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

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.

Serafin DS ，Allyn B ，Sassano MF ，Timoshchenko RG ，Mattox D ，Brozowski JM ，Siderovski DP ，Truong YK ，Esserman D ，Tarrant TK ，Billard MJ ... -  《-》

Multiple functions of G protein-coupled receptor kinases.

Watari K ，Nakaya M ，Kurose H 《-》

Selective recruitment of G protein-coupled receptor kinases (GRKs) controls signaling of the insulin-like growth factor 1 receptor.

Zheng H ，Worrall C ，Shen H ，Issad T ，Seregard S ，Girnita A ，Girnita L ... -  《-》

Chemerin partly mediates tumor-inhibitory effect of all-trans retinoic acid via CMKLR1-dependent natural killer cell recruitment.

Down-regulated chemerin expression has been reported to correlate with poor prognosis of several types of cancer including melanoma. All-trans retinoic acid (atRA) is a potent inducer of chemerin, and we previously reported that atRA inhibited murine melanoma growth through enhancement of anti-tumor T-cell immunity. Here, we aimed to investigate whether loss of endogenous chemerin accelerated melanoma growth and whether chemerin was involved in the melanoma-inhibitory effect of atRA. We demonstrated that chemerin was constitutively expressed in the skin, which was down-regulated during murine melanoma growth. Rarres2-/- mice, which are deficient in chemerin, exhibited aggravated tumor growth and impaired tumor-infiltrating natural killer (NK) cells that express CMKLR1, the functional receptor of chemerin. Topical treatment with atRA up-regulated skin chemerin expression, which was primarily derived from dermal cells. Moreover, atRA treatment significantly enhanced tumor-infiltrating NK cells, which was completely abrogated in Rarres2-/- mice and Cmklr1-/- mice, suggesting a dependency of NK cell recruitment on the chemerin-CMKLR1 axis in melanoma. Despite comparable melanoma growth detected in wild-type mice and Cmklr1-/- mice, lack of CMKLR1 partially abrogated the melanoma-inhibitory effect of atRA. This may be due to the inability to enhance tumor-infiltrating NK cells in Cmklr1-/- mice following atRA treatment. Collectively, our study suggests that down-regulation of chemerin could be a strategy used by cancers such as melanoma to impair anti-tumor NK cell immunity and identifies a new anti-tumor mechanism of atRA by up-regulating chemerin to enhance CMKLR1-dependent NK cell recruitment.

Song Y ，Yin W ，Dan Y ，Sheng J ，Zeng Y ，He R ... -  《-》

Signaling Properties of Chemerin Receptors CMKLR1, GPR1 and CCRL2.

De Henau O ，Degroot GN ，Imbault V ，Robert V ，De Poorter C ，Mcheik S ，Galés C ，Parmentier M ，Springael JY ... -  《PLoS One》