Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF-2 in adipose tissue during endotoxemia
Differential regulation of macrophage activation by the MIF cytokine superfamily members MIF and MIF-2 in adipose tissue during endotoxemia
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DOI：
10.1096/fj.201901511r
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发表时间：
2020-01-21
期刊：
影响因子：
4.8
通讯作者：
Bucala, Richard
中科院分区：
文献类型：
--
作者：
Kim, Bong-Sung;Tilstam, Pathricia V.;Bucala, Richard
脓毒症是世界范围内的主要死亡原因，最近的研究表明白色脂肪组织(WAT)在脓毒症条件下是一个重要的调节因素。本研究探讨炎性细胞因子巨噬细胞移动抑制因子(MIF)及其结构同系物D-DOPAChrome互变酶(D-DT/MIF-2)在小鼠内毒素血症模型中的作用。野生型小鼠腹腔液中MIF和MIF-2水平均升高，而内脏水中MIF和MIF-2的表达存在差异，脂肪细胞MIF升高，MIF-2表达下调。MIF基因缺失使脂肪组织巨噬细胞(ATM)向抗炎表型分化，而MIF-2基因敲除使ATM向促炎表型分化，MIF缺失可提高成纤维细胞的活性。此外，我们观察到这两个MIF家族蛋白在脓毒症患者和健康患者的人类脂肪组织中的差异调节。综上所述，这些数据表明，在全身炎症过程中，脂肪细胞MIF和MIF-2的表达呈负相关，脂肪组织中MIF-2的下调可能会增加促炎症的巨噬细胞极化，从而进一步推动脂肪炎症。
Sepsis is a leading cause of death worldwide and recent studies have shown white adipose tissue (WAT) to be an important regulator in septic conditions. In the present study, the role of the inflammatory cytokine macrophage migration inhibitory factor (MIF) and its structural homolog D-dopachrome tautomerase (D-DT/MIF-2) were investigated in WAT in a murine endotoxemia model. Both MIF and MIF-2 levels were increased in the peritoneal fluid of LPS-challenged wild-type mice, yet, in visceral WAT, the proteins were differentially regulated, with elevated MIF but downregulated MIF-2 expression in adipocytes. Mif gene deletion polarized adipose tissue macrophages (ATM) toward an anti-inflammatory phenotype while Mif-2 gene knockout drove ATMs toward a pro-inflammatory phenotype and Mif-deficiency was found to increase fibroblast viability. Additionally, we observed the same differential regulation of these two MIF family proteins in human adipose tissue in septic vs healthy patients. Taken together, these data suggest an inverse relationship between adipocyte MIF and MIF-2 expression during systemic inflammation, with the downregulation of MIF-2 in fat tissue potentially increasing pro-inflammatory macrophage polarization to further drive adipose inflammation.