Docosahexaenoic acid modulates inflammatory and antineurogenic functions of activated microglial cells
Docosahexaenoic acid modulates inflammatory and antineurogenic functions of activated microglial cells
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DOI：
10.1002/jnr.22783
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发表时间：
2012-03-01
影响因子：
4.2
通讯作者：
Minghetti, Luisa
中科院分区：
文献类型：
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作者：
Ajmone-Cat, Maria Antonietta;Salvatori, Maria Lavinia;Minghetti, Luisa
小胶质细胞激活的复杂过程包括与神经毒性/抗神经原性或与神经营养/原神经原性特性相关的几种功能性激活状态，主要取决于激活的程度和激活刺激的性质。几项研究表明，急性暴露于典型的活化剂脂多糖（LPS）赋予小胶质细胞抗神经原性。急性激活的小胶质细胞或其条件培养液（CM）可降低神经干祖细胞（NPC）的存活率并阻止NPC分化为神经元。本研究验证了一种假设，即二十二碳六烯酸（DHA），一种具有强效免疫调节特性的长链多不饱和脂肪酸（L-PUFA），可以抑制小胶质细胞的促炎功能并调节其抗神经原性作用。我们证明，DHA剂量依赖性地抑制在激活的小胶质细胞中的炎症产物的合成，而不诱导替代性炎症表型。在可能的DHA作用机制中，我们提出抑制p38 MAPK磷酸化和激活核受体过氧化物酶体增殖物激活受体（PPAR）-γ。M1促炎表型的衰减对NPC的存活和分化具有相关的后果，因为DHA逆转了来自LPS激活的小胶质细胞的条件培养基的抗神经发生活性。我们的研究确定了DHA的新的相关潜在保护和前神经功能，通过调节小胶质细胞功能发挥作用，可用于维持或促进受损/老化大脑的神经再生过程。(c)2011 Wiley Periodicals，Inc.
The complex process of microglial activation encompasses several functional activation states associated either with neurotoxic/antineurogenic or with neurotrophic/proneurogenic properties, depending mainly on the extent of activation and the nature of the activating stimuli. Several studies have demonstrated that acute exposure to the prototypical activating agent lipopolysaccharide (LPS) confers antineurogenic properties upon microglial cells. Acutely activated microglia ortheir conditioned media (CM) reduce neural stem progenitor cell (NPC) survival and prevent NPC differentiation into neurons. The present study tested the hypothesis that docosahexaenoic acid (DHA), a long-chain polyunsatured fatty acid (L-PUFA) with potent immunomodulatory properties, could dampen microglial proinflammatory functions and modulate their antineurogenic effect. We demonstrate that DHA dose dependently inhibits the synthesis of inflammatory products in activated microglia without inducing an alternative antiinflammatory phenotype. Among the possible DHA mechanisms of action, we propose the inhibition of p38 MAPK phosphorylation and the activation of the nuclear receptor peroxisome proliferator activated receptor (PPAR)-gamma. The attenuation of M1 proinflammatory phenotype has relevant consequences for the survival and differentiation of NPC, because DHA reverses the antineurogenic activities of conditioned media from LPS-activated microglia. Our study identifies new relevant potentially protective and proneurogenic functions of DHA, exerted through the modulation of microglial functions, that could be exploited to sustain or promote neuroregenerative processes in damaged/aged brain. (c) 2011 Wiley Periodicals, Inc.