Targeted inhibition of CD74 attenuates adipose COX-2-MIF-mediated M1 macrophage polarization and retards obesity-related adipose tissue inflammation and insulin resistance

doi:10.1042/CS20180041

CNU IR > Pharmacy and Science > Dept. of Health and Nutrition (including master's program) > Periodical Articles > Item 310902800/32264

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Title:	Targeted inhibition of CD74 attenuates adipose COX-2-MIF-mediated M1 macrophage polarization and retards obesity-related adipose tissue inflammation and insulin resistance
Authors:	Chan, Pei-Chi Wu, Ting-Ni Chen, Ying-Chuan Lu, Chieh-Hua Wabitsch, Martin Tian, Yu-Feng Hsieh, Po-Shiuan
Contributors:	Natl Def Med Ctr, Dept Physiol & Biophys NDMC, Inst Prevent Med NDMC, Div Endocrinol & Metab, Dept Internal Med, Triserv Gen Hosp Ulm Univ, Div Pediat Endocrinol & Diabet, Dept Pediat & Adolescent Med Chi Mei Med Ctr, Dept Surg, Div Gen Surg, Yung Kung Campus Chia Nan Univ Pharm & Sci, Dept Hlth & Nutr NDMC, Dept Med Res, Triserv Gen Hosp
Keywords:	Mif Signal-Transduction Cd4(+) T-Cells Thp-1 Macrophages Human Adipocytes Liver-Disease Cyclooxygenase-2 Modulation Insights Immunity Release
Date:	2018-07-31
Issue Date:	2019-11-15 15:47:21 (UTC+8)
Publisher:	PORTLAND PRESS LTD
Abstract:	Adipose tissue (AT) inflammation is crucial to the development of obesity-associated insulin resistance. Our aim was to investigate the contribution of cyclooxygenase-2 (COX-2)/macrophage migration inhibitory factor (MIF)-mediated cross-talk between hypertrophic adipocytes and macrophages to the etiology of AT inflammation and the involvement of CD74 using human SGBS adipocytes, THP-1 macrophages and mice fed a high-fat (HF) diet. The MIF and CD74 mRNA levels in the adipocytes and stromal vascular cells (SVCs) of white fat were highly correlated with body weight (BW), homeostatic model assessment for insulin resistance (HOMA-IR), and adipose macrophage marker expression levels, especially those in SVCs. COX-2 inhibition suppressed the elevation of MIF production in HF white adipocytes as well as palmitate and hypoxic-treated SGBS adipocytes. Treatment of adipocytes transfected with shCOX-2 and siMIF or subjected to MIF depletion in the medium reversed the pro-inflammatory responses in co-incubated THP-1 cells. Inhibition of NF-kappa B activation reversed the COX2-dependent MIF secretion from treated adipocytes. The targeted inhibition of macrophage CD74 prevented M1 macrophage polarization in the above co-culture model. The COX-2-dependent increases in CD74 gene expression and MIF release in M1-polarized macrophages facilitated the expression of COX-2 and MIF in co-cultured SGBS adipocytes. CD74 shRNA intravenous injection suppressed HF-induced AT M1 macrophage polarization and inflammation as well as insulin resistance in mice. The present study suggested that COX-2-mediated MIF secretion through NF-.B activation from hypertrophic and hypoxic adipocytes as well as M1 macrophages might substantially contribute to the phenotypic switch of AT macrophages through CD74 in obesity. Inhibition of CD74 could attenuate AT inflammation and insulin resistance in the development of HF diet-induced obesity.
???metadata.dc.relation.uri???:	http://dx.doi.org/10.1042/CS20180041
Relation:	Clinical Science, v.132, n.14, pp.1581-1596
Appears in Collections:	[Dept. of Health and Nutrition (including master's program)] Periodical Articles

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