title: MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases.
abstract: Low-grade systemic inflammation is often associated with metabolic syndrome, which plays a critical role in the development of the obesity-associated inflammatory diseases, including insulin resistance and atherosclerosis. Here, we investigate how Toll-like receptor-MyD88 signaling in myeloid and endothelial cells coordinately participates in the initiation and progression of high fat diet-induced systemic inflammation and metabolic inflammatory diseases. MyD88 deficiency in myeloid cells inhibits macrophage recruitment to adipose tissue and their switch to an M1-like phenotype. This is accompanied by substantially reduced diet-induced systemic inflammation, insulin resistance, and atherosclerosis. MyD88 deficiency in endothelial cells results in a moderate reduction in diet-induced adipose macrophage infiltration and M1 polarization, selective insulin sensitivity in adipose tissue, and amelioration of spontaneous atherosclerosis. Both in vivo and ex vivo studies suggest that MyD88-dependent GM-CSF production from the endothelial cells might play a critical role in the initiation of obesity-associated inflammation and development of atherosclerosis by priming the monocytes in the adipose and arterial tissues to differentiate into M1-like inflammatory macrophages. Collectively, these results implicate a critical MyD88-dependent interplay between myeloid and endothelial cells in the initiation and progression of obesity-associated inflammatory diseases.
authors.affiliation: Department of Immunology, 2 Department of Cellular and Molecular Medicine, 3 Department of Pathobiology, 4 Department of Molecular Cardiology, Cleveland Clinic, Cleveland, OH 44195.
authors.forename: Minjia
authors.initials: M
authors.lastname: Yu
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhao
authors.forename: Nengming
authors.initials: N
authors.lastname: Xiao
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Roychowdhury
authors.forename: David
authors.initials: D
authors.lastname: Schmitt
authors.forename: Bingqing
authors.initials: B
authors.lastname: Hu
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.forename: Clifford V
authors.initials: CV
authors.lastname: Harding
authors.forename: Amy G
authors.initials: AG
authors.lastname: Hise
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.forename: Anthony L
authors.initials: AL
authors.lastname: DeFranco
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
authors.forename: Richard E
authors.initials: RE
authors.lastname: Morton
authors.forename: Paul E
authors.initials: PE
authors.lastname: Dicorleto
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Smith
authors.forename: Jian-an
authors.initials: JA
authors.lastname: Wang
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology*; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D022423:Myeloid Cells / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009765:Obesity / Q000150:complications*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D039481:CD11b Antigen; D007328:Insulin; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88
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