title: Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses.
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.
authors: 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.
authors: Valerio
authors: V
authors: Chiurchiù
authors: 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.
authors: Alessandro
authors: A
authors: Leuti
authors: 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.
authors: Jesmond
authors: J
authors: Dalli
authors: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, SE-106 91 Stockholm, Sweden.
authors: Anders
authors: A
authors: Jacobsson
authors: European Center for Brain Research, Neuroimmunology Unit, IRCCS Santa Lucia Foundation, 00143 Rome, Italy.
authors: Luca
authors: L
authors: Battistini
authors: 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.
authors: Mauro
authors: M
authors: Maccarrone
authors: 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.
authors: Charles N
authors: CN
authors: Serhan
mesh_terms: D000123:Acetyltransferases / Q000172:deficiency / Q000235:genetics; D056704:Adaptive Immunity; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D000081031:Fatty Acid Elongases; D006801:Humans; D007249:Inflammation / Q000628:therapy; D018836:Inflammation Mediators / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D050356:Lipid Metabolism; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*
chemical_list: C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; D048868:Adaptor Proteins, Signal Transducing; C000630967:ELOVL2 protein, human; C000630951:ELOVL2 protein, mouse; C105101:FPR2 protein, human; C114479:GPR32 protein, human; C442142:HSH2D protein, human; C508594:IL2 protein, human; D018836:Inflammation Mediators; D007376:Interleukin-2; D044042:Receptors, Formyl Peptide; D043562:Receptors, G-Protein-Coupled; D044067:Receptors, Lipoxin; C518399:resolvin D1; C545423:resolvin D2; D004281:Docosahexaenoic Acids; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases