Data from: Differential impact of the dual CCR2/CCR5 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury

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.

急性肝损伤的标志性特征之一，是中性粒细胞、单核细胞及淋巴细胞（包括自然杀伤（NK）细胞或T细胞）向炎症区域募集。白细胞从其储存库骨髓或脾脏向肝脏的募集，由CCL2（靶向单核细胞）、CCL5（靶向淋巴细胞）等趋化因子所介导。本研究阐明了CCR2与CCR5双重抑制剂西尼罗利（cenicriviroc, CVC）对急性肝损伤时髓系与淋巴系免疫细胞群组成的影响。体外实验中，CVC处理可有效抑制骨髓单核细胞及脾脏淋巴细胞（NK细胞、CD4阳性T细胞）向CCL2或CCL5的迁移。在小鼠经腹腔注射四氯化碳（carbon tetrachloride, CCl4）诱导肝损伤后，予其反复口服CVC，对肝内白细胞的流式细胞术及无偏t分布邻域嵌入（t-SNE）分析结果显示，体内双重抑制CCR2/CCR5可显著降低急性损伤肝脏内单核细胞源性巨噬细胞的数量。损伤后，CVC还可分别减少库普弗细胞（KC）或具有库普弗细胞样表型的单核细胞源性巨噬细胞的数量。与体外的抑制效果不同，CVC对体内肝脏淋巴系细胞群的组成无显著影响。有效抑制单核细胞募集，可使CCl4给药36小时后炎症性巨噬细胞标志物水平降低，并中度改善肝脏坏死情况。综上，体内急性肝损伤时，CCR2/CCR5双重抑制主要可减少单核细胞募集，提示该策略可有效降低肝脏疾病状态下的炎症性巨噬细胞数量。