Department of Physiology and Biophysics, National Defense Medical Center (NDMC), Taipei, Taiwan.
Headquater, Institute of Preventive Medicine, NDMC, Taipei, Taiwan.
Clin Sci (Lond). 2018 Jul 31;132(14):1581-1596. doi: 10.1042/CS20180041.
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.
脂肪组织（AT）炎症对于肥胖相关胰岛素抵抗的发生至关重要。我们的目的是研究环氧合酶-2（COX-2）/巨噬细胞迁移抑制因子（MIF）介导的肥大脂肪细胞与巨噬细胞之间的串扰对 AT 炎症的发生机制的贡献，以及使用人 SGBS 脂肪细胞、THP-1 巨噬细胞和高脂肪（HF）饮食喂养的小鼠研究 CD74 的作用。脂肪细胞和白色脂肪的基质血管细胞（SVC）中的 和 mRNA 水平与体重（BW）、胰岛素抵抗的稳态模型评估（HOMA-IR）以及脂肪巨噬细胞标志物表达水平高度相关，尤其是 SVC 中的表达水平。COX-2 抑制抑制了 HF 白色脂肪细胞以及棕榈酸和缺氧处理的 SGBS 脂肪细胞中 MIF 产生的升高。用 shCOX-2 和 siMIF 转染的脂肪细胞或在用培养基中耗尽 MIF 处理的脂肪细胞进行处理，逆转了共孵育的 THP-1 细胞中的促炎反应。NF-κB 激活的抑制逆转了处理后的脂肪细胞中 COX2 依赖性的 MIF 分泌。巨噬细胞 CD74 的靶向抑制防止了上述共培养模型中 M1 巨噬细胞的极化。在共培养模型中，M1 极化巨噬细胞中 COX-2 依赖性 CD74 基因表达和 MIF 释放的增加促进了共培养的 SGBS 脂肪细胞中 COX-2 和 MIF 的表达。CD74 shRNA 静脉注射抑制了 HF 诱导的 AT M1 巨噬细胞极化和炎症以及肥胖小鼠的胰岛素抵抗。本研究表明，肥大和缺氧脂肪细胞以及 M1 巨噬细胞中 COX-2 介导的通过 NF-κB 激活的 MIF 分泌，通过 CD74 可能会极大地促进肥胖中 AT 巨噬细胞的表型转换。抑制 CD74 可能会减轻 HF 饮食诱导的肥胖中 AT 炎症和胰岛素抵抗的发展。
