Focus on Inflammatory Disease

Inflammasomes: mechanism of action, role in disease, and therapeutics

Journal name:
Nature Medicine
Volume:
21,
Pages:
677–687
Year published:
DOI:
doi:10.1038/nm.3893
Received
Accepted
Published online

Abstract

The inflammasomes are innate immune system receptors and sensors that regulate the activation of caspase-1 and induce inflammation in response to infectious microbes and molecules derived from host proteins. They have been implicated in a host of inflammatory disorders. Recent developments have greatly enhanced our understanding of the molecular mechanisms by which different inflammasomes are activated. Additionally, increasing evidence in mouse models, supported by human data, strongly implicates an involvement of the inflammasome in the initiation or progression of diseases with a high impact on public health, such as metabolic disorders and neurodegenerative diseases. Finally, recent developments pointing toward promising therapeutics that target inflammasome activity in inflammatory diseases have been reported. This review will focus on these three areas of inflammasome research.

At a glance

Figures

  1. Mechanisms of NLRP3 inflammasome activation.
    Figure 1: Mechanisms of NLRP3 inflammasome activation.

    NLRP3 must be primed before activation. Priming involves two distinct steps. First, an NF-κB–activating stimulus, such as LPS binding to TLR4, induces elevated expression of NLRP3 (as well as IL1B), which leads to increased expression of NLRP3 protein. Additionally, priming immediately licenses NLRP3 by inducing its deubiquitination. The adaptor protein ASC must become linearly ubiquitinated and phosphorylated for inflammasome assembly to occur. After priming, canonical NLRP3 inflammasome activation requires a second, distinct signal to activate NLRP3 and lead to the formation of the NLRP3 inflammasome complex. The most commonly accepted activating stimuli for NLRP3 include relocalization of NLRP3 to the mitochondria, the sensation of mitochondrial factors released into the cytosol (mitochondrial ROS, mitochondrial DNA, or cardiolipin), potassium efflux through ion channels, and cathepsin release following destabilization of lysosomal membranes. Recent studies have determined that activated NLRP3 nucleates ASC into prion-like filaments through PYD-PYD interactions. Pro-caspase-1 filaments subsequently form off of the ASC filaments through CARD-CARD interactions, allowing autoproteolytic activation of pro-caspase-1. Inset shows domain arrangement of the NLRP3 inflammasome components. Pro-caspase-1 and caspase-1 domains are simplified for clarity, the CARD domain is actually removed by cleavage, and two heterodimers form with the p20 and p10 effector domains (p20/10).

  2. Mechanisms of NLRC4, AIM2 and noncanonical NLRP3 inflammasome activation.
    Figure 2: Mechanisms of NLRC4, AIM2 and noncanonical NLRP3 inflammasome activation.

    (a) NLRC4 inflammasome agonists such as the bacterial needle protein bind directly to regions within the NACHT domains of the NAIP subfamily of proteins. hNAIP and mNAIP1 bind needle protein, mNAIP2 binds rod protein, and both mNAIP5 and mNAIP6 bind flagellin. Ligand-bound NAIP proteins then oligomerize with NLRC4 to form a caspase-1–activating inflammasome. Though NLRC4 can directly oligomerize with caspase-1 through CARD-CARD interactions, ASC is required for caspase-1 activation by the NLRC4 inflammasome, possibly through the formation of prion-like filaments (blue) by ASC. However, ASC is dispensable for the induction of pyroptosis. Inset shows domain arrangement of NLRC4 inflammasome components. NAIP proteins have three N-terminal BIR domains. hNAIP, human NAIP; mNAIP, mouse NAIP. (b) The mechanism of AIM2 inflammasome activation is well defined. The HIN domain of AIM2 directly binds cytosolic dsDNA, displacing the PYD and relieving autoinhibition. This allows oligomerization of AIM2 PYD with ASC PYD, converting ASC into its prion form. Prion-like filaments of pro-caspase-1 (violet) are then able to form off of the ASC filaments, inducing caspase-1 activation. Inset shows domain arrangement of AIM2 inflammasome components. (c) Studies have determined that mouse pro-caspase-11 (mPro-caspase-11) and human pro-caspases-4 and -5 (hPro-caspase-4/5) can directly bind intracellular LPS and activate a noncanonical NLRP3 inflammasome. This induces oligomerization of these pro-caspases, leading to their proximity-induced activation. This is sufficient for the induction of pyroptosis but not for the processing of pro-IL-1β. However, active mCaspase-11 and hCaspase-4 can promote full assembly and activation of the NLRP3 inflammasome following a priming signal.

  3. Mechanisms of NLRP3 inflammasome action in Alzheimer's disease.
    Figure 3: Mechanisms of NLRP3 inflammasome action in Alzheimer's disease.

    In Alzheimer's disease, CD36 mediates the internalization of soluble amyloid-β and its intracellular conversion to fibrillary amyloid-β. This leads to disruption of the phagolysosome and activation of the NLRP3 inflammasome due to cathepsin B release. However, this does not exclude the possibility that phagocytosis of extracellular fibrillary amyloid-β also activates the NLRP3 inflammasome. Cathepsin B inhibition prevents amyloid-β–induced NLRP3 activation.

  4. Mechanism of inflammasome activation in inflammatory disease.
    Figure 4: Mechanism of inflammasome activation in inflammatory disease.

    (a) In atherosclerosis, free fatty acids (FFA) can prime the NLRP3 inflammasome through TLR2-TLR4 signaling. Additionally, oxidized low-density lipoprotein (oxLDL) primes the NLRP3 inflammasome through a CD36-TLR4-TLR6 signaling complex. CD36 also facilitates the internalization of oxLDL and its intracellular conversion to cholesterol crystals, which disrupt the phagolysosome and activate the NLRP3 inflammasome through cathepsin release. Phagocytosis of extracellular cholesterol crystals may also contribute to inflammasome activation. Cathepsin inhibition prevents the NLRP3 inflammasome activation induced by cholesterol crystals. (b) In type 2 diabetes (T2D), the NLRP3 inflammasome is activated in both islet β-cells and myeloid cells. In β-cells, elevated glucose increases thioredoxin (TRX)-interacting protein (TXNIP). Intracellular ROS also causes a conformational change in TXNIP, leading to its dissociation from TRX. TXNIP then binds NLRP3 and promotes NLRP3 inflammasome activation. In myeloid cells, the endocannabinoid anandamide binds the CB1 receptor to increase the expression of NLRP3, ASC and IL1B. Saturated fatty acid (SFA) inhibits intracellular AMP-activated protein kinase (AMPK). This decreases autophagy, which leads to an increase in mitochondrial ROS (mtROS), a known NLRP3 inflammasome stimulus. CD36 facilitates the internalization of soluble islet amyloid polypeptide (IAPP), which is converted intracellularly to its amyloid form. This disrupts the phagolysosome and activates the NLRP3 inflammasome due to cathepsin release. As the amyloid form of IAPP builds up in the pancreatic islets of individuals with T2D, phagocytosis of extracellular amyloid IAPP may also contribute to NLRP3 inflammasome activation.

References

  1. Chen, G.Y. & Nunez, G. Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10, 826837 (2010).
  2. Takeuchi, O. & Akira, S. Pattern recognition receptors and inflammation. Cell 140, 805820 (2010).
  3. Lamkanfi, M. & Dixit, V.M. Inflammasomes and their roles in health and disease. Annu. Rev. Cell Dev. Biol. 28, 137161 (2012).
  4. Strowig, T., Henao-Mejia, J., Elinav, E. & Flavell, R. Inflammasomes in health and disease. Nature 481, 278286 (2012).
  5. Wen, H., Miao, E.A. & Ting, J.P. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39, 432441 (2013).
  6. Vanaja, S.K., Rathinam, V.A. & Fitzgerald, K.A. Mechanisms of inflammasome activation: recent advances and novel insights. Trends Cell Biol. 25, 308315 (2015).
  7. Lamkanfi, M. & Dixit, V.M. Mechanisms and functions of inflammasomes. Cell 157, 10131022 (2014).
  8. Sutterwala, F.S., Haasken, S. & Cassel, S.L. Mechanism of NLRP3 inflammasome activation. Ann. NY Acad. Sci. 1319, 8295 (2014).
  9. Martinon, F., Burns, K. & Tschopp, J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10, 417426 (2002).
  10. Yang, X., Chang, H.Y. & Baltimore, D. Autoproteolytic activation of pro-caspases by oligomerization. Mol. Cell 1, 319325 (1998).
  11. Howard, A.D. et al. IL-1-converting enzyme requires aspartic acid residues for processing of the IL-1 beta precursor at two distinct sites and does not cleave 31-kDa IL-1 alpha. J. Immunol. 147, 29642969 (1991).
  12. Gu, Y. et al. Activation of interferon-gamma inducing factor mediated by interleukin-1beta converting enzyme. Science 275, 206209 (1997).
  13. Ghayur, T. et al. Caspase-1 processes IFN-γ-inducing factor and regulates LPS-induced IFN-γ production. Nature 386, 619623 (1997).
  14. Vance, R.E. The NAIP/NLRC4 inflammasomes. Curr. Opin. Immunol. 32, 8489 (2015).
  15. Poyet, J.L. et al. Identification of Ipaf, a human caspase-1-activating protein related to Apaf-1. J. Biol. Chem. 276, 2830928313 (2001).
  16. Srinivasula, S.M. et al. The PYRIN-CARD protein ASC is an activating adaptor for caspase-1. J. Biol. Chem. 277, 2111921122 (2002).
  17. Hornung, V. et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458, 514518 (2009).
  18. Chavarría-Smith, J. & Vance, R.E. The NLRP1 inflammasomes. Immunol. Rev. 265, 2234 (2015).
  19. Ratsimandresy, R.A., Dorfleutner, A. & Stehlik, C. An update on PYRIN domain-containing pattern recognition receptors: from immunity to pathology. Front.Immunol. 4, 440 (2013).
  20. Rathinam, V.A., Vanaja, S.K. & Fitzgerald, K.A. Regulation of inflammasome signaling. Nat. Immunol. 13, 333342 (2012).
  21. Murakami, T. et al. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc. Natl. Acad. Sci. USA 109, 1128211287 (2012).
  22. Lee, G.S. et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492, 123127 (2012).
  23. Katsnelson, M.A., Rucker, L.G., Russo, H.M. & Dubyak, G.R. K+ efflux agonists induce NLRP3 inflammasome activation independently of Ca2+ signaling. J. Immunol. 194, 39373952 (2015).
  24. Dostert, C. et al. Malarial hemozoin is a Nalp3 inflammasome activating danger signal. PLoS ONE 4, e6510 (2009).
  25. Bauernfeind, F.G. et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 183, 787791 (2009).
  26. Juliana, C. et al. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J. Biol. Chem. 287, 3661736622 (2012).
  27. Py, B.F., Kim, M.S., Vakifahmetoglu-Norberg, H. & Yuan, J. Deubiquitination of NLRP3 by BRCC3 critically regulates inflammasome activity. Mol. Cell 49, 331338 (2013).
  28. Rodgers, M.A. et al. The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J. Exp. Med. 211, 13331347 (2014).
  29. Lu, A. et al. Unified polymerization mechanism for the assembly of ASC-dependent inflammasomes. Cell 156, 11931206 (2014).
  30. Cai, X. et al. Prion-like polymerization underlies signal transduction in antiviral immune defense and inflammasome activation. Cell 156, 12071222 (2014).
  31. Salvesen, G.S. & Walsh, C.M. Functions of caspase 8: the identified and the mysterious. Semin. Immunol. 26, 246252 (2014).
  32. Ganesan, S. et al. Caspase-8 modulates dectin-1 and complement receptor 3-driven IL-1β production in response to β-glucans and the fungal pathogen, Candida albicans. J. Immunol. 193, 25192530 (2014).
  33. Gurung, P. et al. FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J. Immunol. 192, 18351846 (2014).
  34. Allam, R. et al. Mitochondrial apoptosis is dispensable for NLRP3 inflammasome activation but non-apoptotic caspase-8 is required for inflammasome priming. EMBO Rep. 15, 982990 (2014).
  35. Sagulenko, V. et al. AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC. Cell Death Differ. 20, 11491160 (2013).
  36. Man, S.M. et al. Salmonella infection induces recruitment of Caspase-8 to the inflammasome to modulate IL-1β production. J. Immunol. 191, 52395246 (2013).
  37. Gringhuis, S.I. et al. Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1β via a noncanonical caspase-8 inflammasome. Nat. Immunol. 13, 246254 (2012).
  38. Monie, T.P. & Bryant, C.E. Caspase-8 functions as a key mediator of inflammation and pro-IL-1β processing via both canonical and non-canonical pathways. Immunol. Rev. 265, 181193 (2015).
  39. Tenthorey, J.L., Kofoed, E.M., Daugherty, M.D., Malik, H.S. & Vance, R.E. Molecular basis for specific recognition of bacterial ligands by NAIP/NLRC4 inflammasomes. Mol. Cell 54, 1729 (2014).
  40. Yang, J., Zhao, Y., Shi, J. & Shao, F. Human NAIP and mouse NAIP1 recognize bacterial type III secretion needle protein for inflammasome activation. Proc. Natl. Acad. Sci. USA 110, 1440814413 (2013).
  41. Rayamajhi, M., Zak, D.E., Chavarria-Smith, J., Vance, R.E. & Miao, E.A. Cutting edge: mouse NAIP1 detects the type III secretion system needle protein. J. Immunol. 191, 39863989 (2013).
  42. Kofoed, E.M. & Vance, R.E. Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477, 592595 (2011).
  43. Zhao, Y. et al. The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477, 596600 (2011).
  44. Canna, S.W. et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat. Genet. 46, 11401146 (2014).
  45. Romberg, N. et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat. Genet. 46, 11351139 (2014).
  46. Qu, Y. et al. Phosphorylation of NLRC4 is critical for inflammasome activation. Nature 490, 539542 (2012).
  47. Matusiak, M. et al. Flagellin-induced NLRC4 phosphorylation primes the inflammasome for activation by NAIP5. Proc. Natl. Acad. Sci. USA 112, 15411546 (2015).
  48. Jin, T. et al. Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity 36, 561571 (2012).
  49. Fernandes-Alnemri, T., Yu, J.W., Datta, P., Wu, J. & Alnemri, E.S. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458, 509513 (2009).
  50. Jin, T., Perry, A., Smith, P., Jiang, J. & Xiao, T.S. Structure of the absent in melanoma 2 (AIM2) pyrin domain provides insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly. J. Biol. Chem. 288, 1322513235 (2013).
  51. Man, S.M. et al. The transcription factor IRF1 and guanylate-binding proteins target activation of the AIM2 inflammasome by Francisella infection. Nat. Immunol. 16, 467475 (2015).
  52. Kang, S.J. et al. Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J. Cell Biol. 149, 613622 (2000).
  53. Kayagaki, N. et al. Non-canonical inflammasome activation targets caspase-11. Nature 479, 117121 (2011).
  54. Kayagaki, N. et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341, 12461249 (2013).
  55. Hagar, J.A., Powell, D.A., Aachoui, Y., Ernst, R.K. & Miao, E.A. Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341, 12501253 (2013).
  56. Shi, J. et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature 514, 187192 (2014).
  57. Kajiwara, Y. et al. A critical role for human caspase-4 in endotoxin sensitivity. J. Immunol. 193, 335343 (2014).
  58. Huang, M.T. et al. Critical role of apoptotic speck protein containing a caspase recruitment domain (ASC) and NLRP3 in causing necrosis and ASC speck formation induced by Porphyromonas gingivalis in human cells. J. Immunol. 182, 23952404 (2009).
  59. Bryan, N.B., Dorfleutner, A., Rojanasakul, Y. & Stehlik, C. Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain. J. Immunol. 182, 31733182 (2009).
  60. Franklin, B.S. et al. The adaptor ASC has extracellular and 'prionoid' activities that propagate inflammation. Nat. Immunol. 15, 727737 (2014).
  61. Hara, H. et al. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat. Immunol. 14, 12471255 (2013).
  62. Goverman, J. Autoimmune T cell responses in the central nervous system. Nat. Rev. Immunol. 9, 393407 (2009).
  63. Compston, A. & Coles, A. Multiple sclerosis. Lancet 372, 15021517 (2008).
  64. Gris, D. et al. NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J. Immunol. 185, 974981 (2010).
  65. Matsuki, T., Nakae, S., Sudo, K., Horai, R. & Iwakura, Y. Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int. Immunol. 18, 399407 (2006).
  66. Furlan, R. et al. Caspase-1 regulates the inflammatory process leading to autoimmune demyelination. J. Immunol. 163, 24032409 (1999).
  67. Shi, F.D., Takeda, K., Akira, S., Sarvetnick, N. & Ljunggren, H.G. IL-18 directs autoreactive T cells and promotes autodestruction in the central nervous system via induction of IFN-gamma by NK cells. J. Immunol. 165, 30993104 (2000).
  68. Inoue, M., Williams, K.L., Gunn, M.D. & Shinohara, M.L. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc. Natl. Acad. Sci. USA 109, 1048010485 (2012).
  69. Jha, S. et al. The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J. Neurosci. 30, 1581115820 (2010).
  70. Peelen, E. et al. Increased inflammasome related gene expression profile in PBMC may facilitate T helper 17 cell induction in multiple sclerosis. Mol. Immunol. 63, 521529 (2015).
  71. Inoue, M. et al. Interferon-beta therapy against EAE is effective only when development of the disease depends on the NLRP3 inflammasome. Sci. Signal. 5, ra38 (2012).
  72. Shaw, P.J. et al. Cutting edge: critical role for PYCARD/ASC in the development of experimental autoimmune encephalomyelitis. J. Immunol. 184, 46104614 (2010).
  73. Dumas, A. et al. The inflammasome pyrin contributes to pertussis toxin-induced IL-1beta synthesis, neutrophil intravascular crawling and autoimmune encephalomyelitis. PLoS Pathog. 10, e1004150 (2014).
  74. Heneka, M.T., Golenbock, D.T. & Latz, E. Innate immunity in Alzheimer's disease. Nat. Immunol. 16, 229236 (2015).
  75. Halle, A. et al. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol. 9, 857865 (2008).
  76. Hook, V.Y., Kindy, M. & Hook, G. Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein. J. Biol. Chem. 283, 77457753 (2008).
  77. Sheedy, F.J. et al. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol. 14, 812820 (2013).
  78. Heneka, M.T. et al. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature 493, 674678 (2013).
  79. Shulman, J.M., De Jager, P.L. & Feany, M.B. Parkinson's disease: genetics and pathogenesis. Annu. Rev. Pathol. 6, 193222 (2011).
  80. Chiti, F. & Dobson, C.M. Protein misfolding, functional amyloid, and human disease. Annu. Rev. Biochem. 75, 333366 (2006).
  81. Lee, S.J. Origins and effects of extracellular alpha-synuclein: implications in Parkinson's disease. J. Mol. Neurosci. 34, 1722 (2008).
  82. Béraud, D. & Maguire-Zeiss, K.A. Misfolded alpha-synuclein and Toll-like receptors: therapeutic targets for Parkinson's disease. Parkinsonism Relat. Disord. 18 (suppl. 1), S17S20 (2012).
  83. Ferrari, C.C. et al. Progressive neurodegeneration and motor disabilities induced by chronic expression of IL-1beta in the substantia nigra. Neurobiol. Dis. 24, 183193 (2006).
  84. Codolo, G. et al. Triggering of inflammasome by aggregated alpha-synuclein, an inflammatory response in synucleinopathies. PLoS ONE 8, e55375 (2013).
  85. Yan, Y. et al. Dopamine controls systemic inflammation through inhibition of NLRP3 inflammasome. Cell 160, 6273 (2015).
  86. Robbins, G.R., Wen, H. & Ting, J.P. Inflammasomes and metabolic disorders: old genes in modern diseases. Mol. Cell 54, 297308 (2014).
  87. Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17, 14101422 (2011).
  88. Duewell, P. et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 13571361 (2010).
  89. Elhage, R. et al. Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice. Cardiovasc. Res. 59, 234240 (2003).
  90. Mallat, Z. et al. Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ. Res. 89, E41E45 (2001).
  91. Tan, H.W. et al. IL-18 overexpression promotes vascular inflammation and remodeling in a rat model of metabolic syndrome. Atherosclerosis 208, 350357 (2010).
  92. de Nooijer, R. et al. Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice. Arterioscler. Thromb. Vasc. Biol. 24, 23132319 (2004).
  93. Masters, S.L., Latz, E. & O'Neill, L.A. The inflammasome in atherosclerosis and type 2 diabetes. Sci. Transl. Med. 3, 81ps17 (2011).
  94. Kirii, H. et al. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler. Thromb. Vasc. Biol. 23, 656660 (2003).
  95. Bhaskar, V. et al. Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in Apolipoprotein E-deficient mice. Atherosclerosis 216, 313320 (2011).
  96. Freigang, S. et al. Fatty acid–induced mitochondrial uncoupling elicits inflammasome-independent IL-1α and sterile vascular inflammation in atherosclerosis. Nat. Immunol. 14, 10451053 (2013).
  97. Menu, P. et al. Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome. Cell Death Dis. 2, e137 (2011).
  98. Donath, M.Y. & Shoelson, S.E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98107 (2011).
  99. Wen, H. et al. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat. Immunol. 12, 408415 (2011).
  100. Hotamisligil, G.S., Shargill, N.S. & Spiegelman, B.M. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259, 8791 (1993).
  101. Legrand-Poels, S. et al. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochem. Pharmacol. 92, 131141 (2014).
  102. Larsen, C.M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 15171526 (2007).
  103. Mandrup-Poulsen, T., Pickersgill, L. & Donath, M.Y. Blockade of interleukin 1 in type 1 diabetes mellitus. Nat. Rev. Endocrinol. 6, 158166 (2010).
  104. Cavelti-Weder, C. et al. Inhibition of IL-1beta improves fatigue in type 2 diabetes. Diabetes Care 34, e158 (2011).
  105. Lee, H.M. et al. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes 62, 194204 (2013).
  106. Stienstra, R. et al. Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl. Acad. Sci. USA 108, 1532415329 (2011).
  107. Vandanmagsar, B. et al. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179188 (2011).
  108. Zhou, R., Tardivel, A., Thorens, B., Choi, I. & Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 11, 136140 (2010).
  109. Stienstra, R., Tack, C.J., Kanneganti, T.D., Joosten, L.A. & Netea, M.G. The inflammasome puts obesity in the danger zone. Cell Metab. 15, 1018 (2012).
  110. Cooper, G.J. et al. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc. Natl. Acad. Sci. USA 84, 86288632 (1987).
  111. Masters, S.L. et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat. Immunol. 11, 897904 (2010).
  112. Janson, J. et al. Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc. Natl. Acad. Sci. USA 93, 72837288 (1996).
  113. Maedler, K. et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J. Clin. Invest. 110, 851860 (2002).
  114. Jourdan, T. et al. Activation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes. Nat. Med. 19, 11321140 (2013).
  115. Finucane, O.M. et al. Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1beta secretion and insulin resistance despite obesity. Diabetes 64, 21162128 (2015).
  116. Yan, Y. et al. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 38, 11541163 (2013).
  117. L'Homme, L. et al. Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages. J. Lipid Res. 54, 29983008 (2013).
  118. Guilherme, A., Virbasius, J.V., Puri, V. & Czech, M.P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 367377 (2008).
  119. Yin, Z. et al. Transcriptome analysis of human adipocytes implicates the NOD-like receptor pathway in obesity-induced adipose inflammation. Mol. Cell. Endocrinol. 394, 8087 (2014).
  120. Stienstra, R. et al. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 12, 593605 (2010).
  121. Wang, H., Capell, W., Yoon, J.H., Faubel, S. & Eckel, R.H. Obesity development in caspase-1-deficient mice. Int. J. Obes. (Lond). 38, 152155 (2014).
  122. Tremaroli, V. & Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242249 (2012).
  123. Netea, M.G. et al. Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance. Nat. Med. 12, 650656 (2006).
  124. Patel, M.N. et al. Hematopoietic IKBKE limits the chronicity of inflammasome priming and metaflammation. Proc. Natl. Acad. Sci. USA 112, 506511 (2015).
  125. Weisberg, S.P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 17961808 (2003).
  126. Kotas, M.E. et al. Role of caspase-1 in regulation of triglyceride metabolism. Proc. Natl. Acad. Sci. USA 110, 48104815 (2013).
  127. Chalkiadaki, A. & Guarente, L. High-fat diet triggers inflammation-induced cleavage of SIRT1 in adipose tissue to promote metabolic dysfunction. Cell Metab. 16, 180188 (2012).
  128. Nagareddy, P.R. et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 19, 821835 (2014).
  129. Jesus, A.A. & Goldbach-Mansky, R. IL-1 blockade in autoinflammatory syndromes. Annu. Rev. Med. 65, 223244 (2014).
  130. Dinarello, C.A., Novick, D., Kim, S. & Kaplanski, G. Interleukin-18 and IL-18 binding protein. Front. Immunol. 4, 289 (2013).
  131. Brydges, S.D. et al. Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. J. Clin. Invest. 123, 46954705 (2013).
  132. Lamkanfi, M. et al. Glyburide inhibits the Cryopyrin/Nalp3 inflammasome. J. Cell Biol. 187, 6170 (2009).
  133. Fowler, B.J. et al. Nucleoside reverse transcriptase inhibitors possess intrinsic anti-inflammatory activity. Science 346, 10001003 (2014).
  134. Juliana, C. et al. Anti-inflammatory compounds parthenolide and Bay 11–7082 are direct inhibitors of the inflammasome. J. Biol. Chem. 285, 97929802 (2010).
  135. Coll, R.C., Robertson, A., Butler, M., Cooper, M. & O'Neill, L.A. The cytokine release inhibitory drug CRID3 targets ASC oligomerisation in the NLRP3 and AIM2 inflammasomes. PLoS ONE 6, e29539 (2011).
  136. Isakov, E., Weisman-Shomer, P. & Benhar, M. Suppression of the pro-inflammatory NLRP3/interleukin-1beta pathway in macrophages by the thioredoxin reductase inhibitor auranofin. Biochim. Biophys. Acta 1840, 31533161 (2014).
  137. Honda, H. et al. Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation. J. Leukoc. Biol. 96, 10871100 (2014).
  138. He, Y. et al. 3,4-methylenedioxy-β-nitrostyrene inhibits NLRP3 inflammasome activation by blocking assembly of the inflammasome. J. Biol. Chem. 289, 11421150 (2014).
  139. Maier, N.K., Leppla, S.H. & Moayeri, M. The cyclopentenone prostaglandin 15d-PGJ2 inhibits the NLRP1 and NLRP3 inflammasomes. J. Immunol. 194, 277685 (2015).
  140. Reboldi, A. et al. Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 345, 679684 (2014).
  141. Youm, Y.H. et al. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat. Med. 21, 263269 (2015).
  142. Coll, R.C. et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat. Med. 21, 248255 (2015).
  143. Guarda, G. et al. Type I interferon inhibits interleukin-1 production and inflammasome activation. Immunity 34, 213223 (2011).

Download references

Author information

  1. These authors contributed equally to this work.

    • Haitao Guo &
    • Justin B Callaway

Affiliations

  1. The Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Haitao Guo,
    • Justin B Callaway &
    • Jenny P-Y Ting
  2. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Jenny P-Y Ting

Competing financial interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to:

Author details

Additional data