1932

Abstract

Rapid removal of apoptotic cells by phagocytes, a process known as efferocytosis, is key for the maintenance of tissue homeostasis, the resolution of inflammation, and tissue repair. However, impaired efferocytosis can result in the accumulation of apoptotic cells, subsequently triggering sterile inflammation through the release of endogenous factors such as DNA and nuclear proteins from membrane permeabilized dying cells. Here, we review the molecular basis of the three key phases of efferocytosis, that is, the detection, uptake, and degradation of apoptotic materials by phagocytes. We also discuss how defects in efferocytosis due to the alteration of phagocytes and dying cells can contribute to the low-grade chronic inflammation that occurs during aging, described as inflammaging. Lastly, we explore opportunities in targeting and harnessing the efferocytic machinery to limit aging-associated inflammatory diseases.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-032723-110507
2024-01-23
2024-12-06
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/64/1/annurev-pharmtox-032723-110507.html?itemId=/content/journals/10.1146/annurev-pharmtox-032723-110507&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Okin D, Medzhitov R. 2012. Evolution of inflammatory diseases. Curr. Biol. 22:17R733–40
    [Google Scholar]
  2. 2.
    Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M et al. 2000. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann. N. Y. Acad. Sci. 908:1244–54
    [Google Scholar]
  3. 3.
    Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S. 2017. Inflammaging and ‘garb-aging. .’ Trends Endocrinol. Metab. 28:3199–212
    [Google Scholar]
  4. 4.
    Sender R, Milo R. 2021. The distribution of cellular turnover in the human body. Nat. Med. 27:145–48
    [Google Scholar]
  5. 5.
    Poon IKH, Lucas CD, Rossi AG, Ravichandran KS. 2014. Apoptotic cell clearance: basic biology and therapeutic potential. Nat. Rev. Immunol. 14:3166–80
    [Google Scholar]
  6. 6.
    Roh JS, Sohn DH. 2018. Damage-associated molecular patterns in inflammatory diseases. Immune Netw. 18:4e27
    [Google Scholar]
  7. 7.
    Mehrotra P, Ravichandran KS. 2022. Drugging the efferocytosis process: concepts and opportunities. Nat. Rev. Drug Discov. 21:8601–20
    [Google Scholar]
  8. 8.
    Doran AC, Yurdagul A, Tabas I. 2020. Efferocytosis in health and disease. Nat. Rev. Immunol. 20:4254–67
    [Google Scholar]
  9. 9.
    Medina CB, Ravichandran KS. 2016. Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes. Cell Death Differ. 23:6979–89
    [Google Scholar]
  10. 10.
    Chekeni FB, Elliott MR, Sandilos JK, Walk SF, Kinchen JM et al. 2010. Pannexin 1 channels mediate ‘find-me’ signal release and membrane permeability during apoptosis. Nature 467:7317863–67
    [Google Scholar]
  11. 11.
    Elliott MR, Chekeni FB, Trampont PC, Lazarowski ER, Kadl A et al. 2009. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461:7261282–86
    [Google Scholar]
  12. 12.
    Lauber K, Bohn E, Kröber SM, Xiao Y, Blumenthal SG et al. 2003. Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell 113:6717–30
    [Google Scholar]
  13. 13.
    Gude DR, Alvarez SE, Paugh SW, Mitra P, Yu J et al. 2008. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J. 22:82629–38
    [Google Scholar]
  14. 14.
    Truman LA, Ford CA, Pasikowska M, Pound JD, Wilkinson SJ et al. 2008. CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112:135026–36
    [Google Scholar]
  15. 15.
    Pontejo SM, Murphy PM. 2021. Chemokines act as phosphatidylserine-bound “find-me” signals in apoptotic cell clearance. PLOS Biol. 19:5e3001259
    [Google Scholar]
  16. 16.
    Bournazou I, Pound JD, Duffin R, Bournazos S, Melville LA et al. 2009. Apoptotic human cells inhibit migration of granulocytes via release of lactoferrin. J. Clin. Investig. 119:120–32
    [Google Scholar]
  17. 17.
    Luo B, Gan W, Liu Z, Shen Z, Wang J et al. 2016. Erythropoeitin signaling in macrophages promotes dying cell clearance and immune tolerance. Immunity 44:2287–302
    [Google Scholar]
  18. 18.
    Medina CB, Mehrotra P, Arandjelovic S, Perry JSA, Guo Y et al. 2020. Metabolites released from apoptotic cells act as tissue messengers. Nature 580:7801130–35
    [Google Scholar]
  19. 19.
    Morioka S, Perry JSA, Raymond MH, Medina CB, Zhu Y et al. 2018. Efferocytosis induces a novel SLC program to promote glucose uptake and lactate release. Nature 563:7733714–18
    [Google Scholar]
  20. 20.
    Fadok VA, Voelker DR, Campbell PA, Cohen JJ, Bratton DL, Henson PM. 1992. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. J. Immunol. 148:72207–16
    [Google Scholar]
  21. 21.
    Verhoven B, Schlegel RA, Williamson P. 1995. Mechanisms of phosphatidylserine exposure, a phagocyte recognition signal, on apoptotic T lymphocytes. J. Exp. Med. 182:51597–601
    [Google Scholar]
  22. 22.
    Baxter AA, Hulett MD, Poon IKH. 2015. The phospholipid code: a key component of dying cell recognition, tumor progression and host-microbe interactions. Cell Death Differ. 22:121893–905
    [Google Scholar]
  23. 23.
    Suzuki J, Denning DP, Imanishi E, Horvitz HR, Nagata S. 2013. Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341:6144403–6
    [Google Scholar]
  24. 24.
    Segawa K, Kurata S, Yanagihashi Y, Brummelkamp TR, Matsuda F, Nagata S. 2014. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344:61881164–68
    [Google Scholar]
  25. 25.
    Kim O-H, Kang G-H, Hur J, Lee J, Jung Y et al. 2022. Externalized phosphatidylinositides on apoptotic cells are eat-me signals recognized by CD14. Cell Death Differ. 29:71423–32
    [Google Scholar]
  26. 26.
    Gardai SJ, McPhillips KA, Frasch SC, Janssen WJ, Starefeldt A et al. 2005. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123:2321–34
    [Google Scholar]
  27. 27.
    Kobayashi N, Karisola P, Peña-Cruz V, Dorfman DM, Jinushi M et al. 2007. TIM-1 and TIM-4 glycoproteins bind phosphatidylserine and mediate uptake of apoptotic cells. Immunity 27:6927–40
    [Google Scholar]
  28. 28.
    Park D, Tosello-Trampont A-C, Elliott MR, Lu M, Haney LB et al. 2007. BAI1 is an engulfment receptor for apoptotic cells upstream of the ELMO/Dock180/Rac module. Nature 450:7168430–34
    [Google Scholar]
  29. 29.
    Park S-Y, Jung M-Y, Kim H-J, Lee S-J, Kim S-Y et al. 2008. Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor. Cell Death Differ. 15:1192–201
    [Google Scholar]
  30. 30.
    Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S. 2002. Identification of a factor that links apoptotic cells to phagocytes. Nature 417:6885182–87
    [Google Scholar]
  31. 31.
    Ishimoto Y, Ohashi K, Mizuno K, Nakano T. 2000. Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, gas6. J. Biochem. 127:3411–17
    [Google Scholar]
  32. 32.
    Anderson HA, Maylock CA, Williams JA, Paweletz CP, Shu H, Shacter E. 2003. Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells. Nat. Immunol. 4:187–91
    [Google Scholar]
  33. 33.
    Kinchen JM, Ravichandran KS. 2008. Phagosome maturation: going through the acid test. Nat. Rev. Mol. Cell Biol. 9:10781–95
    [Google Scholar]
  34. 34.
    Heckmann BL, Green DR. 2019. LC3-associated phagocytosis at a glance. J. Cell Sci. 132:5jcs222984
    [Google Scholar]
  35. 35.
    Trzeciak A, Wang Y-T, Perry JSA. 2021. First we eat, then we do everything else: the dynamic metabolic regulation of efferocytosis. Cell Metab. 33:112126–41
    [Google Scholar]
  36. 36.
    Fond AM, Lee CS, Schulman IG, Kiss RS, Ravichandran KS. 2015. Apoptotic cells trigger a membrane-initiated pathway to increase ABCA1. J. Clin. Investig. 125:72748–58
    [Google Scholar]
  37. 37.
    Viaud M, Ivanov S, Vujic N, Duta-Mare M, Aira L-E et al. 2018. Lysosomal cholesterol hydrolysis couples efferocytosis to anti-inflammatory oxysterol production. Circ. Res. 122:101369–84
    [Google Scholar]
  38. 38.
    Yurdagul A, Subramanian M, Wang X, Crown SB, Ilkayeva OR et al. 2020. Macrophage metabolism of apoptotic cell-derived arginine promotes continual efferocytosis and resolution of injury. Cell Metab. 31:3518–33.e10
    [Google Scholar]
  39. 39.
    Chen W, Frank ME, Jin W, Wahl SM. 2001. TGF-β released by apoptotic T cells contributes to an immunosuppressive milieu. Immunity 14:6715–25
    [Google Scholar]
  40. 40.
    Gao Y, Herndon JM, Zhang H, Griffith TS, Ferguson TA. 1998. Antiinflammatory effects of CD95 ligand (FasL)-induced apoptosis. J. Exp. Med. 188:5887–96
    [Google Scholar]
  41. 41.
    Caruso S, Poon IKH. 2018. Apoptotic cell-derived extracellular vesicles: more than just debris. Front. Immunol. 9:1486
    [Google Scholar]
  42. 42.
    Brock CK, Wallin ST, Ruiz OE, Samms KM, Mandal A et al. 2019. Stem cell proliferation is induced by apoptotic bodies from dying cells during epithelial tissue maintenance. Nat. Commun. 10:11044
    [Google Scholar]
  43. 43.
    Park SJ, Kim JM, Kim J, Hur J, Park S et al. 2018. Molecular mechanisms of biogenesis of apoptotic exosome-like vesicles and their roles as damage-associated molecular patterns. PNAS 115:50E11721–30
    [Google Scholar]
  44. 44.
    Tucher C, Bode K, Schiller P, Claßen L, Birr C et al. 2018. Extracellular vesicle subtypes released from activated or apoptotic T-lymphocytes carry a specific and stimulus-dependent protein cargo. Front. Immunol. 9:534
    [Google Scholar]
  45. 45.
    Wickman GR, Julian L, Mardilovich K, Schumacher S, Munro J et al. 2013. Blebs produced by actin-myosin contraction during apoptosis release damage-associated molecular pattern proteins before secondary necrosis occurs. Cell Death Differ. 20:101293–305
    [Google Scholar]
  46. 46.
    Dalli J, Serhan CN. 2012. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood 120:15e60–72
    [Google Scholar]
  47. 47.
    Cai B, Kasikara C, Doran AC, Ramakrishnan R, Birge RB, Tabas I. 2018. MerTK signaling in macrophages promotes the synthesis of inflammation resolution mediators by suppressing CaMKII activity. Sci. Signal. 11:549eaar3721
    [Google Scholar]
  48. 48.
    Doran AC, Ozcan L, Cai B, Zheng Z, Fredman G et al. 2017. CAMKIIγ suppresses an efferocytosis pathway in macrophages and promotes atherosclerotic plaque necrosis. J. Clin. Investig. 127:114075–89
    [Google Scholar]
  49. 49.
    Gerlach BD, Marinello M, Heinz J, Rymut N, Sansbury BE et al. 2020. Resolvin D1 promotes the targeting and clearance of necroptotic cells. Cell Death Differ. 27:2525–39
    [Google Scholar]
  50. 50.
    Han CZ, Juncadella IJ, Kinchen JM, Buckley MW, Klibanov AL et al. 2016. Macrophages redirect phagocytosis by non-professional phagocytes and influence inflammation. Nature 539:7630570–74
    [Google Scholar]
  51. 51.
    Zhang S, Weinberg S, DeBerge M, Gainullina A, Schipma M et al. 2019. Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair. Cell Metab. 29:2443–56.e5
    [Google Scholar]
  52. 52.
    Perkins EH. 1971. Phagocytic activity of aged mice. J. Reticuloendothel. Soc. 9:642–43
    [Google Scholar]
  53. 53.
    De La Fuente M. 1985. Changes in the macrophage function with aging. Comp. Biochem. Physiol. A Comp. Physiol. 81:4935–38
    [Google Scholar]
  54. 54.
    Linehan E, Dombrowski Y, Snoddy R, Fallon PG, Kissenpfennig A, Fitzgerald DC. 2014. Aging impairs peritoneal but not bone marrow-derived macrophage phagocytosis. Aging Cell 13:4699–708
    [Google Scholar]
  55. 55.
    Hearps AC, Martin GE, Angelovich TA, Cheng W-J, Maisa A et al. 2012. Aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function. Aging Cell 11:5867–75
    [Google Scholar]
  56. 56.
    Fietta A, Merlini C, Santos CD, Rovida S, Grassi C. 1994. Influence of aging on some specific and nonspecific mechanisms of the host defense system in 146 healthy subjects. Gerontology 40:5237–45
    [Google Scholar]
  57. 57.
    Aprahamian T, Takemura Y, Goukassian D, Walsh K. 2008. Ageing is associated with diminished apoptotic cell clearance in vivo. Clin. Exp. Immunol. 152:3448–55
    [Google Scholar]
  58. 58.
    Popi AF, Lopes JD, Mariano M. 2004. Interleukin-10 secreted by B-1 cells modulates the phagocytic activity of murine macrophages in vitro. Immunology 113:3348–54
    [Google Scholar]
  59. 59.
    Arnardottir HH, Dalli J, Colas RA, Shinohara M, Serhan CN. 2014. Aging delays resolution of acute inflammation in mice: reprogramming the host response with novel nano-proresolving medicines. J. Immunol. 193:84235–44
    [Google Scholar]
  60. 60.
    Rymut N, Heinz J, Sadhu S, Hosseini Z, Riley CO et al. 2020. Resolvin D1 promotes efferocytosis in aging by limiting senescent cell-induced MerTK cleavage. FASEB J. 34:1597–609
    [Google Scholar]
  61. 61.
    Frisch BJ, Hoffman CM, Latchney SE, LaMere MW, Myers J et al. 2019. Aged marrow macrophages expand platelet-biased hematopoietic stem cells via interleukin-1B. JCI Insight 4:10e124213
    [Google Scholar]
  62. 62.
    De Maeyer RPH, van de Merwe RC, Louie R, Bracken O, Devine OP et al. 2020. Blocking elevated p38 MAPK restores efferocytosis and inflammatory resolution in the elderly. Nat. Immunol. 21:6615–25
    [Google Scholar]
  63. 63.
    Klein SL, Flanagan KL. 2016. Sex differences in immune responses. Nat. Rev. Immunol. 16:10626–38
    [Google Scholar]
  64. 64.
    Wang Y, Subramanian M, Yurdagul A, Barbosa-Lorenzi VC, Cai B et al. 2017. Mitochondrial fission promotes the continued clearance of apoptotic cells by macrophages. Cell 171:2331–45.e22
    [Google Scholar]
  65. 65.
    Song C-X, Chen J-Y, Li N, Guo Y. 2021. CTRP9 enhances efferocytosis in macrophages via MAPK/Drp1-mediated mitochondrial fission and AdipoR1-induced immunometabolism. J. Inflamm. Res. 14:1007–17
    [Google Scholar]
  66. 66.
    Sharma A, Smith HJ, Yao P, Mair WB. 2019. Causal roles of mitochondrial dynamics in longevity and healthy aging. EMBO Rep. 20:12e48395
    [Google Scholar]
  67. 67.
    Park D, Han CZ, Elliott MR, Kinchen JM, Trampont PC et al. 2011. Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein. Nature 477:7363220–24
    [Google Scholar]
  68. 68.
    Hirose M, Schilf P, Lange F, Mayer J, Reichart G et al. 2016. Uncoupling protein 2 protects mice from aging. Mitochondrion 30:42–50
    [Google Scholar]
  69. 69.
    López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. 2023. Hallmarks of aging: an expanding universe. Cell 186:2243–78
    [Google Scholar]
  70. 70.
    De Martinis M, Modesti M, Ginaldi L. 2004. Phenotypic and functional changes of circulating monocytes and polymorphonuclear leucocytes from elderly persons. Immunol. Cell Biol. 82:4415–20
    [Google Scholar]
  71. 71.
    Crain JM, Nikodemova M, Watters JJ. 2009. Expression of P2 nucleotide receptors varies with age and sex in murine brain microglia. J. Neuroinflammation 6:124
    [Google Scholar]
  72. 72.
    Lananna BV, Imai S. 2021. Friends and foes: extracellular vesicles in aging and rejuvenation. FASEB BioAdv. 3:10787–801
    [Google Scholar]
  73. 73.
    de Vries M, Nwozor KO, Muizer K, Wisman M, Timens W et al. 2022. The relation between age and airway epithelial barrier function. Respir. Res. 23:143
    [Google Scholar]
  74. 74.
    Watson JK, Sanders P, Dunmore R, Rosignoli G, Julé Y et al. 2020. Distal lung epithelial progenitor cell function declines with age. Sci. Rep. 10:110490
    [Google Scholar]
  75. 75.
    Juncadella IJ, Kadl A, Sharma AK, Shim YM, Hochreiter-Hufford A et al. 2013. Apoptotic cell clearance by bronchial epithelial cells critically influences airway inflammation. Nature 493:7433547–51
    [Google Scholar]
  76. 76.
    Yamaguchi H, Maruyama T, Urade Y, Nagata S. 2014. Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells. eLife 3:e02172
    [Google Scholar]
  77. 77.
    Lucas CD, Medina CB, Bruton FA, Dorward DA, Raymond MH et al. 2022. Pannexin 1 drives efficient epithelial repair after tissue injury. Sci. Immunol. 7:71eabm4032
    [Google Scholar]
  78. 78.
    Panyard DJ, Yu B, Snyder MP. The metabolomics of human aging: advances, challenges, and opportunities. Sci. Adv. 8:42eadd6155
    [Google Scholar]
  79. 79.
    Nauta AJ, Trouw LA, Daha MR, Tijsma O, Nieuwland R et al. 2002. Direct binding of C1q to apoptotic cells and cell blebs induces complement activation. Eur. J. Immunol. 32:61726–36
    [Google Scholar]
  80. 80.
    Poon IKH, Hulett MD, Parish CR. 2010. Histidine-rich glycoprotein is a novel plasma pattern recognition molecule that recruits IgG to facilitate necrotic cell clearance via FcγRI on phagocytes. Blood 115:122473–82
    [Google Scholar]
  81. 81.
    Stephan AH, Madison DV, Mateos JM, Fraser DA, Lovelett EA et al. 2013. A dramatic increase of C1q protein in the CNS during normal aging. J. Neurosci. 33:3313460–74
    [Google Scholar]
  82. 82.
    Drasin T, Sahud M. 1996. Blood-type and age affect human plasma levels of histidine-rich glycoprotein in a large population. Thromb. Res. 84:3179–88
    [Google Scholar]
  83. 83.
    Kim K-H, Kim E-Y, Lee K-A. 2021. GAS6 ameliorates advanced age-associated meiotic defects in mouse oocytes by modulating mitochondrial function. Aging 13:1418018–32
    [Google Scholar]
  84. 84.
    Atkin-Smith GK. 2021. Phagocytic clearance of apoptotic, necrotic, necroptotic and pyroptotic cells. Biochem. Soc. Trans. 49:2793–804
    [Google Scholar]
  85. 85.
    Poon IKH, Hulett MD, Parish CR. 2010. Molecular mechanisms of late apoptotic/necrotic cell clearance. Cell Death Differ. 17:3381–97
    [Google Scholar]
  86. 86.
    Lu J, Shi W, Liang B, Chen C, Wu R et al. 2019. Efficient engulfment of necroptotic and pyroptotic cells by nonprofessional and professional phagocytes. Cell Discov. 5:139
    [Google Scholar]
  87. 87.
    Miyoshi N, Oubrahim H, Chock PB, Stadtman ER. 2006. Age-dependent cell death and the role of ATP in hydrogen peroxide-induced apoptosis and necrosis. PNAS 103:61727–31
    [Google Scholar]
  88. 88.
    Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G. 2019. The molecular machinery of regulated cell death. Cell Res. 29:5347–64
    [Google Scholar]
  89. 89.
    Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D et al. 2018. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25:3486–541
    [Google Scholar]
  90. 90.
    Chung L, Ng Y-C. 2006. Age-related alterations in expression of apoptosis regulatory proteins and heat shock proteins in rat skeletal muscle. Biochim. Biophys. Acta 1762:1103–9
    [Google Scholar]
  91. 91.
    Zheng J, Edelman SW, Tharmarajah G, Walker DW, Pletcher SD, Seroude L. 2005. Differential patterns of apoptosis in response to aging in Drosophila. PNAS 102:3412083–88
    [Google Scholar]
  92. 92.
    Anand P, Shenoy R, Palmer JE, Baines AJ, Lai RYK et al. 2011. Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury. Eur. J. Pain. 15:101040–48
    [Google Scholar]
  93. 93.
    Patnaik A, Haluska P, Tolcher AW, Erlichman C, Papadopoulos KP et al. 2016. A first-in-human Phase I study of the oral p38 MAPK inhibitor, ralimetinib (LY2228820 dimesylate), in patients with advanced cancer. Clin. Cancer Res. 22:51095–102
    [Google Scholar]
  94. 94.
    Krashia P, Cordella A, Nobili A, La Barbera L, Federici M et al. 2019. Blunting neuroinflammation with resolvin D1 prevents early pathology in a rat model of Parkinson's disease. Nat. Commun. 10:13945
    [Google Scholar]
  95. 95.
    Calabrese V, Santoro A, Monti D, Crupi R, Di Paola R et al. 2018. Aging and Parkinson's disease: inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis. Free Radic. Biol. Med. 115:80–91
    [Google Scholar]
  96. 96.
    van Deursen MJ. 2014. The role of senescent cells in ageing. Nature 509:7501439–46
    [Google Scholar]
  97. 97.
    Niedernhofer LJ, Robbins PD. 2018. Senotherapeutics for healthy ageing. Nat. Rev. Drug Discov. 17:5377
    [Google Scholar]
  98. 98.
    Fernandez-Boyanapalli R, Frasch SC, Riches DWH, Vandivier RW, Henson PM, Bratton DL. 2010. PPARγ activation normalizes resolution of acute sterile inflammation in murine chronic granulomatous disease. Blood 116:224512–22
    [Google Scholar]
  99. 99.
    Chen H, Shi R, Luo B, Yang X, Qiu L et al. 2015. Macrophage peroxisome proliferator-activated receptor γ deficiency delays skin wound healing through impairing apoptotic cell clearance in mice. Cell Death Dis. 6:1e1597
    [Google Scholar]
  100. 100.
    Nakashima M, Kinoshita M, Nakashima H, Kotani A, Ishikiriyama T et al. 2019. Pioglitazone improves phagocytic activity of liver recruited macrophages in elderly mice possibly by promoting glucose catabolism. Innate Immun. 25:6356–68
    [Google Scholar]
  101. 101.
    Desouza CV, Shivaswamy V. 2010. Pioglitazone in the treatment of type 2 diabetes: safety and efficacy review. Clin. Med. Insights Endocrinol. Diabetes 3:43–51
    [Google Scholar]
  102. 102.
    Martin H. 2010. Role of PPAR-gamma in inflammation. Prospects for therapeutic intervention by food components. Mutat. Res. 690:157–63
    [Google Scholar]
  103. 103.
    Shen D, Li H, Zhou R, Liu M, Yu H, Wu D-F. 2018. Pioglitazone attenuates aging-related disorders in aged apolipoprotein E deficient mice. Exp. Gerontol. 102:101–8
    [Google Scholar]
  104. 104.
    Murao A, Aziz M, Wang H, Brenner M, Wang P. 2021. Release mechanisms of major DAMPs. Apoptosis 26:3152–62
    [Google Scholar]
  105. 105.
    Kojima Y, Volkmer J-P, McKenna K, Civelek M, Lusis AJ et al. 2016. CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis. Nature 536:761486–90
    [Google Scholar]
  106. 106.
    Tseng D, Volkmer J-P, Willingham SB, Contreras-Trujillo H, Fathman JW et al. 2013. Anti-CD47 antibody-mediated phagocytosis of cancer by macrophages primes an effective antitumor T-cell response. PNAS 110:2711103–8
    [Google Scholar]
  107. 107.
    Ferrucci L, Fabbri E. 2018. Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat. Rev. Cardiol. 15:9505–22
    [Google Scholar]
  108. 108.
    Maschalidi S, Mehrotra P, Keçeli BN, De Cleene HKL, Lecomte K et al. 2022. Targeting SLC7A11 improves efferocytosis by dendritic cells and wound healing in diabetes. Nature 606:7915776–84
    [Google Scholar]
  109. 109.
    Morioka S, Kajioka D, Yamaoka Y, Ellison RM, Tufan T et al. 2022. Chimeric efferocytic receptors improve apoptotic cell clearance and alleviate inflammation. Cell 185:264887–903.e17
    [Google Scholar]
  110. 110.
    Poon IKH, Chiu Y-H, Armstrong AJ, Kinchen JM, Juncadella IJ et al. 2014. Unexpected link between an antibiotic, pannexin channels and apoptosis. Nature 507:7492329–34
    [Google Scholar]
  111. 111.
    Atkin-Smith GK, Tixeira R, Paone S, Mathivanan S, Collins C et al. 2015. A novel mechanism of generating extracellular vesicles during apoptosis via a beads-on-a-string membrane structure. Nat. Commun. 6:17439
    [Google Scholar]
  112. 112.
    Tixeira R, Phan TK, Caruso S, Shi B, Atkin-Smith GK et al. 2020. ROCK1 but not LIMK1 or PAK2 is a key regulator of apoptotic membrane blebbing and cell disassembly. Cell Death Differ. 27:1102–16
    [Google Scholar]
  113. 113.
    Navis KE, Fan CY, Trang T, Thompson RJ, Derksen DJ. 2020. Pannexin 1 channels as a therapeutic target: structure, inhibition, and outlook. ACS Chem. Neurosci. 11:152163–72
    [Google Scholar]
  114. 114.
    Wang Y, Gao W, Shi X, Ding J, Liu W et al. 2017. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547:766199–103
    [Google Scholar]
  115. 115.
    Rogers C, Fernandes-Alnemri T, Mayes L, Alnemri D, Cingolani G, Alnemri ES. 2017. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 8:14128
    [Google Scholar]
  116. 116.
    Kayagaki N, Kornfeld OS, Lee BL, Stowe IB, O'Rourke K et al. 2021. NINJ1 mediates plasma membrane rupture during lytic cell death. Nature 591:7848131–36
    [Google Scholar]
  117. 117.
    Van Rossom S, Op de Beeck K, Hristovska V, Winderickx J, Van Camp G 2015. The deafness gene DFNA5 induces programmed cell death through mitochondria and MAPK-related pathways. Front. Cell. Neurosci. 9:231
    [Google Scholar]
  118. 118.
    Luo G, He Y, Yang F, Zhai Z, Han J et al. 2022. Blocking GSDME-mediated pyroptosis in renal tubular epithelial cells alleviates disease activity in lupus mice. Cell Death Discov. 8:1113
    [Google Scholar]
  119. 119.
    Lee H-J, Ahn BJ, Shin MW, Jeong J-W, Kim JH, Kim K-W. 2009. Ninjurin1 mediates macrophage-induced programmed cell death during early ocular development. Cell Death Differ. 16:101395–407
    [Google Scholar]
  120. 120.
    Yin GN, Choi MJ, Kim WJ, Kwon M-H, Song K-M et al. 2014. Inhibition of Ninjurin 1 restores erectile function through dual angiogenic and neurotrophic effects in the diabetic mouse. PNAS 111:26E2731–40
    [Google Scholar]
  121. 121.
    Kayagaki N, Stowe IB, Alegre K, Deshpande I, Wu S et al. 2023. Inhibiting membrane rupture with NINJ1 antibodies limits tissue injury. Nature 618:1072–77
    [Google Scholar]
  122. 122.
    Gray M, Miles K, Salter D, Gray D, Savill J. 2007. Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. PNAS 104:3514080–85
    [Google Scholar]
  123. 123.
    Grau A, Tabib A, Grau I, Reiner I, Mevorach D. 2015. Apoptotic cells induce NF-κB and inflammasome negative signaling. PLOS ONE 10:3e0122440
    [Google Scholar]
  124. 124.
    Mevorach D, Zuckerman T, Reiner I, Shimoni A, Samuel S et al. 2014. Single infusion of donor mononuclear early apoptotic cells as prophylaxis for graft-versus-host disease in myeloablative HLA-matched allogeneic bone marrow transplantation: a Phase I/IIa clinical trial. Biol. Blood Marrow Transplant. 20:158–65
    [Google Scholar]
  125. 125.
    Hofer SJ, Simon AK, Bergmann M, Eisenberg T, Kroemer G, Madeo F. 2022. Mechanisms of spermidine-induced autophagy and geroprotection. Nat. Aging 2:121112–29
    [Google Scholar]
  126. 126.
    Ma Q, Liang M, Wu Y, Ding N, Duan L et al. 2019. Mature osteoclast-derived apoptotic bodies promote osteogenic differentiation via RANKL-mediated reverse signaling. J. Biol. Chem. 294:2911240–47
    [Google Scholar]
  127. 127.
    Pietschmann P, Mechtcheriakova D, Meshcheryakova A, Föger-Samwald U, Ellinger I. 2016. Immunology of osteoporosis: a mini-review. Gerontology 62:2128–37
    [Google Scholar]
  128. 128.
    Fu Y, Sui B, Xiang L, Yan X, Wu D et al. 2021. Emerging understanding of apoptosis in mediating mesenchymal stem cell therapy. Cell Death Dis. 12:6596
    [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-032723-110507
Loading
/content/journals/10.1146/annurev-pharmtox-032723-110507
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error