IL-17A aggravates liver IR injury by mobilizing B1a cells through CXCL13

Abstract

Background: IL-17A was found critical in liver ischemia-reperfusion (IR) injury. However, the mechanism remains unclear. Recently, IL-17A was reported to promote B1a cell differentiation during lung infection. B1a cells are involved in tissue ischemia reperfusion injury by producing IgM. Here we aim to explore the mechanism of IL-17A regulating hepatic ischemia reperfusion injury through clinical study and animal models. Methods: Human liver biopsies from post-liver transplantation were used for clinical study. Hepatic ischemia reperfusion injury models were applied using IL-17A-/-and WT C57BL/6 mice. Lymphocytes were isolated from mice peritoneal cavity, spleen and liver for in vitro functional study. Results: Firstly, IL-17A aggravates liver IR injury. In clinical study, hepatic expression of IL-17A (n=40) correlated with serum aspartate aminotransferase (AST) level post-liver transplantation (p=0.0149) (Figure 1A). Consistently, IL-17A knockout mice (IL-17A-/-) showed decreased apoptosis from Western blot, less lymphocyte infiltration (asterisk) and less endothelial cell swelling (arrow) from H&E staining (Figure 1B). Secondly, IL-17A induces natural IgM secretion and B1a cell mobilization after liver IR injury. In clinical study, liver expression of IL-17A (n=40) correlated with expression of CXCL13 (p=0.0122) and CXCR5 (p=0.0403) (Figure 1A). At 2 hours after hepatic IR injury, downregulation of hepatic mRNA expression of CXCL13 was found in IL-17A-/- mice (p=0.008). Total serum natural IgM titers were significant decreased in IL-17A-/- mice (p=0.0248) (Figure 1C). Consistently, decrease of peritoneal B1a cell population (p=0.019) as well as liver infiltrated B1a cell population (p=0.046) in IL-17A-/-mice were found after liver IR injury (Figure 1D). Conclusion: IL-17A aggravates hepatic ischemia reperfusion injury through natural IgM from B1a cells, which are mobilized by CXCL13 during the acute phase injury.