Novel Resolvin D2 Receptor Axis in Infectious Inflammation [INNATE IMMUNITY AND INFLAMMATION]

Abstract

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.

Footnotes

  • 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:

    BMDM
    bone marrow–derived macrophage
    CLP
    cecal ligation and puncture
    CyTOF
    cytometry by time-of-flight
    DHA
    docosahexaenoic acid
    KO
    knockout
    LM
    lipid mediator
    LT
    leukotriene
    LX
    lipoxin
    MMP
    matrix metalloproteinase
    MRM
    multiple reaction monitoring
    PKA
    protein kinase A
    PMN
    polymorphonuclear neutrophil
    Rv
    resolvin
    RvD2
    resolvin D2 (7S,16R,17S-trihydroxy-docosa-4Z,8E,10Z,12E,14E,19Z-hexaenoic acid)
    SPM
    specialized proresolving mediator
    STZ
    serum-treated zymosan particle
    TX
    thromboxane
    WT
    wild-type.
  • Received September 22, 2016.
  • Accepted November 15, 2016.

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