Role of Chemerin/ChemR23 axis as an emerging therapeutic perspective on obesity-related vascular dysfunction

Over the years, obesity has become a worldwide public health incident [1, 2], which is mainly caused by the accumulation of white adipose tissue (WAT) [3]. Besides, obesity is also an acknowledged predisposing and risk factor for types of disorders, including diabetes, dyslipidemia, vascular dysfunction and so on [4]. Vascular dysfunction then leads to multi-system diseases, such as cardiovascular system diseases (atherosclerosis, hypertension) [5, 6], respiratory system diseases (pulmonary hypertension, adult respiratory distress syndrome) [7, 8], digestive system diseases (Budd-Chiari syndrome, severe acute pancreatitis) [9, 10] and so on.

WAT is a well-acknowledged human endocrine organ with the secretion of various adipokines (i.e. adipocytokines), in addition to serving as energy storage [11]. Adipokines are the conditioning agents of adipogenesis, vascular function, glucose and insulin metabolisms [12‐15], whose regulating ability becomes more pronounced with the expanded mass of WAT due to obesity. Chemerin is also a protein whose systemic level will increase in obesity and plays an extremely important role in regulating vascular function through binding its receptor, chemR23. Notably, chemerin can be activated in obesity, transforming from inert prochemerin to activated chemerin [16].

Interestingly, chemerin is more highly expressed in perivascular adipose tissue (PVAT) than in subcutaneous or visceral adipose tissue [17], which provides a mechanistic explanation for the regulation of vascular function by chemerin, partly due to the natural location advantage and the absence of mechanical barrier between PVAT and blood vessels [18]. Evidence had shown that chemerin/chemR23 axis exerted significant effects on the regulation of vascular function, but the detailed mechanisms and pathways mediated by this axis remained controversial.

In this review, we introduce the formation of chemerin via COOH-terminal processing and the alteration of expressions of both chemerin and chemR23 in obesity. Furthermore, the role of chemerin/chemR23 axis in vascular dysfunction, especially when the body is in the state of obesity is described in detail.

Chemerin is a 16 KDa protein and encoded by tazarotene induced gene 2 (i.e. retinoic acid receptor responder 2). It was initially reported as a synthetic retinoid gene in psoriatic skin lesions in 1997 [19, 20]. In previous studies, chemerin was identified as a natural ligand of orphan guanosine 5'-triphosphate (GTP)-binding protein-coupled receptors (GPCR), also known as chemokine like receptor 1 (CMKLR1) or chemR23 [18]. There exist three phases before chemerin evolves into active modalities: pre-prochemerin, prochemerin, and chemerin stages [22]. So-called pre-prochemerin (1–163) is a 163-amino-acid long protein without biological activity and directly encoded by tazarotene induced gene 2. It transforms into prochemerin (21–163), a 143-amino-acid long protein with low biological activity, by getting rid of 20 NH₂-terminal amino acids in a proteolytic cleavage way [20, 23]. And prochemerin undergoes extracellular COOH-terminal processing by certain proteases [24], ending up as chemerin with higher biological activity and chemR23 receptor binding ability [20].

It is worth mentioning that different types of proteases simultaneously cut prochemerin into diverse length products that differ in COOH-terminal amino acids and potency for chemR23 activation. For instance, the first enzymes shown to activate prochemerin are called elastase and cathepsin G [24], both belonging to neutrophil proteases species. The former removes the 6, 8, or 11 COOH-terminal amino acids to produce three forms, chemerin (21–157), (21–155), or (21–152), respectively [21]. Among them, chemerin (21–157) holds the highest activity. While the latter clears the 7 COOH-terminal amino acids to produce one fragment, chemerin (21–156) [25], which is the second most active form next to chemerin (21–157), and both are the two active forms in the human body.

Prochemerin is also cut into chemerin (21–158) with low activity mediated by tryptase and plasmin through sweeping the 5 COOH-terminal amino acids away. Chemerin (21–158) undergoes the second processing to complement this activity by carboxypeptidases N or B (CPN or CPB), ultimately forming chemerin (21–157) [26, 27]. This illustrates that the segments formed by the COOH-terminal processing might be also the substrates in the subsequent processing.

In addition to the above typical proteases leading to the formation of various fragments, there are some enzymes (e.g., mast cell chymase and angiotensin-converting enzyme) having been reported to cleave certain fragments to generate relatively inactive modalities, including chemerin (21–154) and chemerin (21–155) [28, 29].

Taken together, chemerin is conscripted to undergo proteolytic cleavages to remove amino acids located in NH₂-terminal and COOH-terminal by multitudinous proteases before the formation of diverse isoforms (Table 1), which differ in their activities. Most of them hold a low activity or no activity, even antagonizing the active isoforms, generally referring to chemerin (21–157). This manifests that a complex regulatory network controls chemerin bioactivity.

Noticeably, excessive chemerin tends to be activated when the body is in the state of obesity with the accelerated COOH-terminal processing. To some extent, it is a hint that chemerin seems to have inextricable relation to obesity.

The chemerin receptors that have been recognized and understood mainly include chemR23(i.e. GPCR or CMKLR1), G protein-coupled receptor (GPR)1 and chemokine (C–C motif) receptor-like (CCRL)2. They are all located at the surface of cells but distinct from each other in the affinity of binding to chemerin, signaling, and internalization of the chemerin-receptor complex (Fig. 1).

Blood vessels are the largest network structure of the human body, mainly composed of the intima, media, adventitia, and PVAT surrounding the adventitia [52]. Endothelial cells (ECs) from intima and vascular smooth muscle cells (VSMCs) from media are recognized as the most pivotal cell populations for normal vascular function. In addition, PVAT attracts much attention recently because diverse adipokines from PVAT regulate vascular function more quickly than those from adipose tissue in other areas [76]. Thus, ECs, VSMCs, and PVAT maintain vascular homeostasis together. In other words, alters of structures or features of any one of them could induce vascular dysfunction.

Although we have a general idea of the significant role of chemerin/chemR23 axis in obesity-related vascular dysfunction, it remains a pity that there is almost no drug circulating in the market targeting chemerin/chemR23 axis. Through a variety of related studies, several drugs targeting chemerin/chemR23 axis are still considered to have potential and feasibility for use in humans. They include CCX832, RvE1, chemerin-9, chemerin ASO, and nano-antioxidant.

The significance of chemerin has been illustrated in many researches. Circulating chemerin concentrations are related to the development and progression of multiple system diseases and even are used as a biomarker for the diagnosis of cardiovascular diseases like ACS, AV stenosis, AAA, and so on. The chemerin/chemR23 axis is a complex network strictly involved in the occurrence and development of obesity and regulation of vascular function, which is supported by abundant rationale from clinical and experimental observations. However, the concrete mechanisms and pathways of chemerin/chemR23 axis displaying in these disorders remain a mystery and worth exploring. Thus, uncovering the answer to key questions (Fig. 3) probably conduces to deeply understand and better define the relationship among this axis, obesity, and vascular dysfunction. Moreover, it is helpful to seek the possibility of other treatments in addition to CCX832, RvE1, chemerin ASO, chemerin-9, nano-antioxidants even other alternative and salutary isoforms of chemerin.