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.

Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes

“…There is some evidence for the link between SPMs and other TLRs in the literature. Activation of TLR7 with R-828 stimulates production of SPMs in mouse and human macrophages, which then act in a feedback loop to promote resolution of allergic airway inflammation (45). It is noteworthy that these studies were also stimulus dependent as LPS did not induce production of SPMs and lipoxygenase activity in this model.…”

Low TLR7 gene expression in atherosclerotic plaques is associated with major adverse cardio- and cerebrovascular events

“…5,7 Additionally, recent publications from other groups have reported TLR7-dependent antiinflammatory control mechanisms. 16,17 TLR7 was expressed in all analysed plaques. In our screening of markers for cells that are usually found in the plaque and in healthy intima, we noted a co-expression of TLR7 in infiltrating leukocytes but not in smooth muscle cells or the luminal endothelium.…”

“…Recent studies have identified subtypes of T cells and macrophages that do not necessarily drive pathogenesis but may mediate healing, likely by primarily eliciting anti-inflammatory responses. 18,19 Regarding the downstream effects of TLR7 activation, two recent studies have implicated TLR7 in the control or abatement of inflammation and in the adaptive immune response in both macrophages 16 and T cells, 17 cell types which are frequently found in atherosclerotic lesions. In an experimental study of airway inflammation, imiquimod promoted the resolution of inflammation by inducing the lipid mediator resolvin D in murine macrophages, 16 an effect that has also been observed in vitro in human monocytes.…”

Identification of Novel Chondroprotective Mediators in Resolving Inflammatory Exudates

“…This second phase of inflammation has gained interest in the last decade, with the characterization of specific proresolving mediators (1) and receptors (25) and definition of fundamental proresolving processes, which until recently have been predominantly studied in the context of immune cell reactivity and behavior (4,26). However, the end point of resolution is the repair of the affected tissue with recovery of normal physiological functions.…”