Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice.
Impaired T cell-mediated hepatitis in peroxisome proliferator activated receptor alpha (PPARα)-deficient mice.
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过氧化物酶体增殖物激活受体α（PPARα）缺陷小鼠中T细胞介导的肝炎受损
DOI：
10.1186/s40659-018-0153-z
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发表时间：
2018-02-15
影响因子：
6.7
通讯作者：
Wheeler MD
中科院分区：
文献类型：
--
作者：
Hines IN;Kremer M;Moore SM;Wheeler MD
过氧化物酶体增殖物激活受体α（PPARα）是参与β氧化的酶的调节剂，据报道可影响淋巴细胞活化。本研究旨在探讨过氧化物酶体增殖物激活受体α（PPARα）在刀豆球蛋白A（ConA）诱导的T细胞介导的肝炎中的作用。在处死前0、10或24 h，通过静脉注射ConA（15 mg/kg）处理野生型（wt）或PPARα缺陷型（PPARα−/−）小鼠，并收集血清和组织用于分析组织损伤、细胞因子应答、T细胞活化和表征。ConA给药后10小时和24小时，wt小鼠出现明显的肝损伤，表现为血清转氨酶水平、炎症细胞浸润、肝细胞凋亡以及多种细胞因子（包括白细胞介素4（IL 4）和干扰素γ（IFNγ））的表达。相比之下，尽管具有相似的肝脏T细胞活化和IL 4表达水平，但PPARα−/−小鼠受到保护，免受ConA诱导的肝损伤，血清酶释放显著减少，炎性细胞浸润大大减少，肝细胞凋亡和IFNγ表达。这种对肝损伤的抗性与肝脏自然杀伤T（NKT）细胞数量减少及其对α-半乳糖神经酰胺的体内反应性相关。有趣的是，过继转移野生型或PPARα−/−脾细胞重建了ConA肝损伤和淋巴细胞缺乏的严重联合免疫缺陷小鼠中细胞因子的产生，这可能是通过支持IL 15表达和/或抑制IL 12的产生，而不是淋巴细胞作为T细胞活性和ConA诱导的肝损伤的关键调节因子。综上所述，这些数据表明，肝脏内的PPARα通过调节NKT细胞募集和/或存活在ConA介导的肝损伤中起重要作用。
Peroxisome proliferator activated receptor alpha (PPARα), a regulator of enzymes involved in β oxidation, has been reported to influence lymphocyte activation. The purpose of this study was to determine whether PPARα plays a role in T cell-mediated hepatitis induced by Concanavalin A (ConA). Wild type (wt) or PPARα-deficient (PPARα−/−) mice were treated with ConA (15 mg/kg) by intravenous injection 0, 10 or 24 h prior to sacrifice and serum and tissue collection for analysis of tissue injury, cytokine response, T cell activation and characterization. Ten and 24 h following ConA administration, wt mice had significant liver injury as demonstrated by serum transaminase levels, inflammatory cell infiltrate, hepatocyte apoptosis, and expression of several cytokines including interleukin 4 (IL4) and interferon gamma (IFNγ). In contrast, PPARα−/− mice were protected from ConA-induced liver injury with significant reductions in serum enzyme release, greatly reduced inflammatory cell infiltrate, hepatocellular apoptosis, and IFNγ expression, despite having similar levels of hepatic T cell activation and IL4 expression. This resistance to liver injury was correlated with reduced numbers of hepatic natural killer T (NKT) cells and their in vivo responsiveness to alpha-galactosylceramide. Interestingly, adoptive transfer of either wt or PPARα−/− splenocytes reconstituted ConA liver injury and cytokine production in lymphocyte-deficient, severe combined immunodeficient mice implicating PPARα within the liver, possibly through support of IL15 expression and/or suppression of IL12 production and not the lymphocyte as the key regulator of T cell activity and ConA-induced liver injury. Taken together, these data suggest that PPARα within the liver plays an important role in ConA-mediated liver injury through regulation of NKT cell recruitment and/or survival.
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