Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions
Nan Chiang, … , Xavier de la Rosa, Charles N. Serhan
Nan Chiang, … , Xavier de la Rosa, Charles N. Serhan
Published October 28, 2019
Citation Information: J Clin Invest. 2019;129(12):5294-5311. https://doi.org/10.1172/JCI129448.
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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 2

Human recombinant LGR6 receptor specificity.

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Human recombinant LGR6 receptor specificity. CHO-LGR6 cells were plated ...
CHO-LGR6 cells were plated onto 8-well ECIS arrays (8W10E+), incubated with (A and B) MaR1 (0.01-100 nM), (C and D) MaR1, PD1, LTB4 (100 nM) or vehicle alone (control), and impedance changes across CHO cell monolayers were continuously recorded every 4 seconds for 10 minutes using ECIS. Results are mean (A and C) or mean ± SEM (B and D) (n = 3–4). **P < 0.01, versus vehicle. ##P < 0.01; ###P < 0.001, versus MaR1. One-way ANOVA with Tukey’s multiple comparisons test. (E) Space-filling 3D molecular models of MaR1, PD1, and LTB4 with energy minimization. R and S denote the stereochemistry of the hydroxyl groups; E and Z denote the double-bond geometry. Area within the blue dashed lines denotes the dihydroxyl and triene structures oriented in the E, E, Z configuration of these mediators.