Che Xu1, Chen Zhang1, Jie Ji2, Chao Wang3, Jing Yang1, Biao Geng1, Ting Zhao1, Hong Zhou4, Xianmin Mu1, Jinshun Pan1, Shi Hu1, Yuanfang Lv1, Xingguo Chen5, Hao Wen3, Qiang You1,4,6,7. 1. Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. 2. First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, China. 3. Department of Surgery, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. 4. Department of Immunology, Nanjing Medical University, Nanjing, Jiangsu, China. 5. Department of Rheumatology and Immunology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. 6. Medical Center for Digestive Diseases, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China. 7. Key Laboratory for Aging & Disease, Nanjing Medical University, Nanjing, Jiangsu, China.
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 (ConA)-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 ConA-induced hepatitis and had a significantly lower number of liver MNCs (LMNCs), including CD4+ cells, CD8+ T cells, natural killer cells, natural killer T cells, infiltrating macrophages, and neutrophils, as well as reduced expression of inflammatory mediators (tumor necrosis factor α, CXC chemokine ligand (CXCL) 10, interleukin (IL)-1α, monocyte chemotactic protein 1, and IL-6) compared with controls. Notably, we used bone marrow chimeric mice to demonstrate that CD36 expression on nonhematopoietic cells was required to drive ConA-induced liver injury. Furthermore, our data show that the CD36 receptor was essential for CXCL10-induced hepatocyte apoptosis and activation of IκB kinase, Akt, and Jun N-terminal kinase. Moreover, treatment of wild-type mice with genistein, a tyrosine kinase inhibitor that blocks CD36-Lyn signaling, attenuated ConA-induced liver injury and reduced the number of MNCs. CONCLUSIONS: Our findings suggest that CD36 plays an important proinflammatory role in ConA-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. (Hepatology 2018;67:1943-1955).
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 (ConA)-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 ConA-induced hepatitis and had a significantly lower number of liver MNCs (LMNCs), including CD4+ cells, CD8+ T cells, natural killer cells, natural killer T cells, infiltrating macrophages, and neutrophils, as well as reduced expression of inflammatory mediators (tumor necrosis factor α, CXC chemokine ligand (CXCL) 10, interleukin (IL)-1α, monocyte chemotactic protein 1, and IL-6) compared with controls. Notably, we used bone marrow chimeric mice to demonstrate that CD36 expression on nonhematopoietic cells was required to drive ConA-induced liver injury. Furthermore, our data show that the CD36 receptor was essential for CXCL10-induced hepatocyte apoptosis and activation of IκB kinase, Akt, and Jun N-terminal kinase. Moreover, treatment of wild-type mice with genistein, a tyrosine kinase inhibitor that blocks CD36-Lyn signaling, attenuated ConA-induced liver injury and reduced the number of MNCs. CONCLUSIONS: Our findings suggest that CD36 plays an important proinflammatory role in ConA-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. (Hepatology 2018;67:1943-1955).
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