title: Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain.
abstract: Self-resolving inflammatory exudates and lipid mediator metabolomics recently uncovered a new family of potent anti-inflammatory and proresolving mediators biosynthesized by macrophages (MΦs), denoted maresins. Here we determined that maresin 1 (MaR1) produced by human MΦs from endogenous docosahexaenoic acid (DHA) matched synthetic 7R,14S-dihydroxydocosa-4Z,8E,10E,12Z,16Z,19Z-hexaenoic acid. The MaR1 alcohol groups and Z/E geometry of conjugated double bonds were matched using isomers prepared by total organic synthesis. MaR1's potent defining actions were confirmed with synthetic MaR1, i.e., limiting polymorphonuclear neutrophil (PMN) infiltration in murine peritonitis (ng/mouse range) as well as enhancing human macrophage uptake of apoptotic PMNs. At 1 nM, MaR1 was slightly more potent than resolvin D1 in stimulating human MΦ efferocytosis, an action not shared by leukotriene B(4). MaR1 also accelerated surgical regeneration in planaria, increasing the rate of head reappearance. On injury of planaria, MaR1 was biosynthesized from deuterium-labeled (d(5))-DHA that was blocked with lipoxygenase (LOX) inhibitor. MaR1 dose-dependently inhibited TRPV1 currents in neurons, blocked capsaicin (100 nM)-induced inward currents (IC(50) 0.49±0.02 nM), and reduced both inflammation- and chemotherapy-induced neuropathic pain in mice. These results demonstrate the potent actions of MaR1 in regulating inflammation resolution, tissue regeneration, and pain resolution. These findings suggest that chemical signals are shared in resolution cellular trafficking, a key process in tissue regeneration. Moreover, immunoresolvents of the innate immune response, such as MaR1, offer new opportunities for assessing MΦs and their local DHA metabolome in the return to tissue homeostasis.
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Institutes of Medicine, 77 Ave. Louis Pasteur, HIM 829, Boston, MA 02115, USA. cnserhan@zeus.bwh.harvard.edu
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.forename: Sergey
authors.initials: S
authors.lastname: Karamnov
authors.forename: Alexander
authors.initials: A
authors.lastname: Choi
authors.forename: Chul-Kyu
authors.initials: CK
authors.lastname: Park
authors.forename: Zhen-Zhong
authors.initials: ZZ
authors.lastname: Xu
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D002853:Chromatography, Liquid / Q000379:methods; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D005727:Ganglia, Spinal / Q000166:cytology; D006801:Humans; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D055432:Metabolomics / Q000379:methods; D051379:Mice; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D018408:Patch-Clamp Techniques; D010932:Planarians / Q000033:anatomy & histology / Q000187:drug effects / Q000502:physiology; D012038:Regeneration / Q000187:drug effects* / Q000502:physiology; D050916:TRPV Cation Channels / Q000378:metabolism; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: C535211:7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D004281:Docosahexaenoic Acids