CMKLR1 senses chemerin/resolvin E1 to control adipose thermogenesis and modulate metabolic homeostasis.

Induction of beige fat for thermogenesis is a potential therapy to improve homeostasis against obesity. ß3-adrenoceptor (ß3-AR), a type of G protein-coupled receptor (GPCR), is believed to mediate the thermogenesis of brown fat in mice. However, ß3-AR has low expression in human adipose tissue, precluding its activation as a standalone clinical modality. This study aimed at identifying a potential GPCR target to induce beige fat. We found that chemerin chemokine-like receptor 1 (CMKLR1), one of the novel GPCRs, mediated the development of beige fat via its two ligands, chemerin and resolvin E1 (RvE1). The RvE1 levels were decreased in the obese mice, and RvE1 treatment led to a substantial improvement in obese features and augmented beige fat markers. Inversely, despite sharing the same receptor as RvE1, the chemerin levels were increased in obesogenic conditions, and chemerin treatment led to an augmented obese phenotype and a decline of beige fat markers. Moreover, RvE1 and chemerin induced or restrained the development of beige fat, respectively, via the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. We further showed that RvE1 and chemerin regulated mTORC1 signaling differentially by forming hydrogen bonds with different binding sites of CMKLR1. In conclusion, our study showed that RvE1 and chemerin affected metabolic homeostasis differentially, suggesting that selectively modulating CMKLR1 may be a potential therapeutic target for restoring metabolic homeostasis.

[Gualou Xiebai Banxia Decoction treats type 2 diabetes mellitus combined with acute myocardial infarction via chemerin/ CMKLR1/PPARα signaling pathway].

This study aims to investigate the effects of Gualou Xiebai Banxia Decoction(GXBD) on type 2 diabetes mellitus(T2DM) combined with acute myocardial infarction(AMI) in rats via chemerin/chemokine-like receptor 1(CMKLR1)/peroxisome proliferator-activated receptor α(PPARα) signaling pathway, and to explore the mechanism of GXBD in alleviating glucose and lipid metabolism disorders. The SD rats were randomized into control, model, positive control, and low-and high-dose GXBD groups. The rat model of T2DM was established by administration with high-fat emulsion(HFE) by gavage and intraperitoneal injection with streptozotocin, and then coronary artery ligation was performed to induce AMI. The control and model groups were administrated with the equal volume of normal saline, and other groups were administrated with corresponding drugs by gavage. Changes in relevant metabolic indicators were assessed by ELISA and biochemical assays, and the protein levels of chemerin, CMKLR1, and PPARα in the liver, abdominal fat, and heart were determined by Western blot. The results showed that GXBD alleviated the myocardial damage and reduced the levels of blood lipids, myocardial enzymes, and inflammatory cytokines, while it did not lead to significant changes in blood glucose. Compared with the model group, GXBD down-regulated the expression of chemerin in peripheral blood and up-regulated the expression of cyclic adenosine monophosphate(cAMP) and protein kinase A(PKA) in the liver. After treatment with GXBD, the protein levels of chemerin and CMKLR1 in the liver, abdominal fat, and heart were down-regulated, while the protein levels of PPARα in the liver and abdominal fat were up-regulated. In conclusion, GXBD significantly ameliorated the disorders of glycolipid metabolism in the T2DM-AMI model by regulating the chemerin/CMKLR1/PPARα signaling pathway to exert a protective effect on the damaged myocardium. This study provides a theoretical basis for further clinical study of GXBD against T2DM-AMI and is a manifestation of TCM treatment of phlegm and turbidity causing obstruction at the protein level.

Effect of Regulation of Chemerin/Chemokine-like Receptor 1/Stimulator of Interferon Genes Pathway on Astrocyte Recruitment to Aß Plaques.

Recruitment and accumulation of reactive astrocytes around senile plaques are common pathological features of Alzheimer's disease (AD), with unclear mechanisms. Chemerin, an adipokine implicated in neuroinflammation, acts through its receptor, chemokine-like receptor 1 (CMKLR1), which also functions as a receptor for amyloid ß (Aß). The impact of the chemerin/CMKLR1 axis on astrocyte migration towards Aß plaques is unknown. Here we investigated the effect of CMKLR1 on astrocyte migration around Aß deposition in APP/PS1 mice with Cmklr1 knockout (APP/PS1-Cmklr1-/-). CMKLR1-expressed astrocytes were upregulated in the cortices and hippocampi of 9-month-old APP/PS1 mice. Chemerin mainly co-localized with neurons, and its expression was reduced in the brains of APP/PS1 mice, compared to WT mice. CMKLR1 deficiency decreased astrocyte colocalization with Aß plaques in APP/PS1-Cmklr1-/- mice, compared to APP/PS1 mice. Activation of the chemerin/CMKLR1 axis promoted the migration of primary cultured astrocytes and U251 cells, and reduced astrocyte clustering induced by Aß42. Mechanistic studies revealed that chemerin/CMKLR1 activation induced STING phosphorylation. Deletion of STING attenuated the promotion of the chemerin/CMKLR1 axis relative to astrocyte migration and abolished the inhibitory effect of chemerin on Aß42-induced astrocyte clustering. These findings suggest the involvement of the chemerin/CMKLR1/STING pathway in the regulation of astrocyte migration and recruitment to Aß plaques/Aß42.

The chemerin-CMKLR1 axis in keratinocytes impairs innate host defense against cutaneous Staphylococcus aureus infection.

The skin is the most common site of Staphylococcus aureus infection, which can lead to various diseases, including invasive and life-threatening infections, through evasion of host defense. However, little is known about the host factors that facilitate the innate immune evasion of S. aureus in the skin. Chemerin, which is abundantly expressed in the skin and can be activated by proteases derived from S. aureus, has both direct bacteria-killing activity and immunomodulatory effects via interactions with its receptor CMKLR1. Here, we demonstrate that a lack of the chemerin/CMKLR1 axis increases the neutrophil-mediated host defense against S. aureus in a mouse model of cutaneous infection, whereas chemerin overexpression, which mimics high levels of chemerin in obese individuals, exacerbates S. aureus cutaneous infection. Mechanistically, we identified keratinocytes that express CMKLR1 as the main target of chemerin to suppress S. aureus-induced IL-33 expression, leading to impaired skin neutrophilia and bacterial clearance. CMKLR1 signaling specifically inhibits IL-33 expression induced by cell wall components but not secreted proteins of S. aureus by inhibiting Akt activation in mouse keratinocytes. Thus, our study revealed that the immunomodulatory effect of the chemerin/CMKLR1 axis mediates innate immune evasion of S. aureus in vivo and likely increases susceptibility to S. aureus infection in obese individuals.

Chemerin/CMKLR1 pathway exacerbates cisplatin-induced spiral ganglion neuron injury.

This study investigated whether chemerin/chemokine-like receptor 1 (CMKLR1) pathway participate in cisplatin-induced spiral ganglion neuron (SGN) damage. Middle cochlear turn was collected from C57BL/6 mice and the SGNs were cultured. Cisplatin, 2-(anaphthoyl) ethyltrimethylammonium iodide (α-NETA), or recombinant mouse chemerin was added into the medium for the treatment. Relative mRNA and protein expression was determined by RT-PCR, ELISA and Western blot, respectively. In cultured mouse cochlear SGNs, the treatment of cisplatin enhanced the secretion of chemerin and CMKLR1. Recombinant chemerin promoted but α-NETA inhibited chemerin/CMKLR1 pathway in cisplatin stimulated SGNs. Cisplatin-induced apoptosis and inflammation response in SGNs were enhanced by recombinant chemerin while inhibited by α-NETA. Recombinant chemerin promoted but α-NETA inhibited NF-κB signal in cisplatin stimulated SGNs. In conclusion, chemerin/CMKLR1 pathway regulated apoptosis and inflammation response in cisplatin-induced SGN injury through NF-κB signaling pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s43188-023-00205-0.

The Dual Role of Chemerin in Lung Diseases.

Chemerin is an atypical chemokine first described as a chemoattractant agent for monocytes, natural killer cells, plasmacytoid and myeloid dendritic cells, through interaction with its main receptor, the G protein-coupled receptor chemokine-like receptor 1 (CMKLR1). Chemerin has been studied in various lung disease models, showing both pro- and anti-inflammatory properties. Given the incidence and burden of inflammatory lung diseases from diverse origins (infectious, autoimmune, age-related, etc.), chemerin has emerged as an interesting therapeutical target due to its immunomodulatory role. However, as highlighted by this review, further research efforts to elucidate the mechanisms governing chemerin's dual pro- and anti-inflammatory characteristics are urgently needed. Moreover, although a growing body of evidence suggests chemerin as a potential biomarker for the diagnosis and/or prognosis of inflammatory lung diseases, this review underscores the necessity for standardizing both sampling types and measurement techniques before drawing definitive conclusions.

Polymorphisms of the bovine chemokine receptor-like 1 gene and their associations with meat quality traits in Qinchuan cattle (Bos taurus)

Background: We investigated the polymorphisms of the bovine chemokine receptor-like 1(CMKLR1) gene. The coding region of CMKLR1 was screened in Qinchuan cattle by PCR-RFLP technology. Results: In this study, we discovered two single nucleotide polymorphisms (SNPs) (264G > C and 762C > T) in the coding region of the CMKLR1 gene. Hence, we described the BmgT120l and Pdm1 PCR-RFLP methods for detecting the 64G > C and 762C > T mutations, respectively. PCR-RFLP and sequencing were used to analyze the two loci of CMKLR1 gene in 324 individuals, which were randomly selected from breeding populations. Furthermore, meat quality traits in another 80 Qinchuan individuals were analyzed by the comparison between the genotypes and their phenotypic data. Conclusions: The results showed that the G264C SNP and C762T SNP of bovine CMKLR1 were significantly associated with backfat thickness (BFT) and water holding capacity (WHC), respectively.