Adipose Tissue-Derived CCL5 Enhances Local Pro-Inflammatory Monocytic MDSCs Accumulation and Inflammation via CCR5 Receptor in High-Fat Diet-Fed Mice

Abstract

The C-C chemokine motif ligand 5 (CCL5) and its receptors have recently been thought to be substantially involved in the development of obesity-associated adipose tissue inflammation and insulin resistance. However, the respective contributions of tissue-derived and myeloid-derived CCL5 to the etiology of obesity-induced adipose tissue inflammation and insulin resistance, and the involvement of monocytic myeloid-derived suppressor cells (MDSCs), remain unclear. This study used CCL5-knockout mice combined with bone marrow transplantation (BMT) and mice with local injections of shCCL5/shCCR5 or CCL5/CCR5 lentivirus into bilateral epididymal white adipose tissue (eWAT). CCL5 gene deletion significantly ameliorated HFD-induced inflammatory reactions in eWAT and protected against the development of obesity and insulin resistance. In addition, tissue (non-hematopoietic) deletion of CCL5 using the BMT method not only ameliorated adipose tissue inflammation by suppressing pro-inflammatory M-MDSC (CD11b+Ly6G−Ly6Chi) accumulation and skewing local M1 macrophage polarization, but also recruited reparative M-MDSCs (CD11b+Ly6G−Ly6Clow) and M2 macrophages to the eWAT of HFD-induced obese mice, as shown by flow cytometry. Furthermore, modulation of tissue-derived CCL5/CCR5 expression by local injection of shCCL5/shCCR5 or CCL5/CCR5 lentivirus substantially impacted the distribution of pro-inflammatory and reparative M-MDSCs as well as macrophage polarization in bilateral eWAT. These findings suggest that an obesity-induced increase in adipose tissue CCL5-mediated signaling is crucial in the recruitment of tissue M-MDSCs and their trans-differentiation to tissue pro-inflammatory macrophages, resulting in adipose tissue inflammation and insulin resistance.

Tanshinone IIA and Cryptotanshinone Counteract Inflammation by Regulating Gene and miRNA Expression in Human SGBS Adipocytes

“…However, the genetic deficiency or inactivation of CCL2/MCP-1 or its receptor (CCR2) did not entirely restrain macrophage infiltration in obese adipose tissue, suggesting other chemokines may be involved [12]. In support of this, CCL5/RANTES has also been found to be overexpressed in obese adipose tissue [70,71], and implicated in macrophage accumulation and survival, inflammation and insulin resistance in the visceral adipose tissue during obesity [72,73]. Although CCL5 is thought to be mainly expressed by the stromavascular fraction of adipose tissue in obesity [74] and its deficiency led to a compensatory increase in T cell recruitment [75], adipocytes may also be an important source of CCL5 as demonstrated in previous findings [70], as well as in the present study.…”

Spotlight on pro-inflammatory chemokines: regulators of cellular communication in cognitive impairment

“…CCL5, C-C chemokine motif ligand V, a normal T cell expressed and secreted factor known to be regulated upon activation ( 92 ), is also called RANTES ( 93 ). It belongs to the C-C motif chemokine family.…”

Loss of Lkb1 in CD11c+ myeloid cells protects mice from diet-induced obesity while enhancing glucose intolerance and IL-17/IFN-γ imbalance

“…The results further elaborated the above observations in ATDCs and showed that there was no significant difference between splenic DC in terms of cell number and the expression of CD80/CD86. Since the previous reports demonstrated the alteration of IL1A, CCL5, and OX40 in the Lkb1deficient DC and expression of those genes are also well known to regulate adipose tissue inflammation in obesity [42][43][44][45], we examined the expression of those essential genes on ATM and ATDC. The results showed that ATDC from CD11c Cre Lkb1 f/f has lower levels of CCL5 and OX40 while higher levels of IL1A compared to Lkb1 f/f ATDC.…”