title: Resolvin D1 Polarizes Primary Human Macrophages toward a Proresolution Phenotype through GPR32.
abstract: Resolvin D1 (RvD1) was shown to be a potent anti-inflammatory and proresolution lipid mediator in several animal models of inflammation, but its mechanism of action in humans is not clear. We show that the RvD1 receptor GPR32 is present on resting, proinflammatory M(LPS) and alternatively activated primary human M(IL-4) macrophages, whereas TGF-β and IL-6 reduce its membrane expression. Accordingly, stimulation of resting primary human macrophages with 10 nM RvD1 for 48 h maximally reduced the secretion of the proinflammatory cytokines IL-1β and IL-8; abolished chemotaxis to several chemoattractants like chemerin, fMLF, and MCP-1; and doubled the phagocytic activity of these macrophages toward microbial particles. In contrast, these functional changes were not accompanied by surface expression of markers specific for alternatively activated M(IL-4) macrophages. Similar proresolution effects of RvD1 were observed when proinflammatory M(LPS) macrophages were treated with RvD1. In addition, we show that these RvD1-mediated effects are GPR32 dependent because reduction of GPR32 expression by small interfering RNA, TGF-β, and IL-6 treatment ablated these proresolution effects in primary human macrophages. Taken together, our results indicate that in humans RvD1 triggers GPR32 to polarize and repolarize macrophages toward a proresolution phenotype, supporting the role of this mediator in the resolution of inflammation in humans.
authors.affiliation: Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; and Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Mattia
authors.initials: M
authors.lastname: Schmid
authors.affiliation: Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; and Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Claudio
authors.initials: C
authors.lastname: Gemperle
authors.affiliation: Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; and Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Rimann
authors.affiliation: Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; Children's Research Center, University Children's Hospital Zurich, CH-8032 Zurich, Switzerland; and Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich, Switzerland martin.hersberger@kispi.uzh.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Hersberger
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002464:Cell Migration Inhibition / Q000187:drug effects; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000276:immunology; D016209:Interleukin-8 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology*; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; C508606:CXCL8 protein, human; C114479:GPR32 protein, human; C508585:IL1B protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D016212:Transforming Growth Factor beta; C518399:resolvin D1; D004281:Docosahexaenoic Acids