title: Toll-like receptor 7 stimulates production of specialized pro-resolving lipid mediators and promotes resolution of airway inflammation.
abstract: Although specialized pro-resolving mediators (SPMs) biosynthesized from polyunsaturated fatty acids are critical for the resolution of acute inflammation, the molecules and pathways that induce their production remain elusive. Here, we show that TLR7, a receptor recognizing viral ssRNA and damaged self-RNA, mobilizes the docosahexaenoic acid (DHA)-derived biosynthetic pathways that lead to the generation of D-series SPMs. In mouse macrophages and human monocytes, TLR7 activation triggered production of DHA-derived monohydroxy metabolome markers and generation of protectin D1 (PD1) and resolvin D1 (RvD1). In mouse allergic airway inflammation, TLR7 activation enhanced production of DHA-derived SPMs including PD1 and accelerated the catabasis of Th2-mediated inflammation. D-series SPMs were critical for TLR7-mediated resolution of airway inflammation as this effect was lost in Alox15(-/-) mice, while resolution was enhanced after local administration of PD1 or RvD1. Together, our findings reveal a new previously unsuspected role of TLR7 in the generation of D-series SPMs and the resolution of allergic airway inflammation. They also identify TLR stimulation as a new approach to drive SPMs and resolution of inflammatory diseases.
authors.affiliation: Division of Immunogenetics, Center for Immunology and Transplantation, Biomedical Research Foundation Academy of Athens, Athens, Greece.
authors.forename: Ourania
authors.initials: O
authors.lastname: Koltsida
authors.forename: Sergey
authors.initials: S
authors.lastname: Karamnov
authors.forename: Katerina
authors.initials: K
authors.lastname: Pyrillou
authors.forename: Thad
authors.initials: T
authors.lastname: Vickery
authors.forename: Aikaterini-Dimitra
authors.initials: AD
authors.lastname: Chairakaki
authors.forename: Constantin
authors.initials: C
authors.lastname: Tamvakopoulos
authors.forename: Paschalis
authors.initials: P
authors.lastname: Sideras
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.forename: Evangelos
authors.initials: E
authors.lastname: Andreakos
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001093:Arachidonate 15-Lipoxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D004281:Docosahexaenoic Acids / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000628:therapy; D018836:Inflammation Mediators / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D051199:Toll-Like Receptor 7 / Q000378:metabolism*
chemical_list: D018836:Inflammation Mediators; D051199:Toll-Like Receptor 7; C487679:protectin D1; C518399:resolvin D1; D004281:Docosahexaenoic Acids; C521960:Alox15 protein, mouse; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D001094:Arachidonate 5-Lipoxygenase