Chemerin-activated functions of CMKLR1 are regulated by G protein-coupled receptor kinase 6 (GRK6) and β-arrestin 2 in inflammatory macrophages

D. Stephen Serafin, Brittney Allyn, Maria F. Sassano, Roman G. Timoshchenko, Daniel Mattox, Jaime M. Brozowski, David P. Siderovski, Kinh N Truong, Denise Esserman, Teresa K Tarrant, Matthew John Billard

Research output: Contribution to journalArticle

Abstract

Chemerin receptor (CMKLR1) is a G protein-coupled receptor (GPCR) implicated in macrophage-mediated inflammation and in several forms of human arthritis. Analogous to other GPCR, CMKLR1 is likely regulated by G protein-coupled receptor kinase (GRK) phosphorylation of intracellular domains in an activation-dependent manner, which leads to recruitment and termination of intracellular signaling via desensitization and internalization of the receptor. The ubiquitously expressed GRK family members include GRK2, GRK3, GRK5, and GRK6, but it is unknown which GRK regulates CMKLR1 cellular and signaling functions. Our data show that activation of CMKLR1 by chemerin in primary macrophages leads to signaling and functional outcomes that are regulated by GRK6 and β-arrestin 2. We show that arrestin recruitment to CMKLR1 following chemerin stimulation is enhanced with co-expression of GRK6. Further, internalization of endogenous CMKLR1, following the addition of chemerin, is decreased in inflammatory macrophages from GRK6- and β-arrestin 2-deficient mice. These GRK6- and β-arrestin 2-deficient macrophages display increased migration toward chemerin and altered AKT and Extracellular-signal Related Kinase (ERK) signaling. Our findings show that chemerin-activated CMKLR1 regulation in inflammatory macrophages is largely GRK6 and β-arrestin mediated, which may impact innate immunity and have therapeutic implications in rheumatic disease.

LanguageEnglish (US)
Pages12-21
Number of pages10
JournalMolecular Immunology
Volume106
DOIs
StatePublished - Feb 1 2019

Fingerprint

Arrestin
G-Protein-Coupled Receptors
Arthritis
Macrophages
G-Protein-Coupled Receptor Kinases
Rheumatic Diseases
Innate Immunity
G-protein-coupled receptor kinase 6
beta-Arrestin 2
Phosphotransferases
Phosphorylation
Inflammation

Keywords

  • Arrestin
  • Arthritis
  • Chemerin
  • G protein-coupled receptor (GPCR)
  • G protein-coupled receptor kinase (GRK)
  • Macrophage

ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

Cite this

Chemerin-activated functions of CMKLR1 are regulated by G protein-coupled receptor kinase 6 (GRK6) and β-arrestin 2 in inflammatory macrophages. / Serafin, D. Stephen; Allyn, Brittney; Sassano, Maria F.; Timoshchenko, Roman G.; Mattox, Daniel; Brozowski, Jaime M.; Siderovski, David P.; Truong, Kinh N; Esserman, Denise; Tarrant, Teresa K; Billard, Matthew John.

In: Molecular Immunology, Vol. 106, 01.02.2019, p. 12-21.

Research output: Contribution to journalArticle

Serafin, D. Stephen ; Allyn, Brittney ; Sassano, Maria F. ; Timoshchenko, Roman G. ; Mattox, Daniel ; Brozowski, Jaime M. ; Siderovski, David P. ; Truong, Kinh N ; Esserman, Denise ; Tarrant, Teresa K ; Billard, Matthew John. / Chemerin-activated functions of CMKLR1 are regulated by G protein-coupled receptor kinase 6 (GRK6) and β-arrestin 2 in inflammatory macrophages. In: Molecular Immunology. 2019 ; Vol. 106. pp. 12-21.
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AU - Serafin, D. Stephen

AU - Allyn, Brittney

AU - Sassano, Maria F.

AU - Timoshchenko, Roman G.

AU - Mattox, Daniel

AU - Brozowski, Jaime M.

AU - Siderovski, David P.

AU - Truong, Kinh N

AU - Esserman, Denise

AU - Tarrant, Teresa K

AU - Billard, Matthew John

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AB - Chemerin receptor (CMKLR1) is a G protein-coupled receptor (GPCR) implicated in macrophage-mediated inflammation and in several forms of human arthritis. Analogous to other GPCR, CMKLR1 is likely regulated by G protein-coupled receptor kinase (GRK) phosphorylation of intracellular domains in an activation-dependent manner, which leads to recruitment and termination of intracellular signaling via desensitization and internalization of the receptor. The ubiquitously expressed GRK family members include GRK2, GRK3, GRK5, and GRK6, but it is unknown which GRK regulates CMKLR1 cellular and signaling functions. Our data show that activation of CMKLR1 by chemerin in primary macrophages leads to signaling and functional outcomes that are regulated by GRK6 and β-arrestin 2. We show that arrestin recruitment to CMKLR1 following chemerin stimulation is enhanced with co-expression of GRK6. Further, internalization of endogenous CMKLR1, following the addition of chemerin, is decreased in inflammatory macrophages from GRK6- and β-arrestin 2-deficient mice. These GRK6- and β-arrestin 2-deficient macrophages display increased migration toward chemerin and altered AKT and Extracellular-signal Related Kinase (ERK) signaling. Our findings show that chemerin-activated CMKLR1 regulation in inflammatory macrophages is largely GRK6 and β-arrestin mediated, which may impact innate immunity and have therapeutic implications in rheumatic disease.

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