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

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 and 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-κB activation reversed the COX2-dependent MIF secretion from treated adipocytes. The targetted 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-κB 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.

An update on immune dysregulation in obesity‐related insulin resistance

“…CD9 + macrophages are most similar to the CD11c + macrophages and their adoptive transfer into lean mice activates gene expression profiles related to obesity within the AT . Deletion of CD11c, MHC‐II, TNF‐ɑ, CCR2 and CD74 genes before HFD fed in mice causes a marked local and systemic decrease in inflammatory markers and improved glucose tolerance …”

Tautomerase Activity-Lacking of the Macrophage Migration Inhibitory Factor Alleviates the Inflammation and Insulin Tolerance in High Fat Diet-Induced Obese Mice

“…In the early stage of obesity, chemotactic monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor 2 (CCR2) are secreted by hypertrophic adipocyte, in which the cytokines promote the accumulation of macrophage in obese adipose tissue. Studies showed that the secreted MIF can directly facilitate M1 macrophage polarization through CD74 (26,36). In the advanced stage of obesity, M1 macrophage-derived MIF further exacerbates both adipocyte inflammation and macrophage polarization in a positive feedback loop, resulting in the exaggeration of adipose tissue inflammation and insulin resistance (10,26).…”

“…In addition, adipocyte MIF mRNA concentration was also positively associated with adipocytes diameter and independently predicted the peripheral insulin action (23) and the expression of MIF was increased in patients with obesity and diabetes (24). Inhibition or knockdown of MIF or its receptor CD74 could improve the glucose tolerance and insulin resistance, even ameliorate hepatic steatosis induced by HFD (25,26). However, which enzymatic activity of MIF is responsible for affecting HFDinduced inflammation and insulin tolerance in adipose tissues remains unknown.…”

Remodeling adipose tissue inflammasome for type 2 diabetes mellitus treatment: Current perspective and translational strategies

“…Administration of another small‐molecule inhibitor of MIF, ISO‐1, to diabetic db/db mice reduced blood glucose and diabetic nephropathy conditions such as albuminuria, activation of macrophages, and extracellular matrix growth in diabetic kidney . Inhibition of MIF receptor, CD74, using specific shRNA decreased high‐fat‐diet‐induced polarization of macrophages to M1 phenotype and insulin resistance in mice . Additionally, RNAi therapy to inhibit cyclooxygenase‐2 (COX‐2) was found to reduce MIF levels in adipocytes exposed to high fat …”

“…Inhibition of MIF receptor, CD74, using specific shRNA decreased high‐fat‐diet‐induced polarization of macrophages to M1 phenotype and insulin resistance in mice . Additionally, RNAi therapy to inhibit cyclooxygenase‐2 (COX‐2) was found to reduce MIF levels in adipocytes exposed to high fat …”