Docosahexaenoic acid enhances M2 macrophage polarization via the p38 signaling pathway and autophagy
Docosahexaenoic acid enhances M2 macrophage polarization via the p38 signaling pathway and autophagy
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二十二碳六烯酸通过p38信号通路和自噬增强M2巨噬细胞极化
DOI：
10.1002/jcb.28527
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发表时间：
2019-08-01
影响因子：
4
通讯作者：
Okinaga, Toshinori
中科院分区：
文献类型：
--
作者：
Kawano, Aki;Ariyoshi, Wataru;Okinaga, Toshinori
巨噬细胞是免疫反应的关键调节器，两极分化为各种表型，包括M1和M2。M1巨噬细胞通常被脂多糖激活，并产生促炎细胞因子。相反，M2巨噬细胞在白介素4(IL)-4的刺激下被激活，促进组织重塑和抗炎反应。近年来，多不饱和脂肪酸(PUFAs)已被证明在炎症调节中发挥重要作用。二十二碳六烯酸(DHA)是一种多不饱和脂肪酸，对慢性炎症性疾病具有抗炎作用，但其在巨噬细胞极化中的作用尚不清楚。在这项研究中，我们利用U937细胞阐明了DHA对巨噬细胞极化的影响。经DHA处理后，U937细胞M2巨噬细胞标志物上调，抗炎细胞因子分泌增加。IL-4，而不是DHA，触发了信号转导和转录激活因子6(STAT6)的磷酸化。DHA促进参与巨噬细胞极化调节的转录因子KLF4的表达，并增加p38丝裂原活化蛋白激酶(MAPK)的磷酸化。选择性p38 MAPK抑制剂下调DHA处理的U937细胞CD206的表达。此外，自噬抑制剂抑制了DHA处理的U937细胞中p38MAPK的磷酸化和CD206的表达。在DHA处理的U937细胞中，参与自噬小体形成的微管相关蛋白轻链3-II的表达增强。综上所述，这些结果表明DHA通过p38MAPK信号通路和自噬增强M2巨噬细胞标志物的表达，提示DHA调节M2巨噬细胞极化，在先天免疫中发挥重要作用。
Macrophages, critical modulators of the immune response, polarize into various phenotypes, including M1 and M2. M1 macrophages are typically activated by lipopolysaccharide and produce proinflammatory cytokines. Conversely, M2 macrophages are activated by stimulation with interleukin 4 (IL)-4 and promote tissue remodeling and anti-inflammatory reactions. Recently, polyunsaturated fatty acids (PUFAs) have been shown to play important roles in the regulation of inflammation. Docosahexaenoic acid (DHA), a PUFA, has anti-inflammatory effects on chronic inflammatory disease, but its role in macrophage polarization remains unclear. In this study, we clarified the effects of DHA on macrophage polarization using U937 cells. Treatment with DHA resulted in upregulation of M2 macrophage markers and increased secretion of anti-inflammatory cytokines by U937 cells. IL-4, but not DHA, triggered phosphorylation of signal transducer and activator of transcription 6 (STAT6). DHA enhanced the expression of kruppel-like factor-4 (KLF4), a transcription factor involved in the regulation of macrophage polarization and increased the phosphorylation of p38 mitogen-activated protein kinase (MAPK). A selective inhibitor of p38 MAPK downregulated the expression of CD206 in DHA-treated U937 cells. Moreover, inhibitors of autophagy suppressed the phosphorylation of p38 MAPK and the expression of CD206 in DHA-treated U937 cells. Expression of microtubule-associated protein light chain 3-II, which is involved in autophagosome formation, was enhanced in DHA-treated U937 cells. Taken together, these results indicated that DHA enhanced the expression of M2 macrophage markers through the p38 MAPK signaling pathway and autophagy, suggesting that DHA regulates M2 macrophage polarization and plays an important role in innate immunity.