Resolvin D1, resolvin D2 and maresin 1 activate the GSK3β anti-inflammatory axis in TLR4-engaged human monocytes

Gu, Zhifeng; Lamont, Gwyneth; Lamont, Richard J.; Wang, Huizhi; Scott, David A.

doi:10.1177/1753425916628618

Cited by 71 publications

(50 citation statements)

References 55 publications

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“…In the case of RvE1, ERK/Akt/S6 pathway is involved in RvE1-stimulated phagocytosis in an ERV1-dependent manner (50). In addition, RvD1 and RvD2 increased phosphorylation of Akt and CREB in LPS-stimulate human monocytes (51). Inhibition of STAT3 phosphorylation decreases efferocytosis and M2 macrophage polarization in vitro (52).…”

Section: Discussionmentioning

confidence: 99%

Novel Resolvin D2 Receptor Axis in Infectious Inflammation

Chiang

Rosa

Libreros

et al. 2017

The Journal of Immunology

141

124

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Resolution of acute inflammation is an active process governed by specialized pro-resolving mediators (SPM) including resolvin D2 (RvD2) that activates a cell surface G protein–coupled receptor (GPCR), GPR18/DRV2. Here, we investigated RvD2-DRV2-dependent resolution mechanisms using DRV2-deficient mice (DRV2-KO). In polymicrobial sepsis initiated by cecal ligation and puncture (CLP), RvD2 (~2.7 nmol/mouse) significantly increased survival (>50%) of wild-type (WT), reduced hypothermia and bacterial titers compared to vehicle-treated CLP mice that succumbed at 48h. Protection by RvD2 was abolished in DRV2-KO mice. Mass spectrometry-based lipid mediator metabololipidomics demonstrated that DRV2-KO infectious exudates gave higher pro-inflammatory leukotriene (LT) B4 and pro-coagulating thromboxane (TX) B2, as well as lower SPM, including RvD1 and RvD3, compared to WT. RvD2-DRV2-initiated intracellular signals were investigated using mass cytometry (CyTOF) which demonstrated that RvD2 enhanced phosphorylation of CREB, ERK1/2 and STAT3 that were absent in DRV2-KO macrophages. Monitored by real-time imaging, RvD2-DRV2 interaction significantly enhanced phagocytosis of live E. coli, an action dependent on PKA 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.

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Section: Discussionmentioning

confidence: 99%

Novel Resolvin D2 Receptor Axis in Infectious Inflammation

Chiang

Rosa

Libreros

et al. 2017

The Journal of Immunology

141

124

View full text Add to dashboard Cite

show abstract

“…RvE1 increases phagocytosis by isolated macrophages through GPCR-mediated pathways (that is, the ChemR23 receptor) that activate ribosomal S6 (32). RvD1 and MaR1 each increase the abundance of pCREB in human monocytes (35). Our single-cell analysis demonstrated that RvE1, RvD1, RvD5, LXB 4 , and MaR1 (constituents of the same clot-SPM cluster) each activated CREB and S6 in neutrophils and monocytes, which led to enhanced phagocytosis by these leukocytes in blood, accelerating the first line of defense against pathogens.…”

Section: Discussionmentioning

confidence: 99%

A cluster of immunoresolvents links coagulation to innate host defense in human blood

et al. 2017

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Blood coagulation is a protective response that prevents excessive bleeding upon blood vessel injury. Here, we investigated the relationship between coagulation and the resolution of inflammation and infection by lipid mediators (LMs) through metabololipidomic-based profiling of human whole blood (WB) during coagulation. We identified temporal clusters of endogenously produced pro-thrombotic and proinflammatory LMs (eicosanoids), as well as specialized proresolving mediators (SPMs). In addition to eicosanoids, a specific SPM cluster was identified that consisted of resolvin E1 (RvE1), RvD1, RvD5, lipoxin B4, and maresin 1, each of which was present at bioactive concentrations (0.1 to 1 nM). Removal of adenosine from the coagulating blood markedly enhanced the amounts of SPMs produced and further increased the biosynthesis of RvD3, RvD4, and RvD6. The cyclooxygenase inhibitors celecoxib and indomethacin, which block the production of thomboxanes and prostanoids, did not block the production of clot-driven SPMs. Unbiased mass cytometry analysis demonstrated that the SPM cluster produced in human blood targeted leukocytes at the single-cell level, directly activating ERK and CREB signaling in neutrophils and CD14+ monocytes. Treatment of human whole blood with the components of this SPM cluster enhanced both the phagocytosis and killing of Escherichia coli by leukocytes. Together, these data identify a pro-resolving LM circuit, including endogenous molecular brakes and accelerators, which promoted host defense. These temporal LM-SPM clusters can provide accessible metabolomic profiles for precision and personalized medicine.

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“…In particular, RvD2 has shown efficacy at attenuating inflammation and acting through monocytes/ macrophages to mediate its effects (15,17,(26)(27)(28). Along with producing RvD2, these cells have recently been shown to express the RvD2 receptor, GPR18 (29).…”

Section: Rvd2 Decreases Lps-induced Cytokine Production and Tlr4 In Hmentioning

confidence: 99%

Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes

2016

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TLRs are critical for innate immunity, but excessive activation can lead to tissue damage and disease. Specialized proresolving mediators (SPMs), including resolvin D2 (RvD2), promote the active resolution of inflammation. How SPMs regulate early LPS signaling, including activation of TLR4, is unknown. We treated human THP-1 monocytic cells and primary human blood monocytes with RvD2 and LPS to evaluate modulation of TLRs. miRNA-146a overexpression and inhibition were used to dissect the mechanism of RvD2-mediated actions. We validated our studies using ELISAs for cytokines, PCR, Western blot analysis, and flow cytometry. Cells treated with 0.1% ethanol (control for RvD2) and/or PBS (control for LPS), and control microRNA mimics and inhibitors were used as controls. RvD2 reduced LPS-induced cytokines and TLR4 expression in human monocytes by up to 75%. In THP-1 cells, RvD2 reduced expression of TLR4, lymphocyte antigen 96 (MD-2), and downstream signals (MyD88, TRIF, and TAK1). These effects were partially mediated through RvD2 induction of microRNA-146a, and RvD2's actions were blocked by microRNA-146a inhibition. These new findings reveal the ability of RvD2 to reduce TLR4 expression and attenuate LPS-induced inflammation, providing a new area of SPM activity to investigate in this major area of therapeutic research.-Croasdell, A., Sime, P. J., Phipps, R. P. Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes. FASEB J. 30, 3181-3193 (2016). www.fasebj.org

show abstract

Resolvin D1, resolvin D2 and maresin 1 activate the GSK3β anti-inflammatory axis in TLR4-engaged human monocytes

Cited by 71 publications

References 55 publications

Novel Resolvin D2 Receptor Axis in Infectious Inflammation

Novel Resolvin D2 Receptor Axis in Infectious Inflammation

A cluster of immunoresolvents links coagulation to innate host defense in human blood

Resolvin D2 decreases TLR4 expression to mediate resolution in human monocytes

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