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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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Research Article Inflammation Article has an altmetric score of 9

Maresin 1 activates LGR6 receptor promoting phagocyte immunoresolvent functions

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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 3

[3H]-MaR1 preparation and specific binding with human recombinant LGR6.

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[3H]-MaR1 preparation and specific binding with human recombinant LGR6.
...
(A) Synthetic [12,13]-acetylenic-MaR1 ME was converted to [12,13-3H]-MaR1-ME via catalytic hydrogenation using tritium gas (3H2). See Methods. (B) Chromatographic (green line) and radioactive (gray bars) tracing of [3H]-MaR1-ME. Results are mean ± SEM (n = 3). (Inset) Online UV spectra of [3H]-MaR1-ME; λmax 271 nm; representative of 3 separate experiments. (C and D) Competition binding. CHO cells were transfected with a human LGR6 plasmid. Transfected CHO cells (0.5 × 106 cells in 100-μl DPBS++) were incubated with 2 nM of [3H]-MaR1-ME in the absence or presence of (C) increasing concentrations of unlabeled MaR1-ME (10–10–10–5 M) or (D) unlabeled MaR1-ME (taken as 100% competition), MaR1, MCTR1, MCTR2 or MCTR3 (10–6 M) for 60 minutes at 4°C. Results are mean ± SEM (n = 3). *P < 0.05; ***P < 0.001, versus [3H]-MaR1-ME plus vehicle. One-way ANOVA with Tukey’s multiple comparisons test.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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