CX3CL1-CX3CR1 and Macrophage-Mediated Inflammation

Mayumi Nagashimada, Kazuki Sawamoto, Yinhua Ni, Hironori Kitade, Naoto Nagata, Liang Xu, Masuko Kobori, Naofumi Mukaida, Tatsuya Yamashita, Shuichi Kaneko, Tsuguhito Ota
Endocrinology, Volume 162, Issue 6, June 2021, bqab064
https://doi.org/10.1210/endocr/bqab064

Abstract

The CX3CL1-CX3CR1 system plays an important role in disease progression by regulating inflammation both positively and negatively. We reported previously that C-C chemokine receptors 2 and 5 promote obesity-associated adipose tissue inflammation and insulin resistance. Here, we demonstrate that CX3CL1-CX3CR1 signaling is involved in adipose tissue inflammation and insulin resistance in obese mice via adipose tissue macrophage recruitment and M1∕M2 polarization. Cx3cl1 expression was persistently decreased in the epididymal white adipose tissue (eWAT) of high-fat diet-induced obese (DIO) mice, despite increased expression of other chemokines. Interestingly, in Cx3cr1^−∕− mice, glucose tolerance, insulin resistance, and hepatic steatosis induced by DIO or leptin deficiency were exacerbated. CX3CL1-CX3CR1 signaling deficiency resulted in reduced M2-polarized macrophage migration and an M1-dominant shift of macrophages within eWAT. Furthermore, transplantation of Cx3cr1^−∕− bone marrow was sufficient to impair glucose tolerance, insulin sensitivity, and regulation of M1∕M2 status. Moreover, Cx3cl1 administration in vivo led to the attenuation of glucose intolerance and insulin resistance. Thus, therapy targeting the CX3CL1-CX3CR1 system may be beneficial in the treatment of type 2 diabetes by regulating M1∕M2 macrophages.

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