Abstract
A hallmark of acute hepatic injury is the recruitment of neutrophils, monocytes and lymphocytes, including natural killer (NK) or T cells, towards areas of inflammation. The recruitment of leukocytes from their reservoirs bone marrow or spleen into the liver is directed by chemokines such as CCL2 (for monocytes) and CCL5 (for lymphocytes). We herein elucidated the impact of chemokine receptor inhibition by the dual CCR2 and CCR5 inhibitor cenicriviroc (CVC) on the composition of myeloid and lymphoid immune cell populations in acute liver injury. CVC treatment effectively inhibited the migration of bone marrow monocytes and splenic lymphocytes (NK, CD4 T-cells) towards CCL2 or CCL5 in vitro. When liver injury was induced by an intraperitoneal injection of carbon tetrachloride (CCl4) in mice, followed by repetitive oral application of CVC, flow cytometric and unbiased t-SNE analysis of intrahepatic leukocytes demonstrated that dual CCR2/CCR5 inhibition in vivo significantly decreased numbers of monocyte derived macrophages in acutely injured livers. CVC also reduced numbers of Kupffer cells (KC) or monocyte derived macrophages with a KC-like phenotype, respectively, after injury. In contrast to the inhibitory effects in vitro, CVC had no impact on the composition of hepatic lymphoid cell populations in vivo. Effective inhibition of monocyte recruitment was associated with reduced inflammatory macrophage markers and moderately ameliorated hepatic necroses at 36h after CCl4. In conclusion, dual CCR2/CCR5 inhibition primarily translates into reduced monocyte recruitment in acute liver injury in vivo, suggesting that this strategy will be effective in reducing inflammatory macrophages in conditions of liver disease.
Highlights
Inflammatory reactions determine the clinical course and outcome of acute and chronic liver injury, suggesting that targeting inflammatory cells holds therapeutic potential in liver diseases [1,2]
Bone marrow derived Ly-6Chigh monocytes are recruited into the liver upon acute and chronic injury in mice, mainly attracted via the chemokine ligand 2 (CCL2)-C-C motif chemokine receptor 2 (CCR2) axis, where they constitute hepatic Ly6C+ monocyte derived macrophages (MoMF) [18]
We found that the migration of bone marrow monocytes towards CCL2 was significantly reduced by CVC, whereas no monocyte migration was induced by CCL5 (Fig 1A)
Summary
Inflammatory reactions determine the clinical course and outcome of acute and chronic liver injury, suggesting that targeting inflammatory cells holds therapeutic potential in liver diseases [1,2]. Mouse models revealed a massive recruitment of inflammatory neutrophils and monocytes to sites of hepatic injury, where monocyte derived macrophages (MoMF) represent the dominant macrophage population [3]. CCR2/CCR5 inhibition in acute liver injury this author are articulated in the ‘author contributions’ section
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