Chiurchiù Valerio, Leuti Alessandro, Dalli Jesmond, Jacobsson Anders, Battistini Luca, Maccarrone Mauro, Serhan Charles N
Department of Medicine, Campus Bio-Medico University of Rome, 00128 Rome, Italy. European Center for Brain Research, Laboratory of Neurochemistry of Lipids, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Santa Lucia Foundation, 00143 Rome, Italy.
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Sci Transl Med. 2016 Aug 24;8(353):353ra111. doi: 10.1126/scitranslmed.aaf7483.
Resolution of inflammation is a finely regulated process mediated by specialized proresolving lipid mediators (SPMs), including docosahexaenoic acid (DHA)-derived resolvins and maresins. The immunomodulatory role of SPMs in adaptive immune cells is of interest. We report that D-series resolvins (resolvin D1 and resolvin D2) and maresin 1 modulate adaptive immune responses in human peripheral blood lymphocytes. These lipid mediators reduce cytokine production by activated CD8(+) T cells and CD4(+) T helper 1 (TH1) and TH17 cells but do not modulate T cell inhibitory receptors or abrogate their capacity to proliferate. Moreover, these SPMs prevented naïve CD4(+) T cell differentiation into TH1 and TH17 by down-regulating their signature transcription factors, T-bet and Rorc, in a mechanism mediated by the GPR32 and ALX/FPR2 receptors; they concomitantly enhanced de novo generation and function of Foxp3(+) regulatory T (Treg) cells via the GPR32 receptor. These results were also supported in vivo in a mouse deficient for DHA synthesis (Elovl2(-/-)) that showed an increase in TH1/TH17 cells and a decrease in Treg cells compared to wild-type mice. Additionally, either DHA supplementation in Elovl2(-/-) mice or in vivo administration of resolvin D1 significantly reduced cytokine production upon specific stimulation of T cells. These findings demonstrate actions of specific SPMs on adaptive immunity and provide a new avenue for SPM-based approaches to modulate chronic inflammation.
炎症的消退是一个由特殊的促消退脂质介质（SPM）介导的精细调节过程，这些介质包括二十二碳六烯酸（DHA）衍生的消退素和maresin。SPM在适应性免疫细胞中的免疫调节作用备受关注。我们报告称，D系列消退素（消退素D1和消退素D2）和maresin 1可调节人外周血淋巴细胞中的适应性免疫反应。这些脂质介质可减少活化的CD8(+) T细胞、CD4(+) T辅助1（TH1）细胞和TH17细胞产生的细胞因子，但不会调节T细胞抑制性受体，也不会消除它们的增殖能力。此外，这些SPM通过下调其标志性转录因子T-bet和Rorc，在由GPR32和ALX/FPR2受体介导的机制中，阻止幼稚CD4(+) T细胞分化为TH1和TH17细胞；它们还通过GPR32受体，同时增强了Foxp3(+)调节性T（Treg）细胞的新生和功能。在缺乏DHA合成的小鼠（Elovl2(-/-)）体内也得到了这些结果的支持，与野生型小鼠相比，该小鼠的TH1/TH17细胞增加，Treg细胞减少。此外，在Elovl2(-/-)小鼠中补充DHA或在体内给予消退素D1，在特异性刺激T细胞后，均可显著降低细胞因子的产生。这些发现证明了特定SPM对适应性免疫的作用，并为基于SPM的调节慢性炎症的方法提供了新途径。
