Department of Biotherapy, Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
First Clinical Medical College of Nanjing Medical University, Nanjing, Jiangsu, China.
Hepatology. 2018 May;67(5):1943-1955. doi: 10.1002/hep.29716. Epub 2018 Mar 26.
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.
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).
清道夫受体 CD36 识别多种配体，并与多种正常和病理过程有关，包括脂质代谢、血管生成、动脉粥样硬化和吞噬作用。特别是，最近的发现表明其在无菌炎症和肿瘤转移中具有关键作用。然而，CD36 在免疫介导的肝炎中的作用尚不清楚。刀豆蛋白 A（ConA）诱导的肝损伤是一种公认的实验性 T 细胞介导的肝炎。为了了解 CD36 在肝炎中的作用，我们通过肝酶试验、末端脱氧核苷酸转移酶 dUTP 缺口末端标记（TUNEL）试验、组织学分析、单核细胞（MNC）浸润和肝前炎症因子产生来检测 CD36 缺陷（CD36-/-）小鼠对该模型的易感性。与对照组相比，CD36-/- 小鼠对 ConA 诱导的肝炎的敏感性较低，肝 MNC（LMNC）数量明显减少，包括 CD4 细胞、CD8 T 细胞、自然杀伤细胞、自然杀伤 T 细胞、浸润巨噬细胞和中性粒细胞，以及炎症介质（肿瘤坏死因子 α、CXC 趋化因子配体（CXCL）10、白细胞介素（IL）-1α、单核细胞趋化蛋白 1 和 IL-6）的表达降低。值得注意的是，我们使用骨髓嵌合小鼠证明了非造血细胞上的 CD36 表达是驱动 ConA 诱导的肝损伤所必需的。此外，我们的数据表明，CD36 受体对于 CXCL10 诱导的肝细胞凋亡和 IκB 激酶、Akt 和 Jun N-末端激酶的激活是必需的。此外，用酪氨酸激酶抑制剂金雀异黄素（genistein）处理野生型小鼠可减轻 ConA 诱导的肝损伤并减少 MNC 数量，genistein 可阻断 CD36-Lyn 信号转导。
我们的研究结果表明，CD36 通过促进肝炎症和介导趋化因子 CXCL10 的促凋亡作用，在 ConA 诱导的肝损伤中发挥重要的促炎作用，因此可能是免疫介导的肝炎的潜在治疗靶点。（《肝脏病学》2018；67：1943-1955）。
