38, 209–223.Search in Google Scholar
Kavuri, S.M., Geserick, P., Berg, D., Dimitrova, D.P., Feoktistova, M., Siegmund, D., Gollnick, H., Neumann, M., Wajant, H., and Leverkus, M. (2011). Cellular FLICE-inhibitory protein (cFLIP). isoforms block CD95- and TRAIL death receptor-induced gene induction irrespective of processing of caspase-8 or cFLIP in the death-inducing signaling complex. J. Biol. Chem. 286, 16631–16646.Search in Google Scholar
Kawai, T. and Akira, S. (2007). TLR signalling. Semin. Immunol. 19, 24–32.Search in Google Scholar
Kearney, C.J., Sheridan, C., Cullen, S.P., Tynan, G.A., Logue, S.E., Afonina, I.S., Vucic, D., Lavelle, E.C., and Martin, S.J. (2013). IAPs and their antagonists regulate spontaneous and TNF-induced pro-inflammatory cytokine and chemokine production. J. Biol. Chem. 288, 4878–4890.Search in Google Scholar
Kerr, J.F.R., Wyllie, A.H., and Currie, A.R. (1972). Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–275.Search in Google Scholar
Kleber, S., Sancho-Martinez, I., Wiestler, B., Beisel, A., Gieffers, C., Hill, O., Thiemann, M., Mueller, W., Sykora, J., Kuhn, A., et al. (2008). Yes and PI3K bind CD95 to signal invasion of glioblastoma. Cancer Cell 13, 235–248.Search in Google Scholar
Kovalenko, A. and Wallach, D. (2006). If the prophet does not come to the mountain: dynamics of signaling complexes in NF-κB activation. Mol. Cell 22, 433–436.Search in Google Scholar
Kroemer, G. and Martin, S.J. (2005). Caspase-independent cell death. Nat. Med. 11, 725–730.Search in Google Scholar
Lavrik, I.N. and Krammer, P.H. (2012). Regulation of CD95/Fas signaling at the DISC. Cell Death Differ. 19, 36–41.Search in Google Scholar
Lavrik, I.N., Golks, A., Riess, D., Bentele, M., Eils, R., and Krammer, P.H. (2007). Analysis of CD95 threshold signaling: triggering of CD95 (FAS/APO-1). at low concentrations primarily results in survival signaling. J. Biol. Chem. 282, 13664–13671.Search in Google Scholar
Legembre, P., Barnhart, B.C., Zheng, L., Vijayan, S., Straus, S.E., Puck, J., Dale, J.K., Lenardo, M., and Peter, M.E. (2004). Induction of apoptosis and activation of NF-kB by CD95 require different signaling thresholds. EMBO Rep. 5, 1084–1089.Search in Google Scholar
Linkermann, A., Bräsen, J.H., Darding, M., Jin, M.K., Sanz, A.B., Heller, J.O., De Zen, F., Weinlich, R., Ortiz, A., Walczak, H., et al. (2013). Two independent pathways of regulated necrosis mediate ischemia-reperfusion injury. Proc. Natl. Acad. Sci. USA 110, 12024–12029.Search in Google Scholar
Lüthi, A.U., Cullen, S.P., McNeela, E.A., Duriez, P.J., Afonina, I.S., Sheridan, C., Brumatti, G., Taylor, R.C., Kersse, K., Vandenabeele, P., et al. (2009). Suppression of interleukin-33 bioactivity through proteolysis by apoptotic caspases. Immunity 31, 84–98.Search in Google Scholar
Mahoney, D.J., Cheung, H.H., Mrad, R.L., Plenchette, S., Simard, C., Enwere, E., Arora, V., Mak, T.W., Lacasse, E.C., Waring, J., et al. (2008). Both cIAP1 and cIAP2 regulate TNFα-mediated NF-κB activation. Proc. Natl. Acad. Sci. USA 105, 11778–11783.Search in Google Scholar
Matzinger, P. (1994). Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045.Search in Google Scholar
Matzinger, P. (2002). The danger model: a renewed sense of self. Science 296, 301–305.Search in Google Scholar
Matzinger, P. and Kamala, T. (2011). Tissue-based class control: the other side of tolerance. Nat. Rev. Immun. 11, 221–230.Search in Google Scholar
Medzhitov, R. (2008). Origin and physiological roles of inflammation. Nature 454, 428–435.Search in Google Scholar
Miao, E.A., Rajan, J.V., and Aderem, A. (2011). Caspase-1-induced pyroptotic cell death. Immunol. Rev. 243, 206–214.Search in Google Scholar
Mitsiades, C.S., Poulaki, V., Fanourakis, G., Sozopoulos, E., McMillin, D., Wen, Z., Voutsinas, G., Tseleni-Balafouta, S., and Mitsiades, N. (2006). Fas signaling in thyroid carcinomas is diverted from apoptosis to proliferation. Clin. Cancer Res. 12, 3705–3712.Search in Google Scholar
Mocarski, E.S., Upton, J.W., and Kaiser, W.J. (2012). Viral infection and the evolution of caspase 8-regulated apoptotic and necrotic death pathways. Nat. Rev. Immunol. 12, 79–88.Search in Google Scholar
Moriwaki, K. and Ka-Ming Chan, F. (2013). RIP3: a molecular switch for necrosis and inflammation. Genes Dev. 27, 1640–1649.Search in Google Scholar
Nguyen, V., Cudrici, C., Zernetkina, V., Niculescu, F., Rus, H., Drachenberg, C., and Rus, V. (2009). TRAIL, DR4 and DR5 are upregulated in kidneys from patients with lupus nephritis and exert proliferative and proinflammatory effects. Clin. Immunol. 132, 32–42.Search in Google Scholar
O’Donnell, M.A., Perez-Jimenez, E., Oberst, A., Ng, A., Massoumi, R., Xavier, R., Green, D.R., and Ting, A.T. (2011). Caspase 8 inhibits programmed necrosis by processing CYLD. Nat. Cell Biol. 13, 1437–1442.Search in Google Scholar
Ofengeim, D. and Yuan, J. (2013). Regulation of RIP1 kinase signalling at the crossroads of inflammation and cell death. Nat. Rev. Mol. Cell Biol. 14, 727–736.Search in Google Scholar
Park, D.R., Thomsen, A.R., Frevert, C.W., Pham, U., Skerrett, S.J., Kiener, P.A., and Liles, W.C. (2003). Fas (CD95) induces proinflammatory cytokine responses by human monocytes and monocyte-derived macrophages. J. Immunol. 170, 6209–6216.Search in Google Scholar
Peter, M.E. and Krammer, P.H. (2009). The CD95(APO-1/Fas) DISC and beyond. Cell Death Differ. 10, 26–35.Search in Google Scholar
Peter, M.E., Budd, R.C., Desbarats, J., Hedrick, S.M., Hueber, A.-O., Newell, M.K., Owen, L.B., Pope, R.M., Tschopp, J., Wajant, H., et al. (2007). The CD95 receptor: Apoptosis revisited. Cell 129, 447–450.Search in Google Scholar
Rescigno, M., Piguet, V., Valzasina, B., Lens, S., Zubler, R., French, L., Kindler, V., Tschopp, J., and Ricciardi-Castagnoli, P. (2000). Fas engagement induces the maturation of dendritic cells (DCs), the release of interleukin (IL)-1beta, and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interaction: a new role for Fas ligand in inflammatory responses. J. Exp. Med. 192, 1661–1668.Search in Google Scholar
Robinson, N., McComb, S., Mulligan, R., Dudani, R., Krishnan, L, and Sad, S. (2012). Type I interferon induces necroptosis in macrophages during infection with Salmonella enterica serovar Typhimurium. Nat. Immunol. 13, 954–962.Search in Google Scholar
Shi, Y., Evans, J.E., and Rock, K.L. (2003). Molecular identification of a danger signal that alerts the immune system to dying cells. Nature 425, 516–521.Search in Google Scholar
Sims, J.E. and Smith, D.E. (2010). The IL-1 family: regulators of immunity. Nat. Rev. Immunol. 10, 89–102.Search in Google Scholar
Slee, E.A., Adrain, C., and Martin, S.J. (1999). Serial killers: ordering caspase activation events in apoptosis. Cell Death Differ. 6, 1067–1074.Search in Google Scholar
Strasser, A., Jost, P.J., and Nagata, S. (2009). The many roles of FAS receptor signaling in the immune system. Immunity 30, 180–192.Search in Google Scholar
Sun, L. Wang, H., Wang, Z., He, S., Chen, S., Liao, D., Wang, L., Yan, J., Liu, W, Lei, X., et al. (2012). Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227.Search in Google Scholar
Taylor, R.C., Cullen, S.P., and Martin, S.J. (2008). Apoptosis: controlled demolition at the cellular level. Nat. Rev. Mol. Cell. Biol. 9, 231–241.Search in Google Scholar
Trauzold, A., Siegmund, D., Schniewind, B., Sipos, B., Egberts, J., Zorenkov, D., Emme, D., Röder, C., Kalthoff, H., and Wajant, H. (2006). TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma. Oncogene 25, 7434–7439.Search in Google Scholar
Walczak, H. (2011). TNF and ubiquitin at the crossroads of gene activation, cell death, inflammation, and cancer. Immunol. Rev. 244, 9–28.Search in Google Scholar
Wertz, I.E. and Dixit, V.M. (2008). Ubiquitin-mediated regulation of TNFR1 signaling. Cytokine Growth Factor Rev. 19, 313–324.Search in Google Scholar
Wilson, N.S., Dixit, V., and Ashkenazi, A. (2009). Death receptor signal transducers: nodes of coordination in immune signaling networks. Nat. Immunol. 10, 348–355.Search in Google Scholar
©2014 by De Gruyter
