Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions
Nan Chiang, Stephania Libreros, Paul C. Norris, Xavier de la Rosa, Charles N. Serhan
Nan Chiang, Stephania Libreros, Paul C. Norris, Xavier de la Rosa, Charles N. Serhan
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Research Article Inflammation

Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions

Abstract

Resolution of acute inflammation is an active process orchestrated by endogenous mediators and mechanisms pivotal in host defense and homeostasis. The macrophage mediator in resolving inflammation, maresin 1 (MaR1), is a potent immunoresolvent, stimulating resolution of acute inflammation and organ protection. Using an unbiased screening of greater than 200 GPCRs, we identified MaR1 as a stereoselective activator for human leucine-rich repeat containing G protein–coupled receptor 6 (LGR6), expressed in phagocytes. MaR1 specificity for recombinant human LGR6 activation was established using reporter cells expressing LGR6 and functional impedance sensing. MaR1-specific binding to LGR6 was confirmed using 3H-labeled MaR1. With human and mouse phagocytes, MaR1 (0.01–10 nM) enhanced phagocytosis, efferocytosis, and phosphorylation of a panel of proteins including the ERK and cAMP response element-binding protein. These MaR1 actions were significantly amplified with LGR6 overexpression and diminished by gene silencing in phagocytes. Thus, we provide evidence for MaR1 as an endogenous activator of human LGR6 and a novel role of LGR6 in stimulating MaR1’s key proresolving functions of phagocytes.

Authors

Nan Chiang, Stephania Libreros, Paul C. Norris, Xavier de la Rosa, Charles N. Serhan

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Figure 6

MaR1-LGR6–dependent phosphorylation signals.

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MaR1-LGR6–dependent phosphorylation signals. (A) MaR1-dependent protein ...
(A) MaR1-dependent protein phosphorylation in human macrophages. Heat maps of phosphorylated signaling molecules at 0, 1, 2, 5, and 15 minutes after exposure of 10-nM MaR1 in M1 and M2 human macrophages was obtained using CyTOF (see Methods). (B, C) THP-1 cells transfected with either a mock vector or LGR6-specific shRNA were incubated with 10-nM MaR1 for 0 to 5 minutes. pCREB and pERK levels in GFP+ cells were determined using flow cytometry. Results are (B) representative histograms and (C) heat maps from n = 4. (D and E) Comparisons of MaR1 and its 12E isomer. THP-1 cells transfected with either a mock vector or LGR6-specific shRNA were incubated with MaR1 or 10-nM 12E-MaR1 for 1 (for pERK) or 2 minutes (for pCREB). pCREB and pERK levels were determined using flow cytometry. Results are (D) representative histograms and (E) mean ± SEM from 4 independent experiments. **P < 0.01; ****P < 0.0001 versus MaR1-treated mock vector transfected cells. One-way ANOVA with Tukey’s multiple comparisons test.