Talamonti Emanuela, Pauter Anna M, Asadi Abolfazl, Fischer Alexander W, Chiurchiù Valerio, Jacobsson Anders
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE10691, Stockholm, Sweden.
Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Cell Mol Life Sci. 2017 Aug;74(15):2815-2826. doi: 10.1007/s00018-017-2498-9. Epub 2017 Mar 15.
Docosahexaenoic acid (DHA) is an omega-3 fatty acid obtained from the diet or synthesized from alpha-linolenic acid through the action of fatty acid elongases (ELOVL) and desaturases. DHA plays important roles in the central nervous system as well as in peripheral organs and is the precursor of several molecules that regulate resolution of inflammation. In the present study, we questioned whether impaired synthesis of DHA affected macrophage plasticity and polarization both in vitro and in vivo models. For this we investigated the activation status and inflammatory response of bone marrow-derived M1 and M2 macrophages obtained from mice deficient of Elovl2 (Elovl2), a key enzyme for DHA synthesis in mammals. Although both wild type and Elovl2 mice were able to generate efficient M1 and M2 macrophages, M1 cells derived from Elovl2 mice showed an increased expression of key markers (iNOS, CD86 and MARCO) and cytokines (IL-6, IL-12 and IL-23). However, M2 macrophages exhibited upregulated M1-like markers like CD80, CD86 and IL-6, concomitantly with a downregulation of their signature marker CD206. These effects were counteracted in cells obtained from DHA-supplemented animals. Finally, white adipose tissue of Elovl2 mice presented an M1-like pro-inflammatory phenotype. Hence, impairment of systemic DHA synthesis delineates an alteration of M1/M2 macrophages both in vitro and in vivo, with M1 being hyperactive and more pro-inflammatory while M2 less protective, supporting the view that DHA has a key role in controlling the balance between pro- and anti-inflammatory processes.
二十二碳六烯酸（DHA）是一种ω-3脂肪酸，可从饮食中获取，或通过脂肪酸延长酶（ELOVL）和去饱和酶的作用由α-亚麻酸合成。DHA在中枢神经系统以及外周器官中发挥重要作用，并且是调节炎症消退的几种分子的前体。在本研究中，我们质疑DHA合成受损是否会在体外和体内模型中影响巨噬细胞的可塑性和极化。为此，我们研究了从Elovl2（Elovl2）缺陷小鼠获得的骨髓来源的M1和M2巨噬细胞的激活状态和炎症反应，Elovl2是哺乳动物中DHA合成的关键酶。尽管野生型和Elovl2小鼠都能够产生高效的M1和M2巨噬细胞，但来自Elovl2小鼠的M1细胞显示关键标志物（诱导型一氧化氮合酶、CD86和巨噬细胞清道夫受体）和细胞因子（白细胞介素-6、白细胞介素-12和白细胞介素-23）的表达增加。然而，M2巨噬细胞表现出上调的M1样标志物，如CD80、CD86和白细胞介素-6，同时其标志性标志物CD206下调。这些作用在从补充DHA的动物获得的细胞中被抵消。最后，Elovl2小鼠的白色脂肪组织呈现出M1样促炎表型。因此，全身DHA合成受损描绘了体外和体内M1/M2巨噬细胞的改变，其中M1过度活跃且更具促炎作用，而M2的保护作用较弱，支持了DHA在控制促炎和抗炎过程之间平衡中起关键作用的观点。
