Molecular Medicine

, Volume 23, Issue 1, pp 188–195 | Cite as

Inflammasome and Autophagy Regulation: A Two-way Street

  • Qian Sun
  • Jie Fan
  • Timothy R. Billiar
  • Melanie J. Scott
Research Article


Inflammation plays a significant role in protecting hosts against pathogens. Inflammation induced by noninfectious endogenous agents can be detrimental and, if excessive, can result in organ and tissue damage. The inflammasome is a major innate immune pathway that can be activated via both exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). Inflammasome activation involves formation and oligomerization of a protein complex including a nucleotide oligomerization domain (NOD)-like receptor (NLR), an adaptor protein and pro-caspase-1. This then allows cleavage and activation of caspase-1, followed by downstream cleavage and release of proinflammatory cytokines interleukin (IL)-1β and IL-18 from innate immune cells. Hyperinflammation caused by unrestrained inflammasome activation is linked with multiple inflammatory diseases, including inflammatory bowel disease, Alzheimer’s disease and multiple sclerosis. So there is an understandable rush to understand mechanisms that regulate such potent inflammatory pathways. Autophagy has now been identified as a main regulator of inflammasomes. Autophagy is a vital intracellular process involved in cellular homeostasis, recycling and removal of damaged organelles (eg, mitochondria) and intracellular pathogens. Autophagy is regulated by proteins that are important in endosomal/phagosomal pathways, as well as by specific autophagy proteins coded for by autophagy-related genes. Cytosolic components are surrounded and contained by a double-membraned vesicle, which then fuses with lysosomes to enable degradation of the contents. Autophagic removal of intracellular DAMPs, inflammasome components or cytokines can reduce inflammasome activation. Similarly, inflammasomes can regulate the autophagic process, allowing for a two-way mutual regulation of inflammation that may hold the key for treatment of multiple diseases.



Work performed for this paper was supported by NIH-R01-GM102146 (to MJS).


  1. 1.
    Vanaja SK, Rathinam VA, Fitzgerald KA. (2015) Mechanisms of inflammasome activation: recent advances and novel insights. Trends Cell. Biol. 25:308–15.CrossRefGoogle Scholar
  2. 2.
    Broz P, Dixit VM. (2016) Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16:407–20.CrossRefGoogle Scholar
  3. 3.
    Guo H, Callaway JB, Ting JP. (2015) Inflammasomes: mechanism of action, role in disease, and therapeutics. Nat. Med. 21:677–87.CrossRefGoogle Scholar
  4. 4.
    Glick D, Barth S, Macleod KF. (2010) Autophagy: cellular and molecular mechanisms. J. Pathol. 221:3–12.CrossRefGoogle Scholar
  5. 5.
    Deretic V, Saitoh T, Akira S. (2013) Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol. 13:722–37.CrossRefGoogle Scholar
  6. 6.
    Levine B, Mizushima N, Virgin HW. (2011) Autophagy in immunity and inflammation. Nature. 469:323–35.CrossRefGoogle Scholar
  7. 7.
    Cadwell K. (2016) Crosstalk between autophagy and inflammatory signalling pathways: balancing defence and homeostasis. Nat. Rev. Immunol. 16:661–75.CrossRefGoogle Scholar
  8. 8.
    Schroder K, Tschopp J. (2010) The inflammasomes. Cell. 140:821–32.CrossRefGoogle Scholar
  9. 9.
    Latz E, Xiao TS, Stutz A. (2013) Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13:397–411.CrossRefGoogle Scholar
  10. 10.
    Davis BK, Wen H, Ting JP. (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu. Rev. Immunol. 29:707–35.CrossRefGoogle Scholar
  11. 11.
    Zhao Y, Shao F. (2015) The NAIP-NLRC4 inflammasome in innate immune detection of bacterial flagellin and type III secretion apparatus. Immunol. Rev. 265:85–102.CrossRefGoogle Scholar
  12. 12.
    He Y, Zeng MY, Yang DH, Metro B, Nunez G. (2016) NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature. 530:354–7.CrossRefGoogle Scholar
  13. 13.
    Sun Q, et al. (2017) Redox-dependent regulation of hepatocyte absent in melanoma 2 inflammasome activation in sterile liver injury in mice. Hepatology. 65:253–68.CrossRefGoogle Scholar
  14. 14.
    Kaur J, Debnath J. (2015) Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16:461–72.CrossRefGoogle Scholar
  15. 15.
    Kim YC, Guan KL. (2015) mTOR: a pharmacologic target for autophagy regulation. J. Clin. Invest. 125:25–32.CrossRefGoogle Scholar
  16. 16.
    Fitzwalter BE, Thorburn A. (2015) Recent insights into cell death and autophagy. FEBS J. 282:4279–88.CrossRefGoogle Scholar
  17. 17.
    Saitoh T, et al. (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 456:264–68.CrossRefGoogle Scholar
  18. 18.
    Shibutani ST, Saitoh T, Nowag H, Munz C, Yoshimori T. (2015) Autophagy and autophagy-related proteins in the immune system. Nat. Immunol. 16:1014–24.CrossRefGoogle Scholar
  19. 19.
    Zhou R, Yazdi AS, Menu P, Tschopp J. (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature. 469:221–5.CrossRefGoogle Scholar
  20. 20.
    Nakahira K, et al. (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12:222–30.CrossRefGoogle Scholar
  21. 21.
    Shimada K, et al. (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 36:401–14.CrossRefGoogle Scholar
  22. 22.
    Wen H, et al. (2011) Fatty acid-induced NL-RP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12:408–15.CrossRefGoogle Scholar
  23. 23.
    Lupfer C, et al. (2013) Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat. Immunol. 14:480–8.CrossRefGoogle Scholar
  24. 24.
    Aon MA, et al. (2012) Glutathione/thioredoxin systems modulate mitochondrial H2O2 emission: an experimental-computational study. J. Gen. Physiol. 139:479–91.CrossRefGoogle Scholar
  25. 25.
    Sengupta R, Billiar TR, Kagan VE, Stoyanovsky DA. (2010) Nitric oxide and thioredoxin type 1 modulate the activity of caspase 8 in HepG2 cells. Biochem. Biophys. Res. Commun. 391:1127–30.CrossRefGoogle Scholar
  26. 26.
    Sengupta R, Billiar TR, Atkins JL, Kagan VE, Stoyanovsky DA. (2009) Nitric oxide and dihydrolipoic acid modulate the activity of caspase 3 in HepG2 cells. FEBS Lett. 583:3525–30.CrossRefGoogle Scholar
  27. 27.
    Zamaraev AV, Kopeina GS, Prokhorova EA, Zhivotovsky B, Lavrik IN. (2017) Post-translational Modification of Caspases: The Other Side of Apoptosis Regulation. Trends Cell. Biol. 27:322–39.CrossRefGoogle Scholar
  28. 28.
    Li J, Billiar TR, Talanian RV, Kim YM. (1997) Nitric oxide reversibly inhibits seven members of the caspase family via S-nitrosylation. Biochem. Biophys. Res. Commun. 240:419–24.CrossRefGoogle Scholar
  29. 29.
    Sengupta R, Billiar TR, Atkins JL, Kagan VE, Stoyanovsky DA. (2009) Nitric oxide and dihydrolipoic acid modulate the activity of caspase 3 in HepG2 cells. FEBS Lett. 583:3525–30.CrossRefGoogle Scholar
  30. 30.
    Zhou R, Tardivel A, Thorens B, Choi I, Tschopp J. (2010) Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11:136–40.CrossRefGoogle Scholar
  31. 31.
    Shi CS, et al. Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 13:255–63.Google Scholar
  32. 32.
    Liu T, et al. (2016) TRIM11 Suppresses AIM2 Inflammasome by Degrading AIM2 via p62-Dependent Selective Autophagy. Cell Rep. 16:1988–2002.CrossRefGoogle Scholar
  33. 33.
    Hatakeyama S. (2011) TRIM proteins and cancer. Nat. Rev. Cancer. 11:792–804.CrossRefGoogle Scholar
  34. 34.
    Kimura T, et al. (2015) TRIM-mediated precision autophagy targets cytoplasmic regulators of innate immunity. J. Cell Biol. 210:973–89.CrossRefGoogle Scholar
  35. 35.
    Matsuda N, Tanaka K. (2015) Cell biology: Tagged tags engage disposal. Nature. 524:294–5.CrossRefGoogle Scholar
  36. 36.
    Youle RJ, Narendra DP. Mechanisms of mitophagy. (2011) Nat. Rev. Mol. Cell. Biol. 12:9–14.CrossRefGoogle Scholar
  37. 37.
    Zhong Z, et al. (2016) NF-kappaB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria. Cell. 164:896–910.CrossRefGoogle Scholar
  38. 38.
    Harris J, et al. (2011) Autophagy controls IL-1beta secretion by targeting pro-IL-1beta for degradation. J. Biol. Chem. 286:9587–97.CrossRefGoogle Scholar
  39. 39.
    Wang LJ, et al. (2014) The microtubule-associated protein EB1 links AIM2 inflammasomes with autophagy-dependent secretion. J. Biol. Chem. 289:29322–33.CrossRefGoogle Scholar
  40. 40.
    Dupont N, et al. (2011) Autophagy-based unconventional secretory pathway for extracellular delivery of IL-1beta. EMBO J. 30:4701–11.CrossRefGoogle Scholar
  41. 41.
    Lechtenberg BC, Mace PD, Riedl SJ. (2014) Structural mechanisms in NLR inflammasome signaling. Curr. Opin. Struct. Biol. 29:17–25.CrossRefGoogle Scholar
  42. 42.
    Jounai N, et al. (2011) NLRP4 Negatively Regulates Autophagic Processes through an Association with Beclin1. J. Immunol. 186:1646–55.CrossRefGoogle Scholar
  43. 43.
    Zhang Y, et al. (2014) Endothelial PINK1 mediates the protective effects of NLRP3 deficiency during lethal oxidant injury. J. Immunol. 192:5296–304.CrossRefGoogle Scholar
  44. 44.
    Suzuki T, et al. (2007) Differential regulation of caspase-1 activation, pyroptosis, and autophagy via Ipaf and ASC in Shigella-infected macrophages. PLoS Pathog. 3:1082–91.CrossRefGoogle Scholar
  45. 45.
    Suzuki T, Nunez G. (2008) A role for Nod-like receptors in autophagy induced by Shigella infection. Autophagy. 4:73–5.CrossRefGoogle Scholar
  46. 46.
    Wlodarska M, et al. (2014) NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell. 156:1045–59.CrossRefGoogle Scholar
  47. 47.
    Deng Q, et al. (2015) Pseudomonas aeruginosa Triggers Macrophage Autophagy to Escape Intracellular Killing by Activation of the NLRP3 Inflammasome. Infect. Immun. 84:56–66.CrossRefGoogle Scholar
  48. 48.
    Man SM, Karki R, Kanneganti TD. (2016) AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity. Eur. J. Immunol. 46:269–80.CrossRefGoogle Scholar
  49. 49.
    Dowling JK, O’Neill LAJ. (2012) Biochemical regulation of the inflammasome. Crit. Rev. Biochem. Mol. Biol. 47:424–43.CrossRefGoogle Scholar
  50. 50.
    Hu B, et al. (2016) The DNA-sensing AIM2 inflammasome controls radiation-induced cell death and tissue injury. Science. 354:765–8.CrossRefGoogle Scholar
  51. 51.
    Bodemann BO, et al. (2011) RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell. 144:253–67.CrossRefGoogle Scholar
  52. 52.
    Saiga H, et al. (2015) The Recombinant BCG ΔureC::hly Vaccine Targets the AIM2 Inflammasome to Induce Autophagy and Inflammation. J. Infect. Dis. 211:1831–41.CrossRefGoogle Scholar
  53. 53.
    Sun Q, et al. (2013) Caspase 1 Activation Is Protective against Hepatocyte Cell Death by Up-regulating Beclin 1 Protein and Mitochondrial Autophagy in the Setting of Redox Stress. J. Biol. Chem. 288:15947–58.CrossRefGoogle Scholar
  54. 54.
    Sun Q, Scott MJ. (2016) Caspase-1 as a multifunctional inflammatory mediator: noncytokine maturation roles. J. Leukoc. Biol. 100:961–7.CrossRefGoogle Scholar
  55. 55.
    Yu J, et al. (2014) Inflammasome activation leads to caspase-1-dependent mitochondrial damage and block of mitophagy. Proc. Natl. Acad. Sci. USA. 111:15514–19.CrossRefGoogle Scholar
  56. 56.
    Jabir MS, et al. (2014) Caspase-1 cleavage of the TLR adaptor TRIF inhibits autophagy and beta-interferon production during Pseudomonas aeruginosa infection. Cell Host Microbe. 15:214–27.CrossRefGoogle Scholar
  57. 57.
    Kayagaki N, et al. (2011) Non-canonical inflammasome activation targets caspase-11. Nature. 479:117–21.CrossRefGoogle Scholar
  58. 58.
    Shi J, et al. (2014) Inflammatory caspases are innate immune receptors for intracellular LPS. Nature. 514:187–92.CrossRefGoogle Scholar
  59. 59.
    Sborgi L, et al. (2016) GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 35:1766–78.CrossRefGoogle Scholar
  60. 60.
    He WT, et al. (2015) Gasdermin D is an executor of pyroptosis and required for interleukin-1 beta secretion. Cell Res. 25:1285–98.CrossRefGoogle Scholar
  61. 61.
    Meunier E, et al. (2014) Caspase-11 activation requires lysis of pathogen-containing vacuoles by IFN-induced GTPases. Nature. 509:366–70.CrossRefGoogle Scholar
  62. 62.
    Lupfer CR, et al. (2014) Reactive oxygen species regulate caspase-11 expression and activation of the non-canonical NLRP3 inflammasome during enteric pathogen infection. PLoS Pathog. 10:e1004410.CrossRefGoogle Scholar
  63. 63.
    Akhter A, et al. (2012) Caspase-11 promotes the fusion of phagosomes harboring pathogenic bacteria with lysosomes by modulating actin polymerization. Immunity. 37:35–47.CrossRefGoogle Scholar
  64. 64.
    Roberts JS, Yilmaz. (2015) Dangerous Liaisons: Caspase-11 and Reactive Oxygen Species Crosstalk in Pathogen Elimination. Int. J. Mol. Sci. 16:23337–54.CrossRefGoogle Scholar

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Authors and Affiliations

  • Qian Sun
    • 1
  • Jie Fan
    • 1
    • 2
  • Timothy R. Billiar
    • 1
  • Melanie J. Scott
    • 1
  1. 1.Department of Surgery LabsUniversity of Pittsburgh School of MedicinePittsburghUSA
  2. 2.Research and DevelopmentVeterans Affairs Pittsburgh Healthcare SystemPittsburghUSA

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