CD36 Deficiency Attenuates Immune-Mediated Hepatitis in Mice by Modulating the Proapoptotic Effects of CXCL10

Abstract

The scavenger receptor, CD36, recognizes a diverse set of ligands, and has been implicated in a wide variety of normal and pathological processes, including lipid metabolism, angiogenesis, atherosclerosis, and phagocytosis. In particular, recent findings have demonstrated its crucial functions in sterile inflammation and tumor metastasis. However, the role of CD36 in immune-mediated hepatitis remains unclear. Concanavalin A (Con A)-induced liver injury is a well-established experimental T cell-mediated hepatitis. To understand the role of CD36 in hepatitis, we tested the susceptibility of CD36-deficient (CD36^-/-) mice to this model, evaluated by a liver enzyme test, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay, histological analysis, mononuclear cell (MNC) infiltration, and hepatic proinflammatory factor production. CD36^-/- mice were less sensitive to Con A-induced hepatitis and had a significantly lower number of liver MNCs (LMNCs), including CD4⁺, CD8⁺ T cells, NK, NKT cells, infiltrating macrophages (IMs) and neutrophils, as well as reduced expression of inflammatory mediators (TNF-α, CXCL10, IL-1α, MCP-1, and IL-6) compared with controls. Notably, we used bone marrow chimeric mice to demonstrate that CD36 expression on non-hematopoietic cells was required to drive ConA-induced liver injury. Further, our data show that the CD36 receptor was essential for CXCL10-induced hepatocyte apoptosis and activation of IKK, Akt, and JNK. Moreover, treatment of WT mice with genistein, a tyrosine kinase inhibitor that blocks CD36-Lyn signaling, attenuated Con A-induced liver injury and reduced the number of MNCs. Conclusions: Our findings suggest that CD36 plays an important proinflammatory role in Con A-induced liver injury by promoting hepatic inflammation and mediating the proapoptotic effect of chemokine CXCL10, and therefore, may be a potential therapeutic target for immune-mediated hepatitis. This article is protected by copyright. All rights reserved.

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