Division of Infections and Molecular Biology, Department of Health Promotion, Kyushu Dental University, Kitakyushu, Japan.
School of Oral Health Sciences, Kyushu Dental University, Kitakyushu, Japan.
J Cell Biochem. 2019 Aug;120(8):12604-12617. doi: 10.1002/jcb.28527. Epub 2019 Mar 1.
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 krüppel-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.
巨噬细胞是免疫反应的关键调节者，可极化为多种表型，包括 M1 和 M2。M1 巨噬细胞通常由脂多糖激活，并产生促炎细胞因子。相反，M2 巨噬细胞由白细胞介素 4（IL-4）刺激激活，促进组织重塑和抗炎反应。最近，多不饱和脂肪酸（PUFAs）在炎症调节中发挥重要作用。二十二碳六烯酸（DHA）是一种 PUFAs，对慢性炎症性疾病具有抗炎作用，但它在巨噬细胞极化中的作用尚不清楚。在本研究中，我们使用 U937 细胞阐明了 DHA 对巨噬细胞极化的影响。DHA 处理导致 M2 巨噬细胞标志物上调，并增加 U937 细胞分泌抗炎细胞因子。IL-4 而非 DHA 触发信号转导和转录激活因子 6（STAT6）的磷酸化。DHA 增强了转录因子 kruppel 样因子 4（KLF4）的表达，该因子参与调节巨噬细胞极化并增加丝裂原活化蛋白激酶（MAPK）p38 的磷酸化。p38 MAPK 的选择性抑制剂下调了 DHA 处理的 U937 细胞中 CD206 的表达。此外，自噬抑制剂抑制了 DHA 处理的 U937 细胞中 p38 MAPK 的磷酸化和 CD206 的表达。微管相关蛋白轻链 3-II 的表达增强，该蛋白参与自噬体的形成。总之，这些结果表明 DHA 通过 p38 MAPK 信号通路和自噬增强了 M2 巨噬细胞标志物的表达，表明 DHA 调节 M2 巨噬细胞极化并在先天免疫中发挥重要作用。
