Roles of CCR2 and CCR5 for Hepatic Macrophage Polarization in Mice With Liver Parenchymal Cell-Specific NEMO Deletion

Abstract

Macrophages critically regulate liver inflammation. Using a genetically determined hepatitis mouse model we found that CCR2 controls monocyte and macrophage recruitment to injured livers, while CCR5-dependent functions of liver macrophages limit hepatic injury, thereby reducing steatosis and hepatocarcinogenesis. BACKGROUND & AIMS: Macrophages are key regulators of inflammation and cancer promotion in the liver, and their recruitment and activation is linked to chemokine receptor signaling. However, the exact roles of the chemokine receptors CCR2 and CCR5 for macrophage functions in the liver is obscure. METHODS: To study CCR2 and CCR5 in inflammatory liver injury, we used mice with a hepatocyte-specific knockout of the nuclear factor kB (NF-kB) essential modulator (NEMO), termed NEMO LPC-KO mice, and generated NEMO LPC-KO Ccr2-/and NEMO LPC-KO Ccr5-/mice. NEMO LPC-KO mice develop hepatitis and fibrosis after two and liver tumors after six months. RESULTS: We found that both CCR2 and CCR5 deficiency led to reduced fibrosis, while CCR5 deficiency increased steatosis and tumor burden in NEMO LPC-KO mice. CCR2 was required for recruitment of hepatic macrophages, whereas CCR5 promoted stellate cell activation. The reduction of monocytes and macrophages by either anti-Gr1 antibody or clodronate-loaded liposomes (CLL), but not of CD8 þ T cells or NK cells, significantly aggravated liver injury in NEMO LPC-KO mice and was further increased in NEMO LPC-KO Ccr5-/mice. CLLinduced liver injury was dampened by the adoptive transfer of ex vivo generated macrophages, whereas the adoptive transfer of control CD115 þ immature monocytes or B cells did not reduce liver injury. CONCLUSIONS: Although CCR2 and CCR5 principally promote liver fibrosis, they exert differential functions on hepatic macrophages during liver disease progression in NEMO LPC-KO mice. While CCR2 controls the recruitment of monocytes to injured livers, CCR5-dependent functions of liver macrophages limit hepatic injury, thereby reducing steatosis and hepatocarcinogenesis.

Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy

“…Recently, it was demonstrated that both CCR2 and CCR5 deficiency/inhibition led to reduced fibrosis, and sole CCR5 deficiency increased steatosis and the incidence of HCC in the model of NEMO LPC-KO mice. While CCR2 controlled the recruitment of monocytes to injured livers, CCR5+ macrophages limited liver injury in NEMOLPC-KO mice (CCR5-dependent differential function), thereby reducing steatosis and hepatocarcinogenesis [ 131 ]. In the hypoxic environment of HCC, HIF-1a enhanced the expression of triggering receptor expressed on myeloid cells-1 (TREM-1) in TAMs, leading to immunosuppression through the impairment of the cytotoxic functions of CD8+ T cells.…”

HLJ1 amplifies endotoxin-induced sepsis severity by promoting IL-12 heterodimerization in macrophages

“…In the model of LPS-induced endotoxemia, the technique of macrophage depletion and reconstitution has been used to investigate the role of macrophages ( Fu et al, 2020 ). Recent studies demonstrated that in vivo tracking of transplanted macrophages reveals specific homing in the liver ( Bartneck et al, 2021 ; Nishiwaki et al, 2020 ), while little is known about the location where transplanted macrophages produce IL-12 and mediate IFN-γ production during sepsis. We depleted phagocytes with clodronate liposome and found when macrophage-depleted mice received BMDM isolated from same genotype, serum IL-12 and IFN-γ bounced back to the levels where endogenous macrophages have not yet been depleted ( Figure 8C ).…”

The Current Status of Granulocyte-Colony Stimulating Factor to Treat Acute-on-Chronic Liver Failure

“…[18][19][20][21] Cytokine release leads to a secondary recruitment and activation of neutrophils and predominant polarization of macrophages to the M1 proinflammatory phenotype. 22,23 It is therefore likely that hepatic tissue injury, which also involves oxidative stress and mitochondrial dysfunction, 4,5 results from both an immune cell mediated effect and a direct toxin-hepatocyte interaction. It is also well known that immune cell infiltration in any disease can have ambivalent consequences as proregenerative subsets, such as the M2 macrophage phenotype might propel the regenerative response.…”