Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Timeline
  • Published:

Concepts of tissue injury and cell death in inflammation: a historical perspective

An Erratum to this article was published on 24 January 2014

This article has been updated

Abstract

Emerging evidence indicates that the molecular mechanisms of cell death have regulatory roles in inflammation and that the molecular changes that are associated with different forms of cell death affect the course of inflammation in different ways. In this Timeline article, we discuss how our understanding of the mechanisms and functional roles of tissue injury and cell death in inflammation has evolved on the basis of almost two centuries of study. We describe how such ideas have led to our current models of cell death and inflammation, and we highlight the remaining gaps in our knowledge of the subject.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2: Direct and indirect causes of cell death in inflammation.

Change history

  • 23 December 2013

    In figure 1 (Timeline) of the original article, the dates in the second part of the figure were missing. This has now been corrected online. Nature Reviews Immunology apologizes for this error.

References

  1. Rocha e Silva, M. A brief survey of the history of inflammation. Agents Act. 8, 45–49 (1978).

    Article  Google Scholar 

  2. Scott, A., Khan, K. M., Cook, J. L. & Duronio, V. What is “inflammation''? Are we ready to move beyond celsus? Br. J. Sports Med. 38, 248–249 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vandenabeele, P., Galluzzi, L., Vanden Berghe, T. & Kroemer, G. Molecular mechanisms of necroptosis: An ordered cellular explosion. Nature Rev. Mol. Cell Biol. 11, 700–714 (2010).

    Article  CAS  Google Scholar 

  4. Adams, F. The Genuine Works of Hippocrates (Syndenham Society, 1771).

    Google Scholar 

  5. Long, E. R. The history of pathology (Dover Publications, 1965).

    Google Scholar 

  6. Dutrochet, M. H. Recherches Anatomiques et Physiologiques sur la Structure Intime des Animaux et des Végétaux, et sur leur Motilité (J. B. Baillière, 1824).

    Google Scholar 

  7. Wagner, R. Erlauterungstaflen zur Physiologie und Entwicklungsgeschichte (Leopold Voss, Leipzig, 1839).

    Google Scholar 

  8. Virchow, R. Cellular Pathology as Based upon Physiological and Pathological Histology: Twenty Lectures Delivered in the Pathological Institute of Berlin During the Months of February, March and April, 1858 (R. M. DeWitt, 1860).

    Google Scholar 

  9. Cohnheim, J. F. Ueber entzündung und eiterung. Virch. Arch. path. Anat. 40, 1–79 (in German) (1867).

    Article  Google Scholar 

  10. Weigert, C. Ueber die pathologischen gerinnungsvorgänge. Virch. Arch. path. Anat. 79, 87–123 (in German) (1880).

    Article  Google Scholar 

  11. Schmalstieg, F. C. Jr & Goldman, A. S. Ilya ilich metchnikoff (1845–1915) and paul ehrlich: The centennial of the 1908 nobel prize in physiology or medicine. J. Med. Biogr. 16, 96–103 (2008).

    Article  PubMed  Google Scholar 

  12. Sanarelli, G. De la pathogenic du cholera c (neuvieme memoire). Le cholera experimental. Ann. Inst. Pasteur 38, 11–72 (in French) (1924).

    Google Scholar 

  13. Shwartzman, G. Studies on bacillus typhosus toxic substances: I. Phenomenon of local skin reactivity to B. Typhosus culture filtrate. J. Exp. Med. 48, 247–268 (1928).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Koch, R. Fortsetzung über ein heilmittel gegen tuberculose. Dtsch. Med. Wochenschr. 17, 669–672 (in German) (1891).

    Article  Google Scholar 

  15. Arthus, N. M. Injections répétées de serum du cheval chez le lapin. Comptes Rendus Séances Société Biol. Filiales (Paris). 55, 817–820 (in French) (1903).

    Google Scholar 

  16. Coley, W. B. The treatment of malignant tumors by repeated inoculations of erysipelas: With a report of ten original cases. Am. J. Med. Sci. 105, 487–511 (1893).

    Article  Google Scholar 

  17. Guelliot, O. Note sur trois cas de purpusa infectieux foudroyant. Un. Med. Sci. Nord-Est. 8, 25–37 (in French) (1884).

    Google Scholar 

  18. Mori, W. The shwartzman reaction: A review including clinical manifestations and proposal for a univisceral or single organ third type. Histopathology 5, 113–126 (1981).

    Article  CAS  PubMed  Google Scholar 

  19. Opie, E. L. Intracellular digestion: The enzymes and anti-enzymes concerned. Physiol. Rev. 2, 552–585 (1922).

    Article  Google Scholar 

  20. Henson, P. M. & Johnston, R. B. Jr. Tissue injury in inflammation. Oxidants, proteinases, and cationic proteins. J. Clin. Invest. 79, 669–674 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Weiss, S. J. Tissue destruction by neutrophils. N. Engl. J. Med. 320, 365–376 (1989).

    Article  CAS  PubMed  Google Scholar 

  22. Dale, H. H. & Laidlaw, P. P. The physiological action of β-iminazolylethylamine. J. Physiol. 41, 318–344 (1910).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lewis, T. Blood Vessels of the Human Skin and Their Responses (Shaw and Sons, 1927).

    Google Scholar 

  24. Menkin, V. Newer Concepts of Inflammation (ed. Ryan, E. J.) (Charles C. Thomas, 1948).

    Google Scholar 

  25. Bennett, I. L. Jr & Beeson, P. B. Studies on the pathogenesis of fever. Ii. Characterization of fever-producing substances from polymorphonuclear leukocytes and from the fluid of sterile exudates. J. Exp. Med. 98, 493–508 (1953).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Isaacs, A. & Lindemann, J. Virus interference. I. Interferons. Proc. R. Soc. Ser. B. Biol. Sci. 147, 258–267 (1957).

    Article  CAS  Google Scholar 

  27. Oppenheim, J. J. Cytokines: Past, present, and future. Int. J. Hematol. 74, 3–8 (2001).

    Article  CAS  PubMed  Google Scholar 

  28. Taniguchi, T., Ohno, S., Fujii-Kuriyama, Y. & Muramatsu, M. The nucleotide sequence of human fibroblast interferon cDNA. Gene. 10, 11–15 (1980).

    Article  CAS  PubMed  Google Scholar 

  29. Nagata, S. et al. Synthesis in E. Coli of a polypeptide with human leukocyte interferon activity. Nature 284, 316–320 (1980).

    Article  CAS  PubMed  Google Scholar 

  30. Carswell, E. A., Old, L. J., Fiore, N. & Schwartz, M. K. An endotoxin-induced serum factor that causes necrosis of tumors. Proc. Natl Acad. Sci. USA 72, 3666–3670 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wallach, D., Kovalenko, A. & Feldmann, M. (eds) Advances in TNF Family Research. Proceedings of the 12th International TNF Conference (Springer, 2011).

    Book  Google Scholar 

  32. Medzhitov, R., PrestonHurlburt, P. & Janeway, C. A. A human homologue of the drosophila toll protein signals activation of adaptive immunity. Nature 388, 394–397 (1997).

    Article  CAS  PubMed  Google Scholar 

  33. Poltorak, A. et al. Defective lps signaling in c3h/hej and c57bl/10sccr mice: Mutations in Tlr4 gene. Science 282, 2085–2088 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Earle, W. R. et al. Production of malignancy in vitro. IV. The mouse fibroblast cultures and changes seen in the living cells. J. Natl Cancer Inst. 4, 165–212 (1943).

    CAS  Google Scholar 

  35. Lockshin, R. A. & Zakeri, Z. Programmed cell death and apoptosis: Origins of the theory. Nature Rev. Mol. Cell Biol. 2, 545–550 (2001).

    Article  CAS  Google Scholar 

  36. Majno, G., La Gattuta, M. & Thompson, T. E. Cellular death and necrosis: Chemical, physical and morphologic changes in rat liver. Virchows Arch. Pathol. Anat. Physiol. Klin. Med. 333, 421–465 (1960).

    Article  CAS  PubMed  Google Scholar 

  37. Vogt, C. Untersuchungen über die Entwicklungsgeschichte der Geburtshelferkroete (Alytes Obstetricans) (Jent und Gassman, 1842).

    Google Scholar 

  38. Clarke, P. G. & Clarke, S. Nineteenth century research on naturally occurring cell death and related phenomena. Anat. Embryol. (Berl.). 193, 81–99 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Judah, J. D., Ahmed, K. & McLean, A. E. Pathogenesis of cell necrosis. Fed. Proc. 24, 1217–1221 (1965).

    CAS  PubMed  Google Scholar 

  40. Kerr, J. F., Wyllie, A. H. & Currie, A. R. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Horvitz, H. R., Sternberg, P. W., Greenwald, I. S., Fixsen, W. & Ellis, H. M. Mutations that affect neural cell lineages and cell fates during the development of the nematode Caenorhabditis elegans. Cold Spring Harb. Symp. Quant. Biol. 48, 453–463 (1983).

    Article  PubMed  Google Scholar 

  42. Tsujimoto, Y., Gorham, J., Cossman, J., Jaffe, E. & Croce, C. M. The t(14;18) chromosome translocations involved in B-cell neoplasms result from mistakes in VDJ joining. Science 229, 1390–1393 (1985).

    Article  CAS  PubMed  Google Scholar 

  43. Bakhshi, A. et al. Cloning the chromosomal breakpoint of T(14;18) human lymphomas: Clustering around JH on chromosome 14 and near a transcriptional unit on 18. Cell 41, 899–906 (1985).

    Article  CAS  PubMed  Google Scholar 

  44. Cleary, M. L. & Sklar, J. Nucleotide sequence of a T(14;18) chromosomal breakpoint in follicular lymphoma and demonstration of a breakpoint-cluster region near a transcriptionally active locus on chromosome 18. Proc. Natl Acad. Sci. USA 82, 7439–7443 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Vaux, D. L., Cory, S. & Adams, J. M. Bcl-2 gene promotes haemopoietic cell survival and cooperates with c-Myc to immortalize pre-B cells. Nature 335, 440–442 (1988).

    Article  CAS  PubMed  Google Scholar 

  46. Yuan, J. & Horvitz, H. R. The Caenorhabditis elegans cell death gene ced-4 encodes a novel protein and is expressed during the period of extensive programmed cell death. Development 116, 309–320 (1992).

    CAS  PubMed  Google Scholar 

  47. Vaux, D. L. Apoptosis timeline. Cell Death Differ. 9, 349–354 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Schweich, J. U. & Merker, H. J. Morphology of various types of cell death in prenatal tissues. Teratology 7, 253–266 (1973).

    Article  Google Scholar 

  49. Kroemer, G. et al. Classification of cell death: Recommendations of the nomenclature committee on cell death 2009. Cell Death Differ. 16, 3–11 (2009).

    Article  CAS  PubMed  Google Scholar 

  50. Kajstura, J. et al. Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats. Lab. Invest. 74, 86–107 (1996).

    CAS  PubMed  Google Scholar 

  51. McCully, J. D., Wakiyama, H., Hsieh, Y. J., Jones, M. & Levitsky, S. Differential contribution of necrosis and apoptosis in myocardial ischemia-reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 286, H1923–H1935 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Raff, M. C. Social controls on cell-survival and cell-death. Nature 356, 397–400 (1992).

    Article  CAS  PubMed  Google Scholar 

  53. Kalfayan, B. & Kidd, J. G. Structural changes produced in brown-pearce carcinoma cells by means of a specific antibody and complement. J. Exp. Med. 97, 145–162 (1953).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Clark, R. A., Olsson, I. & Klebanoff, S. J. Cytotoxicity for tumor cells of cationic proteins from human neutrophil granules. J. Cell Biol. 70, 719–723 (1976).

    Article  CAS  PubMed  Google Scholar 

  55. Clark, R. A. & Klebanoff, S. J. Neutrophil-mediated tumor cell cytotoxicity: Role of the peroxidase system. J. Exp. Med. 141, 1442–1447 (1975).

    Article  CAS  PubMed  Google Scholar 

  56. Badwey, J. A. & Karnovsky, M. L. Active oxygen species and the functions of phagocytic leukocytes. Annu. Rev. Biochem. 49, 695–726 (1980).

    Article  CAS  PubMed  Google Scholar 

  57. Paucker, K., Cantell, K. & Henle, W. Quantitative studies on viral interference in suspended l cells: Iii. Effect of interfering viruses and interferon on the growth rate of cells. Virology 17, 324–334 (1962).

    Article  CAS  PubMed  Google Scholar 

  58. Govaerts, A. Cellular antibodies in kidney homotransplantation. J. Immunol. 85, 516–522 (1960).

    CAS  PubMed  Google Scholar 

  59. Rosenau, W. & Moon, H. D. Lysis of homologous cells by sensitized lymphocytes in tissue culture. J. Natl Cancer Inst. 27, 471–483 (1961).

    CAS  PubMed  Google Scholar 

  60. Granger, G. A. & Kolb, W. P. Lymphocyte in vitro cytotoxicity: Mechanisms of immune and non-immune small lymphocyte mediated target l cell destruction. J. Immunol. 101, 111–120 (1968).

    CAS  PubMed  Google Scholar 

  61. Ruddle, N. H. & Waksman, B. H. Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. Iii. Analysis of mechanisms. J. Exp. Med. 128, 1267–1279 (1968).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Hahn, T. et al. Use of monoclonal antibodies to a human cytotoxin for its isolation and for examining the self-induction of resistance to this protein. Proc. Natl Acad. Sci. USA 82, 3814–3818 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gray, P. W. et al. Expression of human immune interferon cDNA in E. Coli and monkey cells. Nature 295, 503–508 (1982).

    Article  CAS  PubMed  Google Scholar 

  64. Gray, P. W. et al. Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumor necrosis activity. Nature 312, 721–724 (1984).

    Article  CAS  PubMed  Google Scholar 

  65. Pennica, D. et al. Human tumor necrosis factor: Precursor structure, cDNA cloning, expression, and homology to lymphotoxin. Nature 312, 724–729 (1984).

    Article  CAS  PubMed  Google Scholar 

  66. Wallach, D. et al. Tumor necrosis factor receptor and fas signaling mechanisms. Annu. Rev. Immunol. 17, 331–367 (1999).

    Article  CAS  PubMed  Google Scholar 

  67. Laster, S. M., Wood, J. G. & Gooding, L. R. Tumor necrosis factor can induce both apoptic and necrotic forms of cell lysis. J. Immunol. 141, 2629–2634 (1988).

    CAS  PubMed  Google Scholar 

  68. Aggarwal, B. B., Moffat, B. & Harkins, R. N. Human lymphotoxin. Production by a lymphoblastoid cell line, purification, and initial characterization. J. Biol. Chem. 259, 686–691 (1984).

    CAS  PubMed  Google Scholar 

  69. Suda, T., Takahashi, T., Golstein, P. & Nagata, S. Molecular cloning and expression of the fas ligand, a novel member of the tumor necrosis factor family. Cell 75, 1169–1178 (1993).

    Article  CAS  PubMed  Google Scholar 

  70. Wiley, S. R. et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity 3, 673–682 (1995).

    Article  CAS  PubMed  Google Scholar 

  71. Pitti, R. M. et al. Induction of apoptosis by apo-2 ligand, a new member of the the tumor necrosis factor cytokine family. J. Biol. Chem. 271, 12687–12690 (1996).

    Article  CAS  PubMed  Google Scholar 

  72. Ashida, H. et al. Cell death and infection: A double-edged sword for host and pathogen survival. J. Cell. Biol. 195, 931–942 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Engelmann, H. et al. Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J. Biol. Chem. 265, 14497–14504 (1990).

    CAS  PubMed  Google Scholar 

  74. Boldin, M. P. et al. A novel protein that interacts with the death domain of fas/apo1 contains a sequence motif related to the death domain. J. Biol. Chem. 270, 7795–7798 (1995).

    Article  CAS  PubMed  Google Scholar 

  75. Chinnalyan, A. M., O'Rourke, K., Tewari, M. & Dixit, V. M. Fadd, a novel death domain-containing protein, interacts with the death domain of FAS and initiates apoptosis. Cell 81, 505–512 (1995).

    Article  Google Scholar 

  76. Boldin, M. P., Goncharov, T. M., Goltsev, Y. V. & Wallach, D. Involvement of mach, a novel mort1/fadd-interacting protease, in fas/apo-1- and TNF receptor-induced cell death. Cell 85, 803–815 (1996).

    Article  CAS  PubMed  Google Scholar 

  77. Muzio, M. et al. 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 (1996).

    Article  CAS  PubMed  Google Scholar 

  78. Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nature Immunol. 1, 489–495 (2000).

    Article  CAS  Google Scholar 

  79. Degterev, A. et al. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nature Chem. Biol. 4, 313–321 (2008).

    Article  CAS  Google Scholar 

  80. Zhang, D. W. et al. Rip3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNFα. Cell 137, 1100–1111 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012).

    Article  CAS  PubMed  Google Scholar 

  84. Zhao, J. et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc. Natl Acad. Sci. USA 109, 5322–5327 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  85. Beg, A. A. & Baltimore, D. An essential role for NF-κB in preventing TNF-α-induced cell death. Science 274, 782–784 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Zychlinsky, A., Prevost, M. C. & Sansonetti, P. J. Shigella flexneri induces apoptosis in infected macrophages. Nature 358, 167–169 (1992).

    Article  CAS  PubMed  Google Scholar 

  87. Zychlinsky, A., Fitting, C., Cavaillon, J. M. & Sansonetti, P. J. Interleukin 1 is released by murine macrophages during apoptosis induced by Shigella flexneri. J. Clin. Invest. 94, 1328–1332 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. von Moltke, J., Ayres, J. S., Kofoed, E. M., Chavarria-Smith, J. & Vance, R. E. Recognition of bacteria by inflammasomes. Annu. Rev. Immunol. 31, 73–106 (2013).

    Article  CAS  PubMed  Google Scholar 

  89. Massart, J. & Bordet, C. Le chimiotaxisme des leukocytes et l'infection microbienne Ann. Inst. Pasteur. 5, 417–444 (1891).

    Google Scholar 

  90. Matzinger, P. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12, 991–1045 (1994).

    Article  CAS  PubMed  Google Scholar 

  91. Rock, K. L. & Kono, H. The inflammatory response to cell death. Annu. Rev. Pathol. 3, 99–126 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Kerr, J. F. R. Shrinkage necrosis - distinct mode of cellular death. J. Pathol. 105, 13–20 (1971).

    Article  CAS  PubMed  Google Scholar 

  93. Metchnikoff, E. Lectures on the Comparative Pathology of Inflammation. Delivered at Pasteur Institute, 1891. (Trubner, 1893).

    Google Scholar 

  94. Savill, J. S. et al. Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. J. Clin. Invest. 83, 865–875 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Whyte, M. K., Meagher, L. C., MacDermot, J. & Haslett, C. Impairment of function in aging neutrophils is associated with apoptosis. J. Immunol. 150, 5124–5134 (1993).

    CAS  PubMed  Google Scholar 

  96. Kanaly, S. T., Nashleanas, M., Hondowicz, B. & Scott, P. TNF receptor p55 is required for elimination of inflammatory cells following control of intracellular pathogens. J. Immunol. 163, 3883–3889 (1999).

    CAS  PubMed  Google Scholar 

  97. Voll, R. E. et al. Immunosuppressive effects of apoptotic cells. Nature. 390, 350–351 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGFβ, PGE2, and paf. J. Clin. Invest. 101, 890–898 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Silva, M. T., do Vale, A. & dos Santos, N. M. Secondary necrosis in multicellular animals: An outcome of apoptosis with pathogenic implications. Apoptosis 13, 463–482 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Bossaller, L. et al. Cutting edge: Fas (CD95) mediates noncanonical IL-1β and IL-18 maturation via caspase-8 in an RIP3-independent manner. J. Immunol. 189, 5508–5512 (2012).

    Article  CAS  PubMed  Google Scholar 

  101. Cullen, S. P. et al. FAS/CD95-induced chemokines can serve as “find-me” signals for apoptotic cells. Mol. Cell 49, 1034–1048 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Oberst, A. et al. Catalytic activity of the caspase-8-flip(l) complex inhibits RIPK3-dependent necrosis. Nature 471, 363–367 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wallach, D., Kang, T.-B. & Kovalenko, A. The extrinsic cell death pathway and the elan mortel. Cell Death Differ. 15, 1533–1541 (2008).

    Article  CAS  PubMed  Google Scholar 

  104. Hsu, H., Xiong, J. & Goeddel, D. V. The TNF receptor 1-associated protein TRADD signals cell death and NF-κB activation. Cell 81, 495–504 (1995).

    Article  CAS  PubMed  Google Scholar 

  105. 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).

    Article  CAS  PubMed  Google Scholar 

  106. Kuranaga, E. & Miura, M. Nonapoptotic functions of caspases: Caspases as regulatory molecules for immunity and cell-fate determination. Trends Cell Biol. 17, 135–144 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Enari, M. et al. A caspase-activated DNAse that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391, 43–50 (1998).

    Article  CAS  PubMed  Google Scholar 

  108. Bratton, D. L. & Henson, P. M. Neutrophil clearance: When the party is over, clean-up begins. Trends Immunol. 32, 350–357 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Thery, C., Zitvogel, L. & Amigorena, S. Exosomes: composition, biogenesis and function. Nature Rev. Immunol. 2, 569–579 (2002).

    Article  CAS  Google Scholar 

  110. Corriden, R. & Insel, P. A. Basal release of ATP: an autocrine–paracrine mechanism for cell regulation. Sci. Signal. 3, re1 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Gardella, S. et al. The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 3, 995–1001 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Yang, H., Wang, H., Czura, C. J. & Tracey, K. J. The cytokine activity of HMGB1. J. Leukoc. Biol. 78, 1–8 (2005).

    Article  CAS  PubMed  Google Scholar 

  113. Wallach, D., Kovalenko, A. & Kang, T. B. 'Necrosome'-induced inflammation: Must cells die for it? Trends Immunol. 32, 505–509 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Celsus, A. C. & Spencer, W. G. De medicina (Harvard Univ. Press, 1938).

    Google Scholar 

  115. Nunn, J. F. Ancient Egyptian Medicine (Univ. of Oklahoma Press, 2002).

    Google Scholar 

  116. Morgagni, G. B. De Sedibus et Causis Morborum per Anatomen Indagatis: Libri Quinque: In Quibus Continentur Dissectiones et Animadversiones Propemodum Innumerae, Medicis, Chirurgis, Anatomicis Profuturae (Typographia Remondini, 1761).

    Google Scholar 

  117. Flemming, W. Ueber die Bildung von Richtungsfiguren in Säiugethiereiern beim Untergang Graaf'scher Follikel. Arch. Anat. Physiol. 221–244 (1885).

  118. Martinon, F., Burns, K. & Tschopp, J. The inflammasome: A molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol. Cell. 10, 417–426 (2002).

    Article  CAS  PubMed  Google Scholar 

  119. Mallory, G. K., White, P. D. & Salcedo-Salgar, J. The speed of healing of myocardial infarction. Am. Heart J. 18, 647 (1939).

    Article  Google Scholar 

  120. Opie, E. L. On the relation of necrosis and inflammation to denaturation of proteins. J. Exp. Med. 115, 597–608 (1962).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Page, A. R. & Good, R. A. A clinical and experimental study of the function of neutrophils in the inflammatory response. Am. J. Pathol. 34, 645–669 (1958).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Scaffidi, P., Misteli, T. & Bianchi, M. E. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).

    Article  CAS  PubMed  Google Scholar 

  123. Rouhiainen, A., Tumova, S., Valmu, L., Kalkkinen, N. & Rauvala, H. Pivotal advance: Analysis of proinflammatory activity of highly purified eukaryotic recombinant HMGB1 (amphoterin). J. Leukoc. Biol. 81, 49–58 (2007).

    Article  CAS  PubMed  Google Scholar 

  124. Yanai, H. et al. HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses. Nature 462, 99–103 (2009).

    Article  CAS  PubMed  Google Scholar 

  125. Fields, S. & Song, O. A novel genetic system to detect protein–protein interactions. Nature 340, 245–246 (1989).

    Article  CAS  PubMed  Google Scholar 

  126. Burlingame, A. L., Boyd, R. K. & Gaskell, S. J. Mass spectrometry. Anal. Chem. 70, 647R–716R (1998).

    Article  CAS  PubMed  Google Scholar 

  127. Venter, J. C. et al. The sequence of the human genome. Science 291, 1304–1351 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Lander, E. S. et al. Initial sequencing and analysis of the human genome. Nature 409, 860–921 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Cerretti, D. P. et al. Molecular cloning of the interleukin-1β converting enzyme. Science 256, 97–100 (1992).

    Article  CAS  PubMed  Google Scholar 

  130. Thornberry, N. A. et al. A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nature 356, 768–774 (1992).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank O. Brenner, I. Cohen and A. Elson for advice on the manuscript. D.W. is the incumbent of the Joseph and Bessie Feinberg Professorial Chair at The Weizmann Institute of Science, Rehovot, Israel.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to David Wallach.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wallach, D., Kang, TB. & Kovalenko, A. Concepts of tissue injury and cell death in inflammation: a historical perspective. Nat Rev Immunol 14, 51–59 (2014). https://doi.org/10.1038/nri3561

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3561

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing