title: Molecular mechanism for adiponectin-dependent M2 macrophage polarization: link between the metabolic and innate immune activity of full-length adiponectin.
abstract: The anti-inflammatory effects of globular adiponectin (gAcrp) are mediated by IL-10/heme oxygenase 1 (HO-1)-dependent pathways. Although full-length (flAcrp) adiponectin also suppresses LPS-induced pro-inflammatory signaling, its signaling mechanisms are not yet understood. The aim of this study was to examine the differential mechanisms by which gAcrp and flAcrp suppress pro-inflammatory signaling in macrophages. Chronic ethanol feeding increased LPS-stimulated TNF-α expression by Kupffer cells, associated with a shift to an M1 macrophage polarization. Both gAcrp and flAcrp suppressed TNF-α expression in Kupffer cells; however, only the effect of gAcrp was dependent on IL-10. Similarly, inhibition of HO-1 activity or siRNA knockdown of HO-1 in RAW264.7 macrophages only partially attenuated the suppressive effects of flAcrp on MyD88-dependent and -independent cytokine signatures. Instead, flAcrp, acting via the adiponectin R2 receptor, potently shifted the polarization of Kupffer cells and RAW264.7 macrophages to an M2 phenotype. gAcrp, acting via the adiponectin R1 receptor, was much less effective at eliciting an M2 pattern of gene expression. M2 polarization was also partially dependent on AMP-activated kinase. flAcrp polarized RAW264.7 macrophages to an M2 phenotype in an IL-4/STAT6-dependent mechanism. flAcrp also increased the expression of genes involved in oxidative phosphorylation in RAW264.7 macrophages, similar to the effect of flAcrp on hepatocytes. In summary, these data demonstrate that gAcrp and flAcrp utilize differential signaling strategies to decrease the sensitivity of macrophages to activation by TLR4 ligands, with flAcrp utilizing an IL-4/STAT6-dependent mechanism to shift macrophage polarization to the M2/anti-inflammatory phenotype.
authors.affiliation: Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Palash
authors.initials: P
authors.lastname: Mandal
authors.forename: Brian T
authors.initials: BT
authors.lastname: Pratt
authors.forename: Mark
authors.initials: M
authors.lastname: Barnes
authors.forename: Megan R
authors.initials: MR
authors.lastname: McMullen
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D052242:Adiponectin / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002460:Cell Line; D002492:Central Nervous System Depressants / Q000009:adverse effects / Q000494:pharmacology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006419:Heme Oxygenase (Decyclizing) / Q000276:immunology / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects* / Q000276:immunology; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology / Q000378:metabolism; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D050800:STAT6 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D002492:Central Nervous System Depressants; D016207:Cytokines; D008070:Lipopolysaccharides; D008565:Membrane Proteins; C507780:Myd88 protein, mouse; C507781:Myd88 protein, rat; D053594:Myeloid Differentiation Factor 88; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; C493487:Tlr4 protein, mouse; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D000431:Ethanol; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C491523:Hmox1 protein, rat