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Toll-like receptor 7 stimulates production of specialized pro-resolving lipid mediators and promotes resolution of airway inflammation.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Koltsida, Ourania 
Karamnov, Sergey 
Vickery, Thad 
Chairakaki, Aikaterini-Dimitra 

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.

Description

Keywords

Animals, Arachidonate 12-Lipoxygenase, Arachidonate 15-Lipoxygenase, Arachidonate 5-Lipoxygenase, Bronchoalveolar Lavage Fluid, Cells, Cultured, Docosahexaenoic Acids, Humans, Inflammation, Inflammation Mediators, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes, Toll-Like Receptor 7

Journal Title

EMBO Mol Med

Conference Name

Journal ISSN

1757-4676
1757-4684

Volume Title

5

Publisher

Springer Science and Business Media LLC