Resolution of acute inflammation is an active process governed by specialized proresolving mediators, including resolvin (Rv)D2, that activates a cell surface G protein–coupled receptor, GPR18/DRV2. In this study, we investigated RvD2-DRV2–dependent resolution mechanisms using DRV2-deficient mice (DRV2-knockout [KO]). In polymicrobial sepsis initiated by cecal ligation and puncture, RvD2 (∼2.7 nmol/mouse) significantly increased survival (>50%) of wild-type mice and reduced hypothermia and bacterial titers compared with vehicle-treated cecal ligation and puncture mice that succumbed at 48 h. Protection by RvD2 was abolished in DRV2-KO mice. Mass spectrometry–based lipid mediator metabololipidomics demonstrated that DRV2-KO infectious exudates gave higher proinflammatory leukotriene B4 and procoagulating thromboxane B2, as well as lower specialized proresolving mediators, including RvD1 and RvD3, compared with wild-type. RvD2-DRV2–initiated intracellular signals were investigated using mass cytometry (cytometry by time-of-flight), which demonstrated that RvD2 enhanced phosphorylation of CREB, ERK1/2, and STAT3 in WT but not DRV2-KO macrophages. Monitored by real-time imaging, RvD2–DRV2 interaction significantly enhanced phagocytosis of live Escherichia coli, an action dependent on protein kinase A and STAT3 in macrophages. Taken together, we identified an RvD2/DRV2 axis that activates intracellular signaling pathways that increase phagocytosis-mediated bacterial clearance, survival, and organ protection. Moreover, these results provide evidence for RvD2-DRV2 and their downstream pathways in pathophysiology of infectious inflammation.
This article is featured in In This Issue, p.555
This work was supported in part by National Institutes of Health Grants R01 GM38765 (to C.N.S.) and R01 GM38765-29S1 (to S.L.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- bone marrow–derived macrophage
- cecal ligation and puncture
- cytometry by time-of-flight
- docosahexaenoic acid
- lipid mediator
- matrix metalloproteinase
- multiple reaction monitoring
- protein kinase A
- polymorphonuclear neutrophil
- resolvin D2 (7S,16R,17S-trihydroxy-docosa-4Z,8E,10Z,12E,14E,19Z-hexaenoic acid)
- specialized proresolving mediator
- serum-treated zymosan particle
- Received September 22, 2016.
- Accepted November 15, 2016.
- Copyright © 2017 by The American Association of Immunologists, Inc.