Deficiency of p38 in macrophage ameliorates d-galactosamine/TNF--induced acute liver injury in mice
Deficiency of p38 in macrophage ameliorates d-galactosamine/TNF--induced acute liver injury in mice
复制标题
巨噬细胞中 p38 的缺乏可改善 d-半乳糖胺/TNF 诱导的小鼠急性肝损伤
DOI：
10.1111/febs.14294
复制
发表时间：
2017-12-01
期刊：
影响因子：
5.4
通讯作者：
Ying, Hao
中科院分区：
文献类型：
--
作者：
Liu, Jiao;Zhang, Shengjie;Ying, Hao
越来越多的证据表明，肝巨噬细胞通过协调炎症的诱导和消退、清除凋亡细胞和促进肝细胞增殖，在肝损伤后的组织修复中发挥重要作用。了解巨噬细胞在肝损伤发病机制中的作用将有助于为未来的治疗铺平道路。在这里，我们研究了巨噬细胞 p38 是否在 d-半乳糖胺 (GalN)/肿瘤坏死因子 (TNF-) 诱导的急性肝损伤后的组织修复中发挥调节作用。我们发现巨噬细胞 p38 缺陷小鼠的死亡率降低，肝损伤减轻，GalN/TNF 治疗后细胞凋亡减少、再生加速、粒细胞募集减少、单核细胞浸润和细胞因子产生减少。从机制上讲，我们发现脂多糖/干扰素治疗可激活 p38 信号传导，但白细胞介素 4 刺激不会激活 p38 信号传导，而 p38 的药物抑制则诱导极化从 M1 巨噬细胞转向 M2 巨噬细胞。总之，我们的结果表明巨噬细胞p38信号传导参与GalN/TNF-诱导的肝损伤的发病机制，并且抑制巨噬细胞中的p38信号传导可以改善肝损伤并加速再生，可能是通过促进巨噬细胞从M1表型向M2表型的极化来实现的。
Growing evidence suggests that hepatic macrophages play an important role in tissue repair after liver injury by coordinating the induction and resolution of inflammation, removing apoptotic cells, and promoting hepatocyte proliferation. Understanding the role of macrophages in the pathogenesis of liver injury will help pave the way to future therapeutics. Here, we investigated whether macrophage p38 plays a regulatory role in the tissue repair following d-galactosamine (GalN)/tumor necrosis factor- (TNF-)-induced acute liver injury. We found that macrophage p38-deficient mice displayed decreased mortality and relieved liver injury as evident from less apoptosis, accelerated regeneration, decreased granulocytes recruitment, monocytes infiltration, and cytokine production after GalN/TNF- treatment. Mechanistically, we found that p38 signaling was activated by lipopolysaccharide/interferon- treatment but not by inteleukin-4 stimulation, while pharmaceutical inhibition of p38 induced a shift in polarization from M1 macrophages to M2 macrophages. Together, our results indicated that macrophage p38 signaling is involved in the pathogenesis of liver injury induced by GalN/TNF-, and inhibition of p38 signaling in macrophage could ameliorate liver injury and accelerate regeneration, probably by promoting the polarization of macrophages from the M1 phenotype to the M2 phenotype.