and Metabolic Disease

Innate immune response pathways and metabolic pathways are evolutionarily conserved throughout species and are fundamental to survival. As such, the regulation of whole-body and cellular metabolism is intimately integrated with immune responses. However, the introduction of new variables to this delicate evolutionarily conserved physiological interaction can lead to deleterious consequences for organisms as a result of inappropriate immune responses. In recent decades, the prevalence and incidence of metabolic diseases associated with obesity have dramatically increased worldwide. As a recently acquired human characteristic, obesity has exposed the critical role of innate immune pathways in multiple metabolic pathophysiological processes. Here, we review recent evidence that highlights inflammasomes as critical sensors of metabolic perturbations in multiple tissues and their role in the progression of highly prevalent metabolic diseases.

[1]  G. Garg,et al.  Risk factors of non-alcoholic fatty liver disease in patients with inflammatory bowel disease. , 2013, Journal of Crohn's & colitis.

[2]  E. Latz,et al.  Activation and regulation of the inflammasomes , 2013, Nature Reviews Immunology.

[3]  R. Flavell,et al.  NALP3-mediated inflammation is a principal cause of progressive renal failure in oxalate nephropathy , 2013, Kidney international.

[4]  K. Schroder,et al.  AIM2 and NLRP3 inflammasomes activate both apoptotic and pyroptotic death pathways via ASC , 2013, Cell Death and Differentiation.

[5]  Liang Zheng,et al.  Succinate is an inflammatory signal that induces IL-1β through HIF-1α , 2013, Nature.

[6]  Fernanda S. Oliveira,et al.  Critical Role of ASC Inflammasomes and Bacterial Type IV Secretion System in Caspase-1 Activation and Host Innate Resistance to Brucella abortus Infection , 2013, The Journal of Immunology.

[7]  S. Akira,et al.  Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome , 2013, Nature Immunology.

[8]  F. Sutterwala,et al.  TRPM2 links oxidative stress to the NLRP3 inflammasome activation , 2013, Nature Communications.

[9]  Kazuhide Yamamoto,et al.  Role of gut microbiota in liver diseases , 2013, Hepatology research : the official journal of the Japan Society of Hepatology.

[10]  J. Tanti,et al.  Implication of inflammatory signaling pathways in obesity-induced insulin resistance , 2013, Front. Endocrin..

[11]  H. Anders,et al.  Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1β secretion. , 2013, The Journal of clinical investigation.

[12]  M. Heneka,et al.  NLRP3 is activated in Alzheimer´s disease and contributes to pathology in APP/PS1 mice , 2012, Nature.

[13]  E. Elinav,et al.  The intestinal microbiota in chronic liver disease. , 2013, Advances in immunology.

[14]  R. Weiskirchen,et al.  Expression analysis of inflammasomes in experimental models of inflammatory and fibrotic liver disease , 2012, Journal of Inflammation.

[15]  S. Hida,et al.  Critical role of caspase-1 in vascular inflammation and development of atherosclerosis in Western diet-fed apolipoprotein E-deficient mice. , 2012, Biochemical and biophysical research communications.

[16]  C. Siu,et al.  Prognostic implications of surrogate markers of atherosclerosis in low to intermediate risk patients with Type 2 Diabetes , 2012, Cardiovascular Diabetology.

[17]  Jos W. M. van der Meer,et al.  Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases , 2012, Nature Reviews Drug Discovery.

[18]  Kenta Moriwaki,et al.  The RIP1/RIP3 Necrosome Forms a Functional Amyloid Signaling Complex Required for Programmed Necrosis , 2012, Cell.

[19]  S. Subramanian,et al.  Toll-Like Receptor 4 Deficiency Decreases Atherosclerosis But Does Not Protect Against Inflammation in Obese Low-Density Lipoprotein Receptor–Deficient Mice , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[20]  E. Podrez,et al.  Akt3 deficiency in macrophages promotes foam cell formation and atherosclerosis in mice. , 2012, Cell metabolism.

[21]  P. Cresswell,et al.  GBP5 Promotes NLRP3 Inflammasome Assembly and Immunity in Mammals , 2012, Science.

[22]  A. Bowie,et al.  Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. , 2012, Immunity.

[23]  T. Kadowaki,et al.  Saturated fatty acid and TLR signaling link β cell dysfunction and islet inflammation. , 2012, Cell metabolism.

[24]  Y. Rojanasakul,et al.  An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. , 2012, Immunity.

[25]  E. Elinav,et al.  Inflammasomes: far beyond inflammation , 2012, Nature Immunology.

[26]  Haitao Wen,et al.  A role for the NLRP3 inflammasome in metabolic diseases—did Warburg miss inflammation? , 2012, Nature Immunology.

[27]  G. Shulman,et al.  Mechanisms for Insulin Resistance: Common Threads and Missing Links , 2012, Cell.

[28]  J. Gage,et al.  Caspase-1 deficiency decreases atherosclerosis in apolipoprotein E-null mice. , 2012, The Canadian journal of cardiology.

[29]  N. Nakasone,et al.  Inflammasome activation via intracellular NLRs triggered by bacterial infection , 2012, Cellular microbiology.

[30]  Richard A. Flavell,et al.  Inflammasomes in health and disease , 2012, Nature.

[31]  Richard A. Flavell,et al.  Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity , 2012, Nature.

[32]  A. So,et al.  Osteoarthritis: Crystal-gazing into the pathogenesis of osteoarthritis , 2011, Nature Reviews Rheumatology.

[33]  Hyon K. Choi,et al.  Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. , 2011, Arthritis and rheumatism.

[34]  Hao Xu,et al.  The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus , 2011, Nature.

[35]  R. Flavell,et al.  NLRP3 inflammasome plays a critical role in the pathogenesis of hydroxyapatite-associated arthropathy , 2011, Proceedings of the National Academy of Sciences.

[36]  E. Latz,et al.  NLRP3 inflammasomes link inflammation and metabolic disease. , 2011, Trends in immunology.

[37]  R. Vance,et al.  Innate immune recognition of bacterial ligands by NAIPs dictates inflammasome specificity , 2011, Nature.

[38]  Anna K Rieger,et al.  Cutting Edge: Reactive Oxygen Species Inhibitors Block Priming, but Not Activation, of the NLRP3 Inflammasome , 2011, The Journal of Immunology.

[39]  A. Dolganiuc,et al.  Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells , 2011, Hepatology.

[40]  E. Elinav,et al.  Regulation of the antimicrobial response by NLR proteins. , 2011, Immunity.

[41]  Richard A. Flavell,et al.  NLRP6 Inflammasome Regulates Colonic Microbial Ecology and Risk for Colitis , 2011, Cell.

[42]  Michael J. Davis,et al.  Sensing prokaryotic mRNA signifies microbial viability and promotes immunity , 2011, Nature.

[43]  A. So,et al.  Extended Report , 2022 .

[44]  Denis Gris,et al.  Fatty acid–induced NLRP3-ASC inflammasome activation interferes with insulin signaling , 2011, Nature Immunology.

[45]  Ping Zhang,et al.  Alum interaction with dendritic cell membrane lipids is essential for its adjuvanticity , 2011, Nature Medicine.

[46]  S. Tangye,et al.  Inflammatory Mechanisms in Obesity , 2013 .

[47]  G. Hansson,et al.  The immune system in atherosclerosis , 2011, Nature Immunology.

[48]  J. Tschopp,et al.  Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome , 2011, Cell Death and Disease.

[49]  T. Roger,et al.  Basic Calcium Phosphate Crystals Induce Monocyte/Macrophage IL-1β Secretion through the NLRP3 Inflammasome In Vitro , 2011, The Journal of Immunology.

[50]  S. Shoelson,et al.  Type 2 diabetes as an inflammatory disease , 2011, Nature Reviews Immunology.

[51]  A. C. Könner,et al.  Toll-like receptors: linking inflammation to metabolism , 2011, Trends in Endocrinology & Metabolism.

[52]  Kim M. Huffman,et al.  Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation , 2011, Proceedings of the National Academy of Sciences.

[53]  J. Tschopp,et al.  A role for mitochondria in NLRP3 inflammasome activation , 2011, Nature.

[54]  E. Ravussin,et al.  The NALP3/NLRP3 Inflammasome Instigates Obesity-Induced Autoinflammation and Insulin Resistance , 2010, Nature Medicine.

[55]  L. Joosten,et al.  The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. , 2010, Cell metabolism.

[56]  K. Moore,et al.  Atherogenic lipids and lipoproteins trigger CD36-TLR2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. , 2010, Cell metabolism.

[57]  E. Podrez,et al.  Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands , 2010, Nature.

[58]  A. So,et al.  Canakinumab for the treatment of acute flares in difficult-to-treat gouty arthritis: Results of a multicenter, phase II, dose-ranging study. , 2010, Arthritis and rheumatism.

[59]  Christine E. Becker,et al.  Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes , 2010, Nature Immunology.

[60]  M. Donath,et al.  Role of IL-1β in type 2 diabetes , 2010, Current opinion in endocrinology, diabetes, and obesity.

[61]  D. Brenner,et al.  Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. , 2010, Gastroenterology.

[62]  Eva Szomolanyi-Tsuda,et al.  The AIM2 inflammasome is essential for host-defense against cytosolic bacteria and DNA viruses , 2010, Nature Immunology.

[63]  A. Iwasaki,et al.  Influenza virus activates inflammasomes through intracellular M2 channel , 2010, Nature Immunology.

[64]  P. Ricciardi-Castagnoli,et al.  The controversial relationship between NLRP3, alum, danger signals and the next‐generation adjuvants , 2010, European journal of immunology.

[65]  K. Moore,et al.  NLRP3 inflamasomes are required for atherogenesis and activated by cholesterol crystals that form early in disease , 2010, Nature.

[66]  E. Latz The inflammasomes: mechanisms of activation and function. , 2010, Current opinion in immunology.

[67]  J. Tschopp,et al.  Thioredoxin-interacting protein links oxidative stress to inflammasome activation , 2010, Nature Immunology.

[68]  Kate Schroder,et al.  The NLRP3 Inflammasome: A Sensor for Metabolic Danger? , 2010, Science.

[69]  B. Dahlöf,et al.  Cardiovascular disease risk factors: epidemiology and risk assessment. , 2010, The American journal of cardiology.

[70]  F. Sutterwala,et al.  Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome , 2009, Proceedings of the National Academy of Sciences.

[71]  I. Verma,et al.  Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. , 2009, Cell metabolism.

[72]  G. Lacraz,et al.  IL-1 antagonism reduces hyperglycemia and tissue inflammation in the type 2 diabetic GK rat , 2009, Proceedings of the National Academy of Sciences.

[73]  R. Terkeltaub,et al.  The interleukin 1 inhibitor rilonacept in treatment of chronic gouty arthritis: results of a placebo-controlled, monosequence crossover, non-randomised, single-blind pilot study , 2009, Annals of the rheumatic diseases.

[74]  E. Alnemri,et al.  Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 Expression1 , 2009, The Journal of Immunology.

[75]  G. Núñez,et al.  Cutting Edge: TNF-α Mediates Sensitization to ATP and Silica via the NLRP3 Inflammasome in the Absence of Microbial Stimulation1 , 2009, The Journal of Immunology.

[76]  R. Medzhitov Approaching the asymptote: 20 years later. , 2009, Immunity.

[77]  R. Terkeltaub,et al.  Hyperalgesia, synovitis and multiple biomarkers of inflammation are suppressed by interleukin 1 inhibition in a novel animal model of gouty arthritis , 2009, Annals of the rheumatic diseases.

[78]  J. Bastard,et al.  The role of interleukins in insulin resistance and type 2 diabetes mellitus , 2009, Nature Reviews Endocrinology.

[79]  G. La Torre,et al.  Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease , 2009, Hepatology.

[80]  F. Martinon,et al.  The inflammasomes: guardians of the body. , 2009, Annual review of immunology.

[81]  B. Cookson,et al.  Pyroptosis: host cell death and inflammation , 2009, Nature Reviews Microbiology.

[82]  W. Martin,et al.  Resident macrophages initiating and driving inflammation in a monosodium urate monohydrate crystal-induced murine peritoneal model of acute gout. , 2009, Arthritis and rheumatism.

[83]  Marnie L. Gruen,et al.  Impact of macrophage toll-like receptor 4 deficiency on macrophage infiltration into adipose tissue and the artery wall in mice , 2009, Diabetologia.

[84]  M. Lemoine,et al.  Definition and natural history of metabolic steatosis: clinical aspects of NAFLD, NASH and cirrhosis. , 2008, Diabetes & metabolism.

[85]  E. Zorrilla,et al.  Insights into the roles of the inflammatory mediators IL-1, IL-18 and PGE2 in obesity and insulin resistance. , 2008, Swiss medical weekly.

[86]  H. Hammad,et al.  Cutting Edge: Alum Adjuvant Stimulates Inflammatory Dendritic Cells through Activation of the NALP3 Inflammasome , 2008, The Journal of Immunology.

[87]  S. Amar,et al.  Toll-Like Receptor-2 Mediates Diet and/or Pathogen Associated Atherosclerosis: Proteomic Findings , 2008, PloS one.

[88]  K. Rock,et al.  Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization , 2008, Nature Immunology.

[89]  K. Moore,et al.  The NALP3 inflammasome is involved in the innate immune response to amyloid-β , 2008, Nature Immunology.

[90]  F. Re,et al.  Cutting Edge: Inflammasome Activation by Alum and Alum’s Adjuvant Effect Are Mediated by NLRP31 , 2008, The Journal of Immunology.

[91]  Richard A. Flavell,et al.  The Nalp3 inflammasome is essential for the development of silicosis , 2008, Proceedings of the National Academy of Sciences.

[92]  R. Medzhitov Origin and physiological roles of inflammation , 2008, Nature.

[93]  Richard A. Flavell,et al.  Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants , 2008, Nature.

[94]  V. Nizet,et al.  A Nod2–nalp1 Complex Mediates Caspase-1-dependent Il-1␤ Secretion in Response to Bacillus Anthracis Infection and Muramyl Dipeptide Nod2, a Nod-like Receptor (nlr), Is an Intracellular Sensor of Bacterial Muramyl Dipeptide (mdp) That Was Suggested to Promote Secretion of the Proinflammatory Cytokine , 2022 .

[95]  A. Surprenant,et al.  P2X7 Receptor Differentially Couples to Distinct Release Pathways for IL-1β in Mouse Macrophage1 , 2008, The Journal of Immunology.

[96]  J. Tschopp,et al.  Innate Immune Activation Through Nalp3 Inflammasome Sensing of Asbestos and Silica , 2008, Science.

[97]  L. Joosten,et al.  Engagement of NOD2 has a dual effect on proIL‐1β mRNA transcription and secretion of bioactive IL‐1β , 2008, European journal of immunology.

[98]  P. Adegboyega,et al.  Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. , 2007, Journal of hepatology.

[99]  T. Hawn,et al.  Toll-Like Receptor-4 Mediates Vascular Inflammation and Insulin Resistance in Diet-Induced Obesity , 2007, Circulation research.

[100]  Z. Ye,et al.  Cryopyrin/NALP3 binds ATP/dATP, is an ATPase, and requires ATP binding to mediate inflammatory signaling , 2007, Proceedings of the National Academy of Sciences.

[101]  G. Salvesen,et al.  The apoptosome: signalling platform of cell death , 2007, Nature Reviews Molecular Cell Biology.

[102]  Allan Vaag,et al.  Interleukin-1-receptor antagonist in type 2 diabetes mellitus. , 2007, The New England journal of medicine.

[103]  J. Tschopp,et al.  A pilot study of IL-1 inhibition by anakinra in acute gout , 2007, Arthritis research & therapy.

[104]  Y. Le Marchand-Brustel,et al.  Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. , 2007, Endocrinology.

[105]  J. Flier,et al.  TLR4 links innate immunity and fatty acid-induced insulin resistance. , 2006, The Journal of clinical investigation.

[106]  R. Kitazawa,et al.  MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. , 2006, The Journal of clinical investigation.

[107]  Shizuo Akira,et al.  Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance , 2006, Nature Medicine.

[108]  V. Dixit,et al.  Cryopyrin activates the inflammasome in response to toxins and ATP , 2006, Nature.

[109]  F. Martinon,et al.  Gout-associated uric acid crystals activate the NALP3 inflammasome , 2006, Nature.

[110]  R. Leibel,et al.  CCR2 modulates inflammatory and metabolic effects of high-fat feeding. , 2006, The Journal of clinical investigation.

[111]  P. Tobias,et al.  Modulation of atherosclerosis in mice by Toll-like receptor 2. , 2005, The Journal of clinical investigation.

[112]  S. Akira,et al.  Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[113]  M. Torrisi,et al.  Phospholipases C and A2 control lysosome-mediated IL-1 beta secretion: Implications for inflammatory processes. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[114]  K. Moore,et al.  Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways , 2004, Nature Medicine.

[115]  R. North,et al.  Rapid secretion of interleukin-1β by microvesicle shedding , 2001 .

[116]  S. Seino,et al.  S20G mutation of the amylin gene is associated with Type II diabetes in Japanese , 2001, Diabetologia.

[117]  J. Clore,et al.  Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. , 2001, Gastroenterology.

[118]  B. Cookson,et al.  Pro-inflammatory programmed cell death. , 2001, Trends in microbiology.

[119]  T. Wallis,et al.  Salmonella enterica Serovars Typhimurium and Dublin Can Lyse Macrophages by a Mechanism Distinct from Apoptosis , 2000, Infection and Immunity.

[120]  Roger Davis,et al.  The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 * , 2000, The Journal of Biological Chemistry.

[121]  M. Visser,et al.  Elevated C-reactive protein levels in overweight and obese adults. , 1999, JAMA.

[122]  M. Torrisi,et al.  The secretory route of the leaderless protein interleukin 1beta involves exocytosis of endolysosome-related vesicles. , 1999, Molecular biology of the cell.

[123]  M. A. Crook,et al.  Is Type II diabetes mellitus a disease of the innate immune system? , 1998, Diabetologia.

[124]  S. Falkow,et al.  Salmonella typhimurium invasion induces apoptosis in infected macrophages. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[125]  M. Pettermann,et al.  Interleukin 1 and tumor necrosis factor in obese alcoholics compared with normal-weight patients. , 1996, The American journal of clinical nutrition.

[126]  B. Spiegelman,et al.  IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance , 1996, Science.

[127]  R. Simsolo,et al.  The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. , 1995, The Journal of clinical investigation.

[128]  B. Spiegelman,et al.  Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. , 1995, The Journal of clinical investigation.

[129]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.

[130]  M. Prevost,et al.  Shigella flexneri induces apoptosis in infected macrophages , 1992, Nature.