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Sci Transl Med. 2016 Aug 24;8(353):353ra111. doi: 10.1126/scitranslmed.aaf7483.

Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses.

Author information

1
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. v.chiurchiu@hsantalucia.it cnserhan@zeus.bwh.harvard.edu.
2
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.
3
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.
4
Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden.
5
European Center for Brain Research, Neuroimmunology Unit, IRCCS Santa Lucia Foundation, 00143 Rome, Italy.
6
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. v.chiurchiu@hsantalucia.it cnserhan@zeus.bwh.harvard.edu.

Abstract

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.

PMID:
27559094
PMCID:
PMC5149396
DOI:
10.1126/scitranslmed.aaf7483
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

C.N.S. is an inventor on several patents assigned to Brigham and Women's Hospital and licensed to Resolvyx Pharmaceuticals [WO2004014835 A3, Resolvins: biotemplates for therapeutic interventions; WO2005089744 A3, Use of docosatrienes, resolvins and their stable analogs in the treatment of airway diseases and asthma; EP 2344441 A2, 14-hydroxy-docosahexaenoic acid compounds]. C.N.S. was also the scientific founder of Resolvyx Pharmaceuticals with equity ownership in the company; and has interests reviewed and managed by the Brigham and Women's Hospital and Partners Health Care in accordance with their conflict of interest policies. L.B. received honoraria for speaking or consultation fees from TEVA, Baxter, and Genzyme. He also received grants from TEVA. The other authors declare no commercial or financial conflict of interest.

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