Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ)
Microglial p38α MAPK is a key regulator of proinflammatory cytokine up-regulation induced by toll-like receptor (TLR) ligands or beta-amyloid (Aβ)
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DOI：
10.1186/1742-2094-8-79
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发表时间：
2011-07-06
影响因子：
9.3
通讯作者：
Van Eldik, Linda J.
中科院分区：
文献类型：
--
作者：
Bachstetter, Adam D.;Xing, Bin;Van Eldik, Linda J.
背景：活化的小胶质细胞过度产生促炎细胞因子被认为是急性和慢性神经退行性疾病病理生理进展的重要因素。因此，阐明细胞内信号通路至关重要，这些通路是暴露于特定应激源的小胶质细胞中细胞因子过量产生的重要因素，特别是适用于药物干预的通路。丝氨酸/苏氨酸蛋白激酶p38 α MAPK是平行和会聚细胞内信号通路的关键酶，参与应激源诱导的外周组织IL-1 β和TNF α的产生，是外周炎症性疾病的药物开发靶点。然而，关于小胶质细胞p38 α MAPK在应激源诱导的细胞因子过度产生中的定量重要性，或者小胶质细胞p38 α MAPK作为中枢神经系统疾病的可药物靶点的潜力，我们知之甚少。因此，我们研究了小胶质细胞p38 α MAPK对细胞因子上调的贡献，重点研究了通过药理学或遗传学方法抑制激酶来抑制细胞因子增加的潜力。方法：在cns渗透p38 α MAPK抑制剂MW01-2-069A-SRM存在的情况下，检测小胶质细胞因子对TLR配体2/3/4/7/8/9或A β(1-42)的反应。来自p38 α MAPK基因缺陷小鼠的原代小胶质细胞被用于进一步建立p38 α MAPK与细胞因子过量产生之间的联系。在lps诱导的急性神经炎症模型中，通过p38 α MAPK抑制剂治疗来确定其体内意义。结果：BV-2小胶质细胞系和原代小胶质细胞培养物增加的IL-1 β和TNF α的产生被p38 α mapk靶向抑制剂以浓度依赖的方式抑制。两种p38 α MAPK蛋白底物MK2和MSK1的磷酸化状态随之降低，证明了细胞靶标参与。与药理学发现一致，p38 α缺陷小鼠的小胶质细胞对LPS的细胞因子反应减弱。此外，口服该抑制剂可阻断腹腔注射LPS应激小鼠大脑皮层中IL-1 β的增加。结论：p38 α MAPK通路是多种应激源诱导小胶质细胞产生促炎细胞因子增加的重要因素。结果还表明靶向p38 α MAPK调节中枢神经系统促炎细胞因子过量产生的可行性。
Background: Overproduction of proinflammatory cytokines from activated microglia has been implicated as an important contributor to pathophysiology progression in both acute and chronic neurodegenerative diseases. Therefore, it is critical to elucidate intracellular signaling pathways that are significant contributors to cytokine overproduction in microglia exposed to specific stressors, especially pathways amenable to drug interventions. The serine/threonine protein kinase p38 alpha MAPK is a key enzyme in the parallel and convergent intracellular signaling pathways involved in stressor-induced production of IL-1 beta and TNF alpha in peripheral tissues, and is a drug development target for peripheral inflammatory diseases. However, much less is known about the quantitative importance of microglial p38 alpha MAPK in stressor-induced cytokine overproduction, or the potential of microglial p38 alpha MAPK to be a druggable target for CNS disorders. Therefore, we examined the contribution of microglial p38 alpha MAPK to cytokine up-regulation, with a focus on the potential to suppress the cytokine increase by inhibition of the kinase with pharmacological or genetic approaches.Methods: The microglial cytokine response to TLR ligands 2/3/4/7/8/9 or to A beta(1-42) was tested in the presence of a CNS-penetrant p38 alpha MAPK inhibitor, MW01-2-069A-SRM. Primary microglia from mice genetically deficient in p38 alpha MAPK were used to further establish a linkage between microglia p38 alpha MAPK and cytokine overproduction. The in vivo significance was determined by p38 alpha MAPK inhibitor treatment in a LPS-induced model of acute neuroinflammation.Results: Increased IL-1 beta and TNF alpha production by the BV-2 microglial cell line and by primary microglia cultures was inhibited in a concentration-dependent manner by the p38 alpha MAPK-targeted inhibitor. Cellular target engagement was demonstrated by the accompanying decrease in the phosphorylation state of two p38 alpha MAPK protein substrates, MK2 and MSK1. Consistent with the pharmacological findings, microglia from p38 alpha-deficient mice showed a diminished cytokine response to LPS. Further, oral administration of the inhibitor blocked the increase of IL-1 beta in the cerebral cortex of mice stressed by intraperitoneal injection of LPS.Conclusion: The p38 alpha MAPK pathway is an important contributor to the increased microglial production of proinflammatory cytokines induced by diverse stressors. The results also indicate the feasibility of targeting p38 alpha MAPK to modulate CNS proinflammatory cytokine overproduction.