title: Macrophages control innate inflammation.
abstract: Macrophages play a critical role in the pathogenesis of metabolic diseases including gout and type 2 diabetes. The Nod-like receptor (NLR) family, pyrin domain containing 3 (NLRP3) forms the inflammasome with apoptosis-associated speck-like protein containing a CARD (ASC), the adaptor protein, and mediates inflammatory responses by macrophages. By compound screening, we found that tubulin polymerization inhibitors suppress NLRP3 inflammasome activation. NLRP3 inflammasome inducers reduce the NAD(+) level to inactivate the α-tubulin deacetylase Sirtuin 2, resulting in accumulation of acetylated α-tubulin. Acetylated α-tubulin mediates mitochondrial transport and subsequent proximity of ASC on mitochondria to NLRP3 on the endoplasmic reticulum. Thus, microtubule-driven transport of mitochondria is required for NLRP3 inflammasome activation. Macrophages are comprised of two subsets, M1 (inflammatory) and M2 (anti-inflammatory). Trib1 is an adaptor protein involved in protein degradation of immune-related transcription factors. We found that Trib1 is critical for the differentiation of F4/80(+) MR(+) tissue-resident M2-like macrophages. Mice lacking Trib1 in haematopoietic cells show severe lipodystrophy owing to increased lipolysis, even on a normal diet. In response to a high-fat diet, the mice show hypertriglyceridaemia and insulin resistance, together with increased proinflammatory cytokine production. Thus, Trib1 is critical for adipose tissue maintenance and suppression of metabolic disorders by controlling the differentiation of tissue-resident M2-like macrophages.
authors.affiliation: Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan. sakira@biken.osaka-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: T
authors.initials: T
authors.lastname: Misawa
authors.forename: T
authors.initials: T
authors.lastname: Satoh
authors.forename: T
authors.initials: T
authors.lastname: Saitoh
mesh_terms: D000273:Adipose Tissue / Q000502:physiology; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000502:physiology*; D058847:Inflammasomes / Q000502:physiology; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human
keywords: NLRP3 inflammasome; Sirtuin 2; Trib1; adipose tissue; gout; innate immunity; insulin resistance; lipodystrophy; macrophage; microtubules