Review Article | Published:

Linking cellular stress responses to systemic homeostasis

Abstract

Mammalian cells respond to stress by activating mechanisms that support cellular functions and hence maintain microenvironmental and organismal homeostasis. Intracellular responses to stress, their regulation and their pathophysiological implications have been extensively studied. However, little is known about the signals that emanate from stressed cells to enable a coordinated adaptive response across tissues, organs and the whole organism. Considerable evidence has now accumulated indicating that the intracellular mechanisms that are activated in response to different stresses — which include the DNA damage response, the unfolded protein response, mitochondrial stress signalling and autophagy — as well as the mechanisms ensuring the proliferative inactivation or elimination of terminally damaged cells — such as cell senescence and regulated cell death — are all coupled with the generation of signals that elicit microenvironmental and/or systemic responses. These signals, which involve changes in the surface of stressed cells and/or the secretion of soluble factors or microvesicles, generally support systemic homeostasis but can also contribute to maladaptation and disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Fuchs, Y. & Steller, H. Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat. Rev. Mol. Cell Biol. 16, 329–344 (2015).

  2. 2.

    Chang, H. H. Y., Pannunzio, N. R., Adachi, N. & Lieber, M. R. Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat. Rev. Mol. Cell Biol. 18, 495–506 (2017).

  3. 3.

    Hetz, C. & Papa, F. R. The unfolded protein response and cell fate control. Mol. Cell 69, 169–181 (2018).

  4. 4.

    Shpilka, T. & Haynes, C. M. The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat. Rev. Mol. Cell Biol. 19, 109–120 (2018).

  5. 5.

    Suomalainen, A. & Battersby, B. J. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat. Rev. Mol. Cell Biol. 19, 77–92 (2018).

  6. 6.

    Galluzzi, L., Pietrocola, F., Levine, B. & Kroemer, G. Metabolic control of autophagy. Cell 159, 1263–1276 (2014).

  7. 7.

    Galluzzi, L. et al. Molecular definitions of autophagy and related processes. EMBO J. 36, 1811–1836 (2017).

  8. 8.

    Cao, X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol. 16, 35–50 (2016).

  9. 9.

    Neves, J., Demaria, M., Campisi, J. & Jasper, H. Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging. Dev. Cell 32, 9–18 (2015).

  10. 10.

    Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).

  11. 11.

    Galluzzi, L., Bravo-San Pedro, J. M., Kepp, O. & Kroemer, G. Regulated cell death and adaptive stress responses. Cell. Mol. Life Sci. 73, 2405–2410 (2016).

  12. 12.

    Yatim, N., Cullen, S. & Albert, M. L. Dying cells actively regulate adaptive immune responses. Nat. Rev. Immunol. 17, 262–275 (2017).

  13. 13.

    He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012).

  14. 14.

    Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464, 104–107 (2010).

  15. 15.

    Ermolaeva, M. A. & Schumacher, B. Systemic DNA damage responses: organismal adaptations to genome instability. Trends Genet. 30, 95–102 (2014).

  16. 16.

    Ribezzo, F., Shiloh, Y. & Schumacher, B. Systemic DNA damage responses in aging and diseases. Semin. Cancer Biol. 37–38, 26–35 (2016).

  17. 17.

    Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017). This comprehensive review examines the molecular and cellular mechanism whereby cell death can be perceived as immunogenic by the host and the pathophysiological implication of this process.

  18. 18.

    Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).

  19. 19.

    Wennerberg, E. et al. Immune recognition of irradiated cancer cells. Immunol. Rev. 280, 220–230 (2017).

  20. 20.

    Kang, T. W. et al. Senescence surveillance of pre-malignant hepatocytes limits liver cancer development. Nature 479, 547–551 (2011). This paper provides the first description of senescence surveillance as an immunological mechanism that limits oncogenesis in the liver upon the eradication of senescent hepatocytes.

  21. 21.

    Lopez-Soto, A., Gonzalez, S., Smyth, M. J. & Galluzzi, L. Control of metastasis by NK cells. Cancer Cell 32, 135–154 (2017).

  22. 22.

    Galluzzi, L. & Vitale, I. Oncogene-induced senescence and tumour control in complex biological systems. Cell Death Differ. 25, 1005–1006 (2018).

  23. 23.

    Dou, Z. et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature 550, 402–406 (2017).

  24. 24.

    Mackenzie, K. J. et al. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548, 461–465 (2017).

  25. 25.

    Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).

  26. 26.

    Harding, S. M. et al. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548, 466–470 (2017). References 23–26 independently demonstrate that multiple conditions associated with DNA damage result in the accumulation of double-stranded DNA in the cytoplasm and consequent release of type I IFN upon cGAS and STING activation.

  27. 27.

    Chen, Q., Sun, L. & Chen, Z. J. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat. Immunol. 17, 1142–1149 (2016).

  28. 28.

    Galluzzi, L., Vanpouille-Box, C., Bakhoum, S. F. & Demaria, S. SnapShot: CGAS-STING signaling. Cell 173, 276–276 (2018).

  29. 29.

    Crow, Y. J. et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi–Goutieres syndrome and mimic congenital viral brain infection. Nat. Genet. 38, 910–916 (2006).

  30. 30.

    Crow, Y. J. et al. Mutations in the gene encoding the 3'–5' DNA exonuclease TREX1 cause Aicardi–Goutieres syndrome at the AGS1 locus. Nat. Genet. 38, 917–920 (2006).

  31. 31.

    King, K. R. et al. IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat. Med. 23, 1481–1487 (2017).

  32. 32.

    Dewan, M. Z. et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin. Cancer Res. 15, 5379–5388 (2009).

  33. 33.

    Dewan, M. Z. et al. Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer. Clin. Cancer Res. 18, 6668–6678 (2012).

  34. 34.

    Reijns, M. A. et al. Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell 149, 1008–1022 (2012).

  35. 35.

    Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011). This paper characterizes chromothripsis as a single catastrophic event affecting one or a few chromosomes (or fragments thereof) that simultaneously generates tens of hundreds of genomic rearrangements.

  36. 36.

    Vitale, I., Manic, G., Senovilla, L., Kroemer, G. & Galluzzi, L. Karyotypic aberrations in oncogenesis and cancer therapy. Trends Cancer 1, 124–135 (2015).

  37. 37.

    Valent, A., Penault-Llorca, F., Cayre, A. & Kroemer, G. Change in HER2 (ERBB2) gene status after taxane-based chemotherapy for breast cancer: polyploidization can lead to diagnostic pitfalls with potential impact for clinical management. Cancer Genet. 206, 37–41 (2013).

  38. 38.

    Mitchison, T. J., Pineda, J., Shi, J. & Florian, S. Is inflammatory micronucleation the key to a successful anti-mitotic cancer drug? Open Biol. 7, 170182 (2017).

  39. 39.

    Xia, T., Konno, H., Ahn, J. & Barber, G. N. Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep. 14, 282–297 (2016).

  40. 40.

    Bartsch, K. et al. Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy. Hum. Mol. Genet. 26, 3960–3972 (2017).

  41. 41.

    Dou, Z. et al. Autophagy mediates degradation of nuclear lamina. Nature 527, 105–109 (2015).

  42. 42.

    Rello-Varona, S. et al. Autophagic removal of micronuclei. Cell Cycle 11, 170–176 (2012).

  43. 43.

    Rybstein, M. D., Bravo-San Pedro, J. M., Kroemer, G. & Galluzzi, L. The autophagic network and cancer. Nat. Cell Biol. 20, 243–251 (2018).

  44. 44.

    Dikic, I. & Elazar, Z. Mechanism and medical implications of mammalian autophagy. Nat. Rev. Mol. Cell Biol. 19, 349–364 (2018).

  45. 45.

    Ermolaeva, M. A. et al. DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501, 416–420 (2013).

  46. 46.

    Peng, Y. et al. Cysteine protease cathepsin B mediates radiation-induced bystander effects. Nature 547, 458–462 (2017).

  47. 47.

    Recklies, A. D., Tiltman, K. J., Stoker, T. A. & Poole, A. R. Secretion of proteinases from malignant and nonmalignant human breast tissue. Cancer Res. 40, 550–556 (1980).

  48. 48.

    Shree, T. et al. Macrophages and cathepsin proteases blunt chemotherapeutic response in breast cancer. Genes Dev. 25, 2465–2479 (2011).

  49. 49.

    Bian, B. et al. Cathepsin B promotes colorectal tumorigenesis, cell invasion, and metastasis. Mol. Carcinog. 55, 671–687 (2016).

  50. 50.

    Moon, H. Y. et al. Running-induced systemic cathepsin B secretion is associated with memory function. Cell Metab. 24, 332–340 (2016).

  51. 51.

    Frakes, A. E. & Dillin, A. The UPR(ER): Sensor and coordinator of organismal homeostasis. Mol. Cell 66, 761–771 (2017).

  52. 52.

    Mami, I. et al. A novel extrinsic pathway for the unfolded protein response in the kidney. J. Am. Soc. Nephrol. 27, 2670–2683 (2016).

  53. 53.

    Vecchi, C. et al. ER stress controls iron metabolism through induction of hepcidin. Science 325, 877–880 (2009).

  54. 54.

    Hosomi, S. et al. Intestinal epithelial cell endoplasmic reticulum stress promotes MULT1 up-regulation and NKG2D-mediated inflammation. J. Exp. Med. 214, 2985–2997 (2017).

  55. 55.

    Miyake, M. et al. Skeletal muscle-specific eukaryotic translation initiation factor 2alpha phosphorylation controls amino acid metabolism and fibroblast growth factor 21-mediated non-cell-autonomous energy metabolism. FASEB J. 30, 798–812 (2016).

  56. 56.

    Bohnert, K. R., McMillan, J. D. & Kumar, A. Emerging roles of ER stress and unfolded protein response pathways in skeletal muscle health and disease. J. Cell. Physiol. 233, 67–78 (2018).

  57. 57.

    Ozcan, L. et al. Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab. 9, 35–51 (2009).

  58. 58.

    Williams, K. W. et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab. 20, 471–482 (2014).

  59. 59.

    Taylor, R. C. & Dillin, A. XBP-1 is a cell-nonautonomous regulator of stress resistance and longevity. Cell 153, 1435–1447 (2013).

  60. 60.

    Guan, B. J. et al. A unique ISR program determines cellular responses to chronic stress. Mol. Cell 68, 885–900 e886 (2017).

  61. 61.

    Sundaram, A., Plumb, R., Appathurai, S. & Mariappan, M. The Sec61 translocon limits IRE1alpha signaling during the unfolded protein response. eLife 6, 27187 (2017).

  62. 62.

    Rodvold, J. J. et al. Intercellular transmission of the unfolded protein response promotes survival and drug resistance in cancer cells. Sci. Signal. 10, aah7177 (2017). The authors of this article demonstrate that the UPR ER can be transmitted between cancer cells in a process with important implications for tumour progression and response to treatment that they term ‘transmissible ER stress’.

  63. 63.

    Bezu, L. et al. eIF2alpha phosphorylation is pathognomonic for immunogenic cell death. Cell Death Differ. (2018).

  64. 64.

    Panaretakis, T. et al. Mechanisms of pre-apoptotic calreticulin exposure in immunogenic cell death. EMBO J. 28, 578–590 (2009).

  65. 65.

    Fucikova, J. et al. Calreticulin expression in human non-small cell lung cancers correlates with increased accumulation of antitumor immune cells and favorable prognosis. Cancer Res. 76, 1746–1756 (2016).

  66. 66.

    Fucikova, J. et al. Calreticulin exposure by malignant blasts correlates with robust anticancer immunity and improved clinical outcome in AML patients. Blood 128, 3113–3124 (2016).

  67. 67.

    Osman, R., Tacnet-Delorme, P., Kleman, J. P., Millet, A. & Frachet, P. Calreticulin release at an early stage of death modulates the clearance by macrophages of apoptotic cells. Front. Immunol. 8, 1034 (2017).

  68. 68.

    He, X. Y. et al. Calreticulin fragment 39–272 promotes B16 melanoma malignancy through myeloid-derived suppressor cells in vivo. Front. Immunol. 8, 1306 (2017).

  69. 69.

    De, I., Dogra, N. & Singh, S. The mitochondrial unfolded protein response: role in cellular homeostasis and disease. Curr. Mol. Med. 17, 587–597 (2017).

  70. 70.

    Moehle, E. A., Shen, K. & Dillin, A. Mitochondrial proteostasis in the context of cellular and organismal health and aging. J. Biol. Chem. https://doi.org/10.1074/jbc.TM117.000893 (2018).

  71. 71.

    Tian, Y., Merkwirth, C. & Dillin, A. Mitochondrial UPR: a double-edged sword. Trends Cell Biol. 26, 563–565 (2016).

  72. 72.

    Melber, A. & Haynes, C. M. UPR(mt) regulation and output: a stress response mediated by mitochondrial-nuclear communication. Cell Res. 28, 281–295 (2018).

  73. 73.

    Owusu-Ansah, E., Song, W. & Perrimon, N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155, 699–712 (2013).

  74. 74.

    Wang, X. & Auwerx, J. Systems phytohormone responses to mitochondrial proteotoxic stress. Mol. Cell 68, 540–551.e545 (2017).

  75. 75.

    Shao, L. W., Niu, R. & Liu, Y. Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response. Cell Res. 26, 1182–1196 (2016).

  76. 76.

    Berendzen, K. M. et al. Neuroendocrine coordination of mitochondrial stress signaling and proteostasis. Cell 166, 1553–1563.e1510 (2016).

  77. 77.

    Pellegrino, M. W. et al. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516, 414–417 (2014). The authors of this paper show that the UPR mt in C. elegans has a major impact on the systemic response to bacterial infection by favouring the secretion of lysozyme and other antimicrobial peptides.

  78. 78.

    Pellegrino, M. W., Nargund, A. M. & Haynes, C. M. Signaling the mitochondrial unfolded protein response. Biochim. Biophys. Acta 1833, 410–416 (2013).

  79. 79.

    Nargund, A. M., Fiorese, C. J., Pellegrino, M. W., Deng, P. & Haynes, C. M. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol. Cell 58, 123–133 (2015).

  80. 80.

    Kim, K. H. et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19, 83–92 (2013).

  81. 81.

    Chung, H. K. et al. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J. Cell Biol. 216, 149–165 (2017).

  82. 82.

    Hsu, J. Y. et al. Non-homeostatic body weight regulation through a brainstem-restricted receptor for GDF15. Nature 550, 255–259 (2017).

  83. 83.

    Fujita, Y., Taniguchi, Y., Shinkai, S., Tanaka, M. & Ito, M. Secreted growth differentiation factor 15 as a potential biomarker for mitochondrial dysfunctions in aging and age-related disorders. Geriatr. Gerontol. Int. 16 (Suppl. 1), 17–29 (2016).

  84. 84.

    Adela, R. & Banerjee, S. K. GDF-15 as a target and biomarker for diabetes and cardiovascular diseases: a translational prospective. J. Diabetes Res. 2015, 490842 (2015).

  85. 85.

    Xiong, Y. et al. Long-acting MIC-1/GDF15 molecules to treat obesity: evidence from mice to monkeys. Sci. Transl Med. 9, aan8732 (2017).

  86. 86.

    Kim, S. J., Xiao, J., Wan, J., Cohen, P. & Yen, K. Mitochondrially derived peptides as novel regulators of metabolism. J. Physiol. 595, 6613–6621 (2017).

  87. 87.

    Gong, Z. et al. Humanin is an endogenous activator of chaperone-mediated autophagy. J. Cell Biol. 217, 635–647 (2018).

  88. 88.

    Han, K., Jia, N., Zhong, Y. & Shang, X. S14G-humanin alleviates insulin resistance and increases autophagy in neurons of APP/PS1 transgenic mouse. J. Cell. Biochem. 119, 3111–3117 (2017).

  89. 89.

    Gidlund, E. K. et al. Humanin skeletal muscle protein levels increase after resistance training in men with impaired glucose metabolism. Physiol. Rep. 4, e13063 (2016).

  90. 90.

    Lee, C. et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 21, 443–454 (2015).

  91. 91.

    Zhai, D. et al. MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA. Mol. Immunol. 92, 151–160 (2017).

  92. 92.

    Cobb, L. J. et al. Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging (Albany NY) 8, 796–809 (2016).

  93. 93.

    Galluzzi, L., Kepp, O. & Kroemer, G. Mitochondria: master regulators of danger signalling. Nat. Rev. Mol. Cell Biol. 13, 780–788 (2012).

  94. 94.

    White, M. J. et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549–1562 (2014).

  95. 95.

    Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563–1577 (2014). References 94 and 95 independently demonstrate that MOMP generally allows for the release of mtDNA into the cytosol, resulting in type I IFN production by cGAS and STING unless apoptotic caspases are active.

  96. 96.

    Zhou, R., Yazdi, A. S., Menu, P. & Tschopp, J. A role for mitochondria in NLRP3 inflammasome activation. Nature 469, 221–225 (2011).

  97. 97.

    Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222–230 (2011).

  98. 98.

    Zhong, Z. et al. NF-kappaB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164, 896–910 (2016). References 97 and 98 show that NF-κB-driven mitophagy mediates robust anti-inflammatory effects by disposing of damaged mitochondria before they release endogenous inflammasome activators.

  99. 99.

    Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136–140 (2010).

  100. 100.

    Al-Mehdi, A. B. et al. Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription. Sci. Signal 5, ra47 (2012).

  101. 101.

    Dieude, M. et al. Cardiolipin binds to CD1d and stimulates CD1d-restricted gammadelta T cells in the normal murine repertoire. J. Immunol. 186, 4771–4781 (2011).

  102. 102.

    Vance, J. E. MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond. Biochim. Biophys. Acta 1841, 595–609 (2014).

  103. 103.

    Levy, J. M. M., Towers, C. G. & Thorburn, A. Targeting autophagy in cancer. Nat. Rev. Cancer 17, 528–542 (2017).

  104. 104.

    Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R. & Kroemer, G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 16, 487–511 (2017).

  105. 105.

    Martinez-Outschoorn, U. E., Peiris-Pages, M., Pestell, R. G., Sotgia, F. & Lisanti, M. P. Cancer metabolism: a therapeutic perspective. Nat. Rev. Clin. Oncol. 14, 11–31 (2017).

  106. 106.

    Capparelli, C. et al. Autophagy and senescence in cancer-associated fibroblasts metabolically supports tumor growth and metastasis via glycolysis and ketone production. Cell Cycle 11, 2285–2302 (2012).

  107. 107.

    Sousa, C. M. et al. Pancreatic stellate cells support tumour metabolism through autophagic alanine secretion. Nature 536, 479–483 (2016). This study is the first demonstration that autophagic responses in pancreatic stellate cells allow for the release of alanine in the tumour microenvironment, where it can be taken up by malignant cells to support tumour progression.

  108. 108.

    Martin, S. et al. An autophagy-driven pathway of ATP secretion supports the aggressive phenotype of BRAF(V600E) inhibitor-resistant metastatic melanoma cells. Autophagy 13, 1512–1527 (2017).

  109. 109.

    Qu, X. et al. Autophagy gene-dependent clearance of apoptotic cells during embryonic development. Cell 128, 931–946 (2007).

  110. 110.

    Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011). The authors of this study report that the immunogenicity of anthracycline-driven cell death obligatorily relies on the activation of autophagic responses that precede RCD and enable robust ATP release.

  111. 111.

    Elliott, M. R. et al. Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286 (2009).

  112. 112.

    Buque, A. et al. Trial Watch-Small molecules targeting the immunological tumor microenvironment for cancer therapy. Oncoimmunology 5, e1149674 (2016).

  113. 113.

    Galluzzi, L., Bravo-San Pedro, J. M., Demaria, S., Formenti, S. C. & Kroemer, G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat. Rev. Clin. Oncol. 14, 247–258 (2017).

  114. 114.

    Martinez-Lopez, N. et al. System-wide benefits of intermeal fasting by autophagy. Cell Metab. 26, 856–871 (2017).

  115. 115.

    Dupont, N. et al. Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1beta. EMBO J. 30, 4701–4711 (2011).

  116. 116.

    Loomis, W. F., Behrens, M. M., Williams, M. E. & Anjard, C. Pregnenolone sulfate and cortisol induce secretion of acyl-CoA-binding protein and its conversion into endozepines from astrocytes. J. Biol. Chem. 285, 21359–21365 (2010).

  117. 117.

    Claude-Taupin, A., Jia, J., Mudd, M. & Deretic, V. Autophagy’s secret life: secretion instead of degradation. Essays Biochem. 61, 637–647 (2017).

  118. 118.

    Zhang, M., Kenny, S. J., Ge, L., Xu, K. & Schekman, R. Translocation of interleukin-1β into a vesicle intermediate in autophagy-mediated secretion. eLife 4, 11205 (2015).

  119. 119.

    Kimura, T. et al. Dedicated SNAREs and specialized TRIM cargo receptors mediate secretory autophagy. EMBO J. 36, 42–60 (2017).

  120. 120.

    Shi, C. S. et al. Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13, 255–263 (2012).

  121. 121.

    Harris, J. et al. Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J. Biol. Chem. 286, 9587–9597 (2011).

  122. 122.

    Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016).

  123. 123.

    Ip, W. K. E., Hoshi, N., Shouval, D. S., Snapper, S. & Medzhitov, R. Anti-inflammatory effect of IL-10 mediated by metabolic reprogramming of macrophages. Science 356, 513–519 (2017). This study is the first demonstration that the anti-inflammatory effects of IL-10 result (at least in part) from the activation of a mitophagic response that limits inflammasome activation in macrophages.

  124. 124.

    Esteban-Martinez, L. et al. Programmed mitophagy is essential for the glycolytic switch during cell differentiation. EMBO J. 36, 1688–1706 (2017).

  125. 125.

    Bel, S. et al. Paneth cells secrete lysozyme via secretory autophagy during bacterial infection of the intestine. Science 357, 1047–1052 (2017).

  126. 126.

    McHugh, D. & Gil, J. Senescence and aging: causes, consequences, and therapeutic avenues. J. Cell Biol. 217, 65–77 (2018).

  127. 127.

    Hoare, M. et al. NOTCH1 mediates a switch between two distinct secretomes during senescence. Nat. Cell Biol. 18, 979–992 (2016).

  128. 128.

    Morancho, B., Martinez-Barriocanal, A., Villanueva, J. & Arribas, J. Role of ADAM17 in the non-cell autonomous effects of oncogene-induced senescence. Breast Cancer Res. 17, 106 (2015).

  129. 129.

    Gluck, S. et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat. Cell Biol. 19, 1061–1070 (2017).

  130. 130.

    Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

  131. 131.

    Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).

  132. 132.

    Katlinskaya, Y. V. et al. Suppression of type I interferon signaling overcomes oncogene-induced senescence and mediates melanoma development and progression. Cell Rep. 15, 171–180 (2016).

  133. 133.

    Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

  134. 134.

    Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

  135. 135.

    Wajapeyee, N., Serra, R. W., Zhu, X., Mahalingam, M. & Green, M. R. Oncogenic BRAF induces senescence and apoptosis through pathways mediated by the secreted protein IGFBP7. Cell 132, 363–374 (2008).

  136. 136.

    Lehmann, B. D. et al. Senescence-associated exosome release from human prostate cancer cells. Cancer Res. 68, 7864–7871 (2008).

  137. 137.

    Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

  138. 138.

    Baker, D. J. et al. Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016).

  139. 139.

    Baker, D. J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011).

  140. 140.

    Baar, M. P. et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell 169, 132–147.e116 (2017).

  141. 141.

    Farr, J. N. et al. Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 23, 1072–1079 (2017).

  142. 142.

    Xu, M. et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 4, e12997 (2015).

  143. 143.

    Xu, M. et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl Acad. Sci. USA 112, E6301–E6310 (2015).

  144. 144.

    Rodier, F. & Campisi, J. Four faces of cellular senescence. J. Cell Biol. 192, 547–556 (2011).

  145. 145.

    Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014).

  146. 146.

    Iannello, A., Thompson, T. W., Ardolino, M., Lowe, S. W. & Raulet, D. H. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J. Exp. Med. 210, 2057–2069 (2013).

  147. 147.

    Takasugi, M. et al. Small extracellular vesicles secreted from senescent cells promote cancer cell proliferation through EphA2. Nat. Commun. 8, 15729 (2017).

  148. 148.

    Uderhardt, S. et al. 12/15-lipoxygenase orchestrates the clearance of apoptotic cells and maintains immunologic tolerance. Immunity 36, 834–846 (2012).

  149. 149.

    Roberts, A. W. et al. Tissue-resident macrophages are locally programmed for silent clearance of apoptotic cells. Immunity 47, 913–927 (2017).

  150. 150.

    Mistry, P. & Kaplan, M. J. Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis. Clin. Immunol. 185, 59–73 (2017).

  151. 151.

    Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17, 860–866 (2011).

  152. 152.

    Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).

  153. 153.

    Suzuki, J., Denning, D. P., Imanishi, E., Horvitz, H. R. & Nagata, S. Xk-related protein 8 and CED-8 promote phosphatidylserine exposure in apoptotic cells. Science 341, 403–406 (2013).

  154. 154.

    Segawa, K. et al. Caspase-mediated cleavage of phospholipid flippase for apoptotic phosphatidylserine exposure. Science 344, 1164–1168 (2014).

  155. 155.

    Fadok, V. A. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000).

  156. 156.

    Li, M. O., Sarkisian, M. R., Mehal, W. Z., Rakic, P. & Flavell, R. A. Phosphatidylserine receptor is required for clearance of apoptotic cells. Science 302, 1560–1563 (2003). References 155 and 156 characterize the receptor for PtdSer and its critical importance for the silent removal of apoptotic cells in the context of PCD.

  157. 157.

    Martinez, J. et al. Noncanonical autophagy inhibits the autoinflammatory, lupus-like response to dying cells. Nature 533, 115–119 (2016). The authors of this study demonstrate that defects in LC3-associated phagocytosis cause deficient removal of dead cells by phagocytosis, culminating in an autoimmune disease similar to SLE, at least in mice.

  158. 158.

    Zitvogel, L., Galluzzi, L., Kepp, O., Smyth, M. J. & Kroemer, G. Type I interferons in anticancer immunity. Nat. Rev. Immunol. 15, 405–414 (2015).

  159. 159.

    Franz, K. M. & Kagan, J. C. Innate immune receptors as competitive determinants of cell fate. Mol. Cell 66, 750–760 (2017).

  160. 160.

    Zanoni, I., Tan, Y., Di Gioia, M., Springstead, J. R. & Kagan, J. C. By capturing inflammatory lipids released from dying cells, the receptor CD14 induces inflammasome-dependent phagocyte hyperactivation. Immunity 47, 697–709 (2017).

  161. 161.

    Vacchelli, E. et al. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science 350, 972–978 (2015).

  162. 162.

    Jorgensen, I., Rayamajhi, M. & Miao, E. A. Programmed cell death as a defence against infection. Nat. Rev. Immunol. 17, 151–164 (2017).

  163. 163.

    Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187–192 (2014).

  164. 164.

    Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017). This paper provides the first description of a pyroptotic variant of RCD that depends on CASP3 and GSDME, rather than on inflammatory caspases and GDSMD, which might contribute to the side effects of chemotherapy.

  165. 165.

    Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).

  166. 166.

    Galluzzi, L., Kepp, O., Chan, F. K. & Kroemer, G. Necroptosis: mechanisms and relevance to disease. Annu. Rev. Pathol. 12, 103–130 (2017).

  167. 167.

    Weinlich, R., Oberst, A., Beere, H. M. & Green, D. R. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 18, 127–136 (2017).

  168. 168.

    Yang, H. et al. Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy. Oncoimmunology 5, e1149673 (2016).

  169. 169.

    Conos, S. A. et al. Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner. Proc. Natl Acad. Sci. USA 114, E961–E969 (2017).

  170. 170.

    Vince, J. E. et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36, 215–227 (2012).

  171. 171.

    Yatim, N. et al. RIPK1 and NF-kappaB signaling in dying cells determines cross-priming of CD8+ T cells. Science 350, 328–334 (2015).

  172. 172.

    Aaes, T. L. et al. Vaccination with necroptotic cancer cells induces efficient anti-tumor immunity. Cell Rep. 15, 274–287 (2016). References 171 and 172 demonstrate that RIPK3-driven necroptotic cell death is immunogenic and is accompanied by the activation of an NF-κB-dependent transcriptional response.

  173. 173.

    Kepp, O. et al. Consensus guidelines for the detection of immunogenic cell death. Oncoimmunology 3, e955691 (2014).

  174. 174.

    Sistigu, A. et al. Cancer cell-autonomous contribution of type I interferon signaling to the efficacy of chemotherapy. Nat. Med. 20, 1301–1309 (2014).

  175. 175.

    Giampazolias, E. et al. Mitochondrial permeabilization engages NF-κB-dependent anti-tumour activity under caspase deficiency. Nat. Cell Biol. 19, 1116–1129 (2017).

  176. 176.

    Galluzzi, L., Lopez-Soto, A., Kumar, S. & Kroemer, G. Caspases connect cell-death signaling to organismal homeostasis. Immunity 44, 221–231 (2016).

  177. 177.

    Senovilla, L. et al. An immunosurveillance mechanism controls cancer cell ploidy. Science 337, 1678–1684 (2012).

  178. 178.

    Galluzzi, L. et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ. 22, 58–73 (2015).

  179. 179.

    Xu, X., Zhao, Y., Kirkman, E. & Lin, X. Secreted Acb1 contributes to the yeast-to-hypha transition in Cryptococcus neoformans. Appl. Environ. Microbiol. 82, 1069–1079 (2015).

  180. 180.

    Vitale, I., Manic, G., De Maria, R., Kroemer, G. & Galluzzi, L. DNA damage in stem cells. Mol. Cell 66, 306–319 (2017).

  181. 181.

    Luo, S., Baumeister, P., Yang, S., Abcouwer, S. F. & Lee, A. S. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements. J. Biol. Chem. 278, 37375–37385 (2003).

  182. 182.

    Lee, A. H., Iwakoshi, N. N. & Glimcher, L. H. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. Mol. Cell. Biol. 23, 7448–7459 (2003).

  183. 183.

    Haze, K., Yoshida, H., Yanagi, H., Yura, T. & Mori, K. Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol. Biol. Cell 10, 3787–3799 (1999).

  184. 184.

    Johannes, G. & Sarnow, P. Cap-independent polysomal association of natural mRNAs encoding c-myc, BiP, and eIF4G conferred by internal ribosome entry sites. RNA 4, 1500–1513 (1998).

  185. 185.

    Novoa, I., Zeng, H., Harding, H. P. & Ron, D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J. Cell Biol. 153, 1011–1022 (2001).

  186. 186.

    Zinszner, H. et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev. 12, 982–995 (1998).

  187. 187.

    Galluzzi, L., Bravo-San Pedro, J. M. & Kroemer, G. Organelle-specific initiation of cell death. Nat. Cell Biol. 16, 728–736 (2014).

  188. 188.

    Sica, V. et al. Organelle-specific initiation of autophagy. Mol. Cell 59, 522–539 (2015).

  189. 189.

    Stolz, A., Ernst, A. & Dikic, I. Cargo recognition and trafficking in selective autophagy. Nat. Cell Biol. 16, 495–501 (2014).

Download references

Acknowledgements

The authors apologize to the authors of several high-quality articles dealing with the links between intracellular stress responses and the regulation of organismal homeostasis that were not able to be discussed and cited owing to space limitations. L.G. is supported by a start-up grant from the Department of Radiation Oncology at Weill Cornell Medicine (New York, NY, USA), by industrial grants from Lytix (Oslo, Norway) and Phosplatin (New York, NY, USA), and by donations from Sotio a.s. (Prague, Czech Republic), the Luke Heller TECPR2 Foundation (Boston, MA, USA) and Phosplatin (New York, NY, USA). G.K. is supported by the Ligue contre le Cancer Comité de Charente-Maritime (Équipe Labellisée); the Agence National de la Recherche (ANR) — Projets Blancs; ANR under the framework of E-Rare-2, the ERA-Net for Research on Rare Diseases; the Association pour la Recherche sur le Cancer (ARC); Cancéropôle Ile-de-France; Chancelerie des Universités de Paris (Legs Poix), the Fondation pour la Recherche Médicale (FRM); a donation by Elior; the European Commission (ArtForce); the European Research Council (ERC); the Fondation Carrefour; the Institut National du Cancer (INCa); INSERM (HTE); the Institut Universitaire de France; the LeDucq Foundation; the LabEx Immuno-Oncology; RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine (CARPEM). L.G.’s homepage: http://www.galluzzilab.com. G.K.’s homepage: http://www.kroemerlab.com.

Reviewer information

Nature Reviews Molecular Cell Biology thanks C. Hetz, B. Schumacher and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Author information

All authors researched data for the article, wrote the article and edited the manuscript. L.G. and G.K. contributed to discussion of the content before submission.

Competing interests

The authors declare no competing interests.

Correspondence to Lorenzo Galluzzi or Guido Kroemer.

Glossary

Pattern recognition receptors

Evolutionarily conserved receptors that elicit inflammation and innate immunity upon recognition of conserved microbial products or endogenous danger signals.

Regulated cell death

(RCD). Variant of cell death that relies on a dedicated, genetically encoded machinery and hence can be delayed or accelerated with pharmacological or genetic interventions.

Cell cycle checkpoints

Control mechanisms that ensure the progression of eukaryotic cells along the cell cycle only in the presence of favourable conditions.

Immunogenicity

The ability to trigger an immune response, resulting from antigenicity (the property of being recognized by immune cells) and adjuvanticity (the property of delivering activating signals to immune cells).

Natural killer (NK) cells

A group of cells from the innate lymphoid immune system that can mediate cytotoxic functions independent of antigen recognition.

Major histocompatibility complex

(MHC). Set of cell surface proteins essential for the immune system to recognize foreign molecules in vertebrates.

Abscopal responses

Measurable reductions in the size of a non-irradiated tumour or metastasis thereof following the irradiation of another lesion.

Hypofractionated irradiation

The delivery of radiation therapy in a few fractions, each with a larger dose than the standard 1.8 or 2 Gy.

Micronuclei

Small enveloped structures that encompass chromosomes of fragments thereof that are not incorporated into one of the daughter nuclei during mitosis.

Chromothripsis

A process whereby up to thousands of clustered chromosomal rearrangements occur in a single event in localized genomic regions affecting one or a few chromosomes.

Proteostasis

The maintenance of protein homeostasis within a defined organelle, cell or tissue, which involves correct protein synthesis, folding, distribution and degradation.

Myokine

One of several small proteins or proteoglycans that are released by myocytes upon contraction to mediate autocrine, paracrine or endocrine effects.

Nuclear factor-κB (NF-κB) signalling

Biological output of NF-κB-dependent transcription, generally involving a robust pro-inflammatory component.

Hepcidin antimicrobial peptide

(HAMP). Key negative regulator of circulating iron availability in mammals, promoting a state of accrued bacterial resistance.

Brown adipose tissue

Highly specialized adipose tissue, the main function of which is to produce heat (thermogenesis).

Dendritic cells

Myeloid cells that play a major role in the initiation of T cell-dependent immune responses.

Myeloid-derived suppressor cells

(MDSCs). A heterogeneous population of cells that are defined by their myeloid origin, immature state and ability to potently suppress T cell responses.

Integrated stress response

Evolutionarily conserved homeostatic programme common to all eukaryotic cells.

Mitokines

Soluble factors released by cells experiencing mitochondrial stress and operating as autocrine, paracrine or endocrine mediators.

AMP-activated protein kinase

(AMPK). Phylogenetically conserved enzyme expressed by all mammalian cells that has a major role in the regulation of energy metabolism.

Mitochondrial outer membrane permeabilization

(MOMP). Loss of integrity of the outer mitochondrial membrane that generally precipitates regulated cell death through apoptosis.

Inflammasome

Supramolecular complex responsible for the caspase 1-dependent maturation of IL-1β and IL-18 in response to microbial products or other danger signals.

γδ T lymphocytes

T cells expressing a γδ (rather than an αβ) T cell receptor, which is associated with a fairly limited antigenic repertoire but major histocompatibility complex-independent recognition.

Cancer-associated fibroblasts

Fibroblasts that are found in the tumour microenvironment and generally support malignant cells by nutritional and immunological mechanisms.

Ketone bodies

Three related compounds (acetone, acetoacetic acid and β-hydroxybutyric acid) that are produced during the metabolism of lipids.

Stellate cells

Hepatic or pancreatic cells that have a major role in the establishment and maintenance of fibrosis.

Pro-opiomelanocortin neurons

Hypothalamic neurons capable of synthesizing pro-opiomelanocortin (POMC), the precursor of circulating melanocyte stimulating hormone, adrenocorticotropin hormone and β-endorphin

Non-conventional secretion

Process through which intracellular proteins and other cytoplasmic components are released into the extracellular milieu independently of the endoplasmic reticulum and Golgi apparatus.

Paneth cells

Cells from the intestinal epithelium that contribute to the maintenance of the gastrointestinal barrier.

Crohn’s disease

Chronic inflammatory condition of the gastrointestinal tract associated with an increased risk of colorectal cancer.

Exosomes

Cell-derived small vesicles that are present in virtually all mammalian fluids, including blood and urine.

Senolytic drugs

Agents that selectively kill senescent cells.

Programmed cell death

(PCD). Purely physiological variant of regulated cell death that contributes to post-embryonic or embryonic development as well as to the maintenance of adult tissue homeostasis.

Systemic lupus erythematosus

(SLE). Mild to severe autoimmune disease affecting a variety of tissues, including joints, skin, heart and lungs.

LC3-associated phagocytosis

Specific variant of the phagocytic process that relies on multiple, but not all, components of the molecular apparatus for autophagy.

Damage-associated molecular patterns

(DAMPs). Endogenous molecules that, upon exposure on the plasma membrane or secretion, can be recognized by a pattern recognition receptor and hence participate in the regulation of inflammatory responses.

Pyroptosis

Variant of regulated cell death that is associated with the formation of pores in the plasma membrane by one of multiple gasdermin family members.

RIGI-like receptors

(RLRs). Intracellular pattern recognition receptors involved in the recognition of nucleic acids (generally, but not exclusively, of viral origin).

Necroptosis

Variant of regulated cell death that involves RIPK3-dependent activation of MLKL, resulting in plasma membrane permeabilization.

Immunogenic cell death

(ICD). Functionally defined variant of regulated cell death that is sufficient (in immunocompetent hosts) to establish protective immune responses specific for antigens from dying cells.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1: Integration of cellular and systemic stress responses and their roles in the maintenance of organismal homeostasis.
Fig. 2: The DDR and UPRER in the regulation of microenvironmental and systemic homeostasis.
Fig. 3: Mitochondrial stress responses and autophagy in the regulation of microenvironmental and systemic homeostasis.
Fig. 4: Cellular senescence and RCD in the regulation of microenvironmental and systemic homeostasis.