Chemokine receptor CCR1 regulates macrophage activation through mTORC1 signaling in nonalcoholic steatohepatitis

Chemokine (CC motif) receptor 1 (CCR1) promotes liver fibrosis in mice. However, its effects on nonalcoholic steatohepatitis (NASH) remain unclear. Therefore, the present study aimed to investigate the role of CCR1 in the progression of NASH. Human serum and liver tissues were obtained from patients with NASH and controls. Systemic (Ccr1−/−) and liver macrophage-knockout Ccr1 (Ccr1LKD) mice were fed a high-cholesterol and high-fat (CL) diet for 12 weeks or a methionine/choline-deficient (MCD) diet for 4 weeks. BX471 was used to pharmacologically inhibit CCR1 in CL-fed mice. CCR1 was significantly upregulated in liver samples from patients with NASH and in animal models of dietary-induced NASH. In the livers of mice fed a CL diet for 12 weeks, the CCR1 protein colocalized with F4/80+ macrophages rather than with hepatic stellate cells. Compared to their wild-type littermates, Ccr1−/− mice fed with the CL or MCD diet showed inhibition of NASH-associated hepatic steatosis, inflammation, and fibrosis. Mechanistically, Ccr1 deficiency suppressed macrophage infiltration and activation by attenuating the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Similar results were observed in Ccr1LKD mice administered the CL diet. Moreover, CCR1 inhibition by BX471 effectively suppressed NASH progression in CL-fed mice. Ccr1 deficiency mitigated macrophage activity by inhibiting mTORC1 signaling, thereby preventing the development of NASH. Notably, the CCR1 inhibitor BX471 protected against NASH. These findings would help in developing novel strategies for the treatment of NASH. [Display omitted] •CCR1 is significantly upregulated in liver samples from patients and mice with NASH.•CCR1 protein is mainly colocalized with liver macrophages rather than stellate cells.•Deficiency of Ccr1 in the system or liver macrophages attenuates recruitment and activation of liver macrophages, leading to suppression of diet-induced steatohepatitis, liver fibrosis, and insulin resistance.•Ccr1 knockout suppresses macrophage infiltration and activation through decreasing mechanistic target of rapamycin complex 1 (mTORC1) signaling.•Inhibition of CCR1 by BX471 suppresses NASH progression in diet-induce mice.