Role of exogenous interleukin 4 in the dynamics of acute liver injury

Abstract

BackgroundMortality in acute liver failure is very high, and the only reliable treatment is transplantation. Interleukin 4 (IL4) has pleiotropic effects on a network of cells directing repair, regeneration, and fibrosis. Pretreatment with subcutaneous IL4 complexed with anti-IL4 antibody (IL4c) promotes repair of carbon tetrachloride-mediated murine liver injury by stimulating hepatocyte proliferation. We hypothesised that IL4c could be administered therapeutically and act by a variety of mechanisms beyond engagement of hepatocytes. MethodsC57Bl/6 mice were given carbon tetrachloride intraperitoneally to induce acute liver injury. Preinjury and postinjury dosing regimens of IL4c were compared. The role of IL4 receptor α-chain (IL4Rα) signalling in bone-marrow-derived cells was investigated using tissue-protected chimeras generated with wild type or IL4Rα−/– donor bone marrow. Liver was analysed by immunohistochemistry and fluorescence-activated cell sorting (FACS). FindingsWhen compared with vehicle, administration of IL4c after injury produced a significant reduction in mean alanine aminotransferase (242 U/L [61·9] vs 131 [30·8], p<0·0001) and necrotic cell area (11·6% [7·04] vs 0·36 [0·6], p<0·0001). Although necrosis was reduced, the necrotic area in IL4c-treated liver was not replaced with hepatocytes but with a cellular infiltrate characterised by high F4/80 expression. FACs analysis showed a reduced proportion and number of Ly6chi MHCIIlo monocytes and a concomitant increase in the number of Ly6clo MHCIIhi F4/80hi macrophages in injured livers treated with IL4c. This phenotypic change was dependent on IL4c signalling to Ly6chi MHCIIlo monocytes, since these cells exhibited developmental arrest when derived from IL4Rα-deficient bone marrow in chimeric mice. InterpretationWe demonstrate that IL4c can be administered therapeutically after carbon tetrachloride injury to improve indices of hepatic injury. Furthermore, IL4c treatment mediates a change in the monocyte–macrophage compartment which is consistent with a switch from a proinflammatory (Ly6chi) to a proreparative (Ly6clo) macrophage phenotype. We postulate that these Ly6clo macrophages mediate clearance of necrotic debris and facilitate hepatic regeneration. FundingWellcome Trust.