Abstract

Inflammation-related diseases, including cardiovascular diseases, immune disorders, and infectious diseases, have high prevalence and disability rates, imposing heavy socioeconomic and healthcare burdens. Thus, elucidating the molecular mechanisms underlying inflammation and identifying therapeutic targets are critical for the treatment of inflammation-related diseases. Chemerin, an adipokine and chemotactic protein, primarily mediates its biological effects through ChemerinR1, a G protein-coupled receptor (GPCR). Over the past 3 decades, the Chemerin/ChemerinR1 axis has been implicated in the regulation of various physiological processes, such as inflammation, metabolism, and immune response. We have comprehensively reviewed this axis plays an important role in the onset, progression, and prognosis of inflammation-related diseases, highlighting its translational potential for understanding these diseases and developing targeted therapies. This review aims to elucidate the specific mechanism of the Chemerin/ChemerinR1 axis in inflammation-related diseases. Specifically, the Chemerin/ChemerinR1 axis activates the mitogen-activated protein kinase (MAPK), PI3K/Akt, and NF-κB signaling pathways, thereby further regulating cell functions and the initiation and progression of inflammation. We also elucidate the effect of the Chemerin/ChemerinR1 axis on various inflammation-related diseases, such as hypertension, atherosclerosis, stroke, obesity, rheumatoid arthritis, and inflammatory bowel disease. Additionally, the Chemerin/ChemerinR1 axis can serve as a biomarker for various inflammation-related diseases, enabling early diagnosis, disease monitoring, and evaluation of treatment effects. Therefore, targeting the Chemerin/ChemerinR1 axis holds great potential for the treatment of vascular inflammatory diseases.

1 Introduction

Inflammation is a fundamental pathological mechanism implicated in a wide range of conditions including cardiovascular, immune-mediated, and infectious diseases (Liberale et al., 2022; Tang et al., 2026). These conditions represent major global health threats owing to their high prevalence, disability, and mortality. With population aging and evolving lifestyle patterns, the incidence of inflammation-related diseases is increasing, imposing substantial socioeconomic and healthcare burdens (Wu et al., 2023). Consequently, elucidating the molecular mechanisms underlying vascular inflammation and identifying novel therapeutic targets are pressing priorities in cardiovascular research (Wang et al., 2015).

Chemerin, an adipokine and chemotactic mediator, exerts its biological effects primarily through chemokine-like receptor 1 (CMKLR1, designated as ChemerinR1), a G protein-coupled receptor (GPCR). The Chemerin/ChemerinR1 axis is involved in the regulation of various physiological functions, such as metabolism, angiogenesis, anti-apoptosis and immunity. Furthermore, the Chemerin/ChemerinR1 axis plays a dual role in the inflammatory response and inflammation-related diseases (Evans et al., 2025; Wittamer et al., 2003; Bondue et al., 2011).

Previous studies have reviewed Chemerin and its receptors in metabolism and inflammation (Zhang J. et al., 2023; Stojek, 2017; Helfer and Wu, 2018). However, the function and mechanism of the Chemerin/ChemerinR1 axis during different stages of inflammation remain unclear. In the review, we systematically elaborate the molecular mechanisms of the Chemerin/ChemerinR1 axis during different stages of inflammation and its functions on inflammation-related diseases. Additionally, this review also discuss current the status of clinical research on the Chemerin/ChemerinR1 axis and future strategies for targeting the Chemerin/ChemerinR1 axis. Targeting this pathway holds considerable translational potential for developing novel diagnostic biomarkers and therapeutic strategies against inflammation-related diseases (Imiela et al., 2025; Treeck et al., 2019).

2 Basic functions of the Chemerin/ChemerinR1 axis2.1 Origin and structure of chemerin

Chemerin, initially identified as retinoic acid receptor responder protein 2 (RARRES2) or tazarotene-induced gene 2 protein (TIG2), was first discovered in psoriatic lesions by Nagpal et al., in 1997 (Stojek, 2017). This protein is synthesized as a 163-amino acid polypeptide called pre-pro-Chemerin. Structurally, it consists of three domains: an N-terminal hydrophobic leader sequence (20 aa) essential for extracellular secretion, a central 137-amino acid region featuring a cysteine protease inhibitor-like (cystatin) fold that mediates protein–protein interactions, and a C-terminal 6-amino acid precursor fragment that serves as the primary site for proteolytic activation (Wittamer et al., 2003; Goralski et al., 2007). The pre-pro-Chemerin undergoes post-translational processing to remove the 20-residue N-terminal signal peptide, yielding the inactive precursor pro-Chemerin (Chemerin-S163) with 143 amino acids and a relative molecular mass of approximately 18 kDa (Helfer and Wu, 2018). Pro-Chemerin exhibits broad tissue expression, with the highest levels observed in the liver, white adipose tissue, lungs, and pituitary gland and moderate expression in the skin, adrenal glands, pancreas, and kidneys (Goralski et al., 2007; Segal et al., 2007). At the cellular level, pro-Chemerin mRNA is widely detected in epithelial cells, fibroblasts, endothelial cells (ECs), chondrocytes, and platelets (Banas et al., 2013).

Pro-Chemerin has no biological activity and requires protease-dependent cleavage to generate its active form at the C-terminus. This process is tightly regulated, and serine proteases play a central role therein (Cash et al., 2010). Depending on the protease involved, distinct forms of Chemerin are produced, each exhibiting differential bioactivity. For example, the low-activity Chemerin-K158 is generated by plasmin, tryptase, and factor XIa. High-activity Chemerin-S157 is produced by cathepsin K/L or elastase (Goralski et al., 2007). Moreover, high-activity Chemerin-F156 and its inactive forms (e.g., Chemerin-A155, Chemerin-F154, and Chemerin-G152) result from the cleavage of cathepsin G, chymotrypsin, and serine protease kinase-releasing enzymes (Segal et al., 2007; Wittamer et al., 2004).

Chemerin-F154 was originally found in human hemofiltrate (Huang et al., 2020). Therein, leukocyte elastase cleaves the Ser157-Lys158 to generate Chemerin-S157, the predominant active form found in ascites (Gao et al., 2022). The human Chemerin form terminating at Lys158 (Chemerin-K158) exhibits significantly reduced potency (EC50 = 54 nM), whereas Ala155 (Chemerin-A155) is completely inactive. In contrast, the most bioactive form, Chemerin-S157, demonstrates markedly higher efficacy (EC50 = 1.2 nM) (Bondue et al., 2011). Chemerin-9 (C9; Y149-S157; YFPGQFAFS), processed human Chemerin minus six amino acids at the C-terminal (Chen et al., 2021), retains most of the activities of the Chemerin-S157 (EC50: 5 nM for C9 vs. 0.1–0.2 nM for Chemerin-S157) (Sato et al., 2019). Cash et al. identified conserved residues by aligning the sequences of putative Chemerin orthologs across several species and subsequently designed a series Chemerin-derived peptides, including C11 (P144–A154; PHGYFLPGQFA), C13 (P144–S156; PHGYFLPGQFAFS), and Chemerin-15 (C15) (A140–A154; AGEDPHGYFLPGQFA) (Cash et al., 2008). Among them, C15 has been studied in depth and has a powerful anti-inflammatory role (Cash et al., 2013) (Table 1) (Figure 1).

CategoryChemerin isoformsContained amino acid fragmentInvolved signaling pathwaysExerted functionsInflammation-related research modelsReferencesLow-activity formChemerin-K158Chemerin fragment terminating at Lys158Low activity, weak activation of signaling pathwaysLow biological activity, no obvious strong pro-inflammatory or anti-inflammatory effectsMouse peritonitis, CHO-K1 cells and derivative cell lines model, human peripheral blood mononuclear cell modelWittamer et al. (2004), Huang et al. (2020)High-activity formChemerin-S157Chemerin fragment terminating at Ser157PI3K/Akt, MAPK (ERK1/2, p38), NF-κBHigh biological activity; recruits monocyte migration, promotes differentiation, activates inflammatory responses; increases vascular permeabilityMouse acute peritonitis model, human umbilical vein endothelial cell (HUVEC) model, RAW264.7 mouse macrophage modelBondue et al. (2011), Goralski et al. (2007), Segal et al. (2007), Wittamer et al. (2004), Gao et al. (2022)High-activity formChemerin-F156Chemerin fragment terminating at Phe156PI3K/Akt, MAPK, NF-κBHas high biological activity; participates in the initiation and amplification of inflammatory responses, and promotes inflammatory cell infiltrationRat adjuvant-induced arthritis model, THP-1 human monocyte cell line modelCash et al. (2008), Zabel et al. (2005)Chemerin-derived peptide (high activity)Chemerin-9 (C9)Y149-S157 (sequence: YFPGQFAFS), a fragment of Chemerin-S157 with 6 C-terminal amino acids deletedMAPK (ERK1/2, p38), PI3K/Akt, NF-κBRetains most of the activity of Chemerin-S157; induces inflammatory responses, promotes insulin resistance; can prevent atherosclerosisApoE−/− mouse atherosclerosis model,APP/PS1 transgenic mice model, Kunming mice model, C57BL/6 J littermate wild-type mice model, 3T3-L1 mouse adipocyte model, mouse primary microglia model, mouse primary hippocampal neurons modelChen et al. (2021), Sato et al. (2019), Cash et al. (2008), Rennier et al. (2020), Lei et al. (2020), Zhan et al. (2025)Chemerin-derived peptide (high activity)Chemerin-15 (C15)A140-A154 (sequence: AGEDPHGYFLPGQFA)AMPK, PI3K/AKT/Nrf2, inhibits NF-κBPotent anti-inflammatory effect; alleviates cerebral ischemia-reperfusion injury, inhibits intimal hyperplasia after angioplasty; promotes the growth and maturation of vascular endothelial cells, and reduces platelet adhesionRat middle cerebral artery occlusion (MCAO) model, mouse mesenteric vascular inflammation model, mouse carotid artery balloon injury model, HUVEC modelCash et al. (2008), Huang et al. (2024), Zhang Y et al. (2023), Wen et al. (2024), Cash et al. (2013)

The role of Chemerin and Chemerin Peptides in inflammation.

Structure of Chemerin. (A) Proteolytic processing of chemerin. Chemerin is produced as a pre-pro-chemerin (163aa) with no activity. The N-terminal cleavage of pre-pro-chemerin forms an inactive precursor protein, pro-chemerin (143aa). Pro-chemerin was cleaved by different protease to produce different Chemerin isoforms. (B) The three-dimensional structures of Chemerin-9 and Chemerin-15.

2.2 Chemerin receptors

The receptors of Chemerin include chemokine-like receptor 1, G protein-coupled receptor 1 (designated as ChemerinR2), and C–C motif chemokine-like receptor 2 (CCRL2) (Guo et al., 2012; Kennedy and Davenport, 2018). Among these, ChemerinR1 serves as the primary signaling receptor, eliciting robust intracellular signal transduction and subsequent receptor internalization upon Chemerin binding (Bondue et al., 2011). In contrast, ChemerinR2 undergoes ligand-induced endocytosis but fails to efficiently initiate classical downstream signaling cascades. CCRL2 lacks both signaling capacity and ligand-driven internalization and primarily functions as a Chemerin-presenting molecule, facilitating its bioavailability to neighboring cells (Bondue et al., 2011). The location and distribution of these receptors may help to elucidate the diversity and specificity of the biological functions of chemerins (Yoshimura and Oppenheim, 2008).

2.2.1 ChemerinR1

ChemerinR1, also known as chemokine-like receptor 1, is the most extensively studied receptor with high affinity for Chemerin (Helfer and Wu, 2018; Ballet et al., 2023; Chen et al., 2024). It is a class A GPCR coupled with Gi/o that initiates intracellular calcium release, intracellular cyclic adenosine monophosphate (cAMP) reduction, and p42-p44 MAP kinase phosphorylation (Wittamer et al., 2003) (Figure 1). ChemerinR1 is highly expressed in the adipose tissue, spleen, skin, ovary, testis, and mesenteric lymph nodes (Luangsay et al., 2009), and has been detected in the prefrontal cortex, hippocampus, cerebellum, and hypothalamus of humans and rodents (Helfer et al., 2016; Peng et al., 2015). ChemerinR1 is also widely expressed in some inflammatory cells, including monocytes, macrophages, microglia, dendritic cells, NK cells, and adipocytes (Goralski et al., 2007). Recently, ChemerinR1 has been detected in human ECs and cultured human venous smooth muscle cells (Kaur et al., 2010). The biological effects of Chemerin are mainly mediated by ChemerinR1. The Chemerin/ChemerinR1 axis will be described in detail.

2.2.2 ChemerinR2

ChemerinR2 is a class A GPCR that was originally cloned as an orphan receptor from human hippocampal tissue in 1994 (Kennedy and Davenport, 2018). ChemerinR2 shares significant sequence homology with ChemerinR1, although its precise physiological role remains less well-characterized than that of its paralog. In humans, ChemerinR2 mRNA was first identified in the hippocampus but not in other brain tissues (Kennedy and Davenport, 2018). High ChemerinR2 mRNA expression has been observed in the adrenal cortex, cardiomyocytes, superior cervical ganglion, and skin (Bondue et al., 2011). Additionally, ChemerinR2 mRNA and proteins are ubiquitously expressed in the smooth muscle cells of human vessels (Kennedy and Davenport, 2018; Lin et al., 2025). Human Chemerin-S157, C9, and C13 also activate ChemerinR2. Chemerin stimulation of ChemerinR2 primarily induces β-arrestin recruitment and triggers RhoA/ROCK-mediated signaling pathways (Figure 1). However, ligand-induced arrestin recruitment is not the only mode of action for ChemerinR2. This receptor exhibits constitutive internalization activity, enabling the efficient internalization of inactive peptides through an activation-independent pathway (Kennedy and Davenport, 2018).

Physiologically, ChemerinR2 has been reported in glucose homeostasis. Under high-fat diets, ChemerinR2 knockout mice show exacerbated glucose intolerance and reduced glucose-stimulated insulin secretion (Rourke et al., 2014). Chemerin also modulates steroidogenesis, as chemerin suppresses progesterone production in mouse follicles and corpus luteum via ChemerinR2. ChemerinR2 is widely expressed in human adrenal cortex, cardiomyocytes, and rodent adipose tissue, skin, and reproductive organs, supporting its roles in metabolism and reproduction (Helfer and Wu, 2018; Rourke et al., 2014).

ChemerinR2, as a co-receptor for HIV-1, HIV-2, and SIV, facilitates viral replication in brain-derived and mesangial cells (Tokizawa S et al., 2000). Additionally, its N-terminal peptide inhibits HIV infection by blocking virion binding. ChemerinR2 has been also reported in cardiovascular disease, as confirmed by regulating vascular smooth muscle cell transformation in atherosclerosis. However, lack of selective antagonists hinders further research, its dual roles in metabolism and disease highlight therapeutic potential (Kennedy and Davenport, 2018).

2.2.3 CCRL2

CCRL2, as a member of the chemokine receptor family, is an atypical 7-transmembrane chemokine receptor structurally similar to atypical chemokine receptors (ACKRs), but lacking chemoattractant-scavenging activity and β-arrestin activation. CCRL2 is strongly expressed by barrier cells and myeloid cells, by mast cells, at low levels by B cells, and nearly absent in other lymphocytes (including NK and T cells) (Ji et al., 2024; Annalisa Del Prete et al., 2017; Migeotte et al., 2002; Monnier et al., 2001; Lisa Patel et al., 2001). CCRL2 forms homodimers and functional heterodimers with neutrophil chemokine receptor CXCR2 at the membrane and in the cytoplasm. CCRL2 modulates CXCR2 surface expression and conformation to enhance downstream signaling (ERK1/2 phosphorylation, RhoA/Rac1 activation, Ca2+ mobilization, β2-integrin clustering), thereby promoting neutrophil arrest, adhesion, and extravasation at inflammatory sites (Annalisa Del Prete et al., 2017). Although it has a high affinity, similar to that of ChemerinR1 and ChemerinR2, Chemerin binding to CCRL2 fails to trigger CCRL2 internalization, chemotaxis, or calcium mobilization (Figure 2). Instead, CCRL2 serves as a non-signaling Chemerin scaffold that increases local Chemerin concentrations and binds Chemerin to its signaling receptor (e.g., ChemerinR1) in adjacent cells. This scaffold mechanism was initially proposed in early studies (Monnier et al., 2001; Zabel et al., 2008), and was recently experimentally validated as a novel regulator of NK cell lung homing (Tiberio et al., 2023).

Receptors of Chemerin. The binding of Chemerin to ChemerinR1 trigger coupling with Gi/o proteins, following by intracellular calcium release, increased cyclic adenosine monophosphate (cAMP) levels, and alterations in the MAPK pathway. Chemerin binding to ChemerinR2 primarily induces β-arrestin recruitment and triggers RhoA/ROCK-mediated signaling pathways. Chemerin binding to CCRL2 does not induce CCRL2 internalization, chemotaxis, or calcium mobilization, nor trigger downstream signal transduction.

2.2.4 The interaction among ChemerinR1, ChemerinR2 and CCRL2

Chemerin binds to all three receptors but with different affinities, with high affinity for ChemerinR1 and ChemerinR2 and lower affinity for CCRL2 (De Henau et al., 2016). Functionally, ChemerinR1 is a fully functional signaling receptor mediating most chemerin-induced activities, while ChemerinR2 and CCRL2 barely activate G proteins and lack independent signaling capabilities (Yu et al., 2022) (Ben Dhaou et al., 2021). CCRL2, as an atypical non-signaling receptor, can amplify local chemerin concentration to facilitate the binding of Chemerin and ChemerinR1. Additionally, CCRL2 also presents chemerin to neighboring ChemerinR1-expressing cells and promotes ChemerinR1-mediated biological effects (Zabel et al., 2008). No direct interaction between ChemerinR1 and ChemerinR2 has been reported, but they competitively bind to chemerin due to similar affinity for the ligand (Yu et al., 2022). Collectively, ChemerinR1 is the primary functional receptor. CCRL2 acts by increasing the local concentration of chemerin and presenting it to ChemerinR1, while ChemerinR2 likely modulates ChemerinR1 activity through ligand competition (Ben Dhaou et al., 2021).

2.3 Activation and regulation of Chemerin/ChemerinR1 axis

As the primary signaling receptor for Chemerin, ChemerinR1 mediates most of its biological effects. We systematically reviewed the intracellular signaling cascades initiated by the Chemerin/ChemerinR1 axis and their consequent functional regulation in target cells (Treeck et al., 2019), showing that the Chemerin/ChemerinR1 signaling cascade is initiated by high-affinity ligand-receptor binding. As a member of the GPCR family, ChemerinR1 has a typical structure of seven transmembrane α-helices, and there are G protein binding sites on the C-terminal of its peptide chain and the intracellular loop connecting the fifth and sixth transmembrane helices (Kaur et al., 2010). Upon binding Chemerin to its extracellular domain, ChemerinR1 undergoes allosteric conformational changes that propagate to its intracellular regions. The third intracellular loop undergoes significant structural rearrangements, adopting a guanine nucleotide exchange factor (GEF)-like conformation that facilitates G protein activation and downstream signaling initiation (Herová et al., 2015).

The heterotrimeric G protein complex consists of three subunits: Gα, Gβ, and Gγ. In the basal state, G protein exists as a trimer (αβγ), and the α subunit binds to GDP. Upon activation by bioactive Chemerin forms (e.g., C15), ChemerinR1 undergoes conformational changes that reduce the affinity of the Gα subunit to GDP, increase its affinity for GTP, and trigger rapid GDP/GTP exchange (Cash et al., 2008). This nucleotide exchange leads to dissociation of Gα-GTP from the Gβγ dimer, exposure of previously masked effector interaction sites, and further activation various downstream signaling pathways, including the MAPK pathway, PI3K/Akt pathway, nuclear factor-κB (NF-κB) pathway and other pathways (Rennier et al., 2020).

The MAPK signaling cascade can be initiated through stimulation by either the Gα subunit or Gβγ subunit of heterotrimeric G proteins. These activated subunits trigger the conversion of Ras from an inactive GDP-bound state to an active GTP-bound conformation. As a member of the small GTPase family, Ras-GTP serves as a critical molecular switch that activates Raf kinase through direct protein–protein interactions. This initiates a sequential phosphorylation cascade: Raf phosphorylates and activates MEK, which, in turn, phosphorylates and activates ERK. Activated ERK translocates to the nucleus where it phosphorylates key transcription factors, including Elk-1 and c-Fos. These phosphorylated transcription factors then bind to specific promoter regions, modulating gene expression patterns that ultimately influence fundamental cellular processes, such as proliferation, differentiation, and survival (Cash et al., 2008). Among them, Chemerin can activate p38 MAPK through ChemerinR1 to promote the migration of endothelial progenitor cells and other cells, while inhibiting the phosphorylation of ERK1/2, thereby suppressing the proliferation of hepatocellular carcinoma cells; in contrast, its isoform C9 can activate ERK1/2 and p38 MAPK via ChemerinR1, thereby inducing inflammatory responses and insulin resistance (Lei et al., 2020; Chen et al., 2022).

The Chemerin/ChemerinR1 axis significantly modulates the PI3K/Akt signaling cascade via G protein-mediated mechanisms (Su et al., 2016). Following receptor activation, Gβγ subunits directly interact with and activate phosphoinositide 3-kinase (PI3K). This enzyme catalyzes the conversion of phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-trisphosphate (PIP3), a potent secondary messenger that accumulates in the plasma membrane. Newly generated PIP3 recruits Akt (protein kinase B) from the cytoplasm to the membrane. Subsequently, Akt is completely activated through phosphorylation modification under the action of a series of auxiliary proteins. Activated Akt phosphorylates and activates downstream proteins such as mTOR, a serine/threonine protein kinase that regulates cell growth and metabolic activities, and maintains cell survival and homeostasis (Lu et al., 2022). In this signaling pathway, Chemerin can inhibit the phosphorylation of Akt at the Ser473 site via the ChemerinR1-PTEN axis, thereby blocking the downstream signaling of the PI3K/Akt pathway and suppressing cell migration and invasion; among its isoforms (Rennier et al., 2020). C9 exerts bidirectional regulation on the PI3K/Akt pathway via ChemerinR1 in different cell types: it activates the PI3K/Akt pathway and promotes the nuclear translocation of NF-κB in some cell types (e.g., endothelial cells), while in insulin-sensitive cells (e.g., skeletal muscle cells), it inhibits insulin-induced Akt phosphorylation, ultimately exacerbating insulin resistance (Rennier et al., 2020; Zhan et al., 2025).

The nuclear factor-κB (NF-κB) pathway serves as a central regulator of inflammatory responses and immune function. In the basal state, NF-κB dimers (typically p50/p65) are sequestered in the cytoplasm through interaction with inhibitory IκB proteins. C15 binding to ChemerinR1 activates the IκB kinase (IKK) complex that phosphorylates IκBα at specific N-terminal residues (Ser32/Ser36), triggering its polyubiquitination and subsequent proteasomal degradation. This post-translational modification releases NF-κB from its cytoplasmic tether, allowing its nuclear translocation (Dranse et al., 2016). Within the nucleus, NF-κB binds to κB enhancer elements in promoter regions of target genes, inducing transcription of pro-inflammatory cytokines (e.g., TNF-α, IL-6), chemokines, and adhesion molecules. This coordinated gene expression program regulates critical biological processes, including immune cell activation, inflammatory responses, and cellular survival (Lin et al., 2017). In this pathway, Chemerin exerts a bidirectional regulatory effect: it can exert an anti-inflammatory effect by inhibiting the nuclear translocation of the p65 subunit, likely the effect exerted by its isoform C15, and can also activate NF-κB through the reactive oxygen species (ROS)-silent information regulator 1 (Sirt1) pathway to promote the inflammatory response (Jaworek et al., 2019); in contrast, its form C9 activates NF-κB via the synergistic effect of PI3K/Akt and p38 MAPK, thereby upregulating the expression of adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) (Wang et al., 2019).

In addition to classical signaling pathways, the Chemerin/ChemerinR1 axis modulates cellular functions through alternative mechanisms. The axis regulates intracellular calcium dynamics. Chemerin binding to ChemerinR1 triggers calcium mobilization from endoplasmic reticulum stores via phospholipase C (PLC)-dependent generation of inositol trisphosphate (IP3), resulting in transient cytosolic calcium elevation (Ferland et al., 2017). This calcium flux serves as a versatile secondary messenger that coordinates diverse cellular processes, including contractile activity in vascular smooth muscle cells, secretory responses in immune cells, and the metabolic reprogramming of adipocytes. Moreover, the Chemerin/ChemerinR1 axis interacts with other cell surface receptors or signaling molecules to form a complex signaling network that jointly regulates vascular inflammation. For instance, it can form heterodimers with other GPCRs, alter the functional characteristics and signal transduction patterns of the receptors, or interact with some non-GPCR signaling molecules, such as receptor tyrosine kinases, and affect intracellular signaling pathways through crosstalk. ChemerinR1 forms heterodimers with CXCR4. This interaction was detected in recombinant cell models using Bioluminescence Resonance Energy Transfer and Homogeneous Time-Resolved Fluorescence technologies (de Poorter et al., 2013). Chemerin exerts distinct functions through its binding to various receptors (Figure 2).

3 Relationship between the Chemerin/ChemerinR1 axis and onset and development of inflammation-related diseases3.1 Inflammation-related diseases

Inflammation is a fundamental defensive response of vascularized tissues to various injurious stimuli, including biological pathogens (bacteria, viruses, and parasites), physical trauma (mechanical injury, burns, and radiation), chemical irritants (corrosive substances and toxins), and necrotic tissue components (Kim and Lee, 2024). This complex pathophysiological process is initiated by characteristic vascular changes including vasodilation and increased blood flow, which manifest clinically as localized redness and warmth. Concurrently, enhanced vascular permeability facilitates the exudation of plasma proteins and leukocytes into the interstitial spaces, resulting in tissue swelling. Subsequently, inflammatory cells are recruited to lesions and perform crucial phagocytic functions to eliminate pathogens and cellular debris while releasing a cascade of chemical mediators including cytokines (e.g., IL-1β, TNF-α), chemokines, and prostaglandins (Mariani and Roncucci, 2015). These mediators amplify the inflammatory response and stimulate nociceptors, causing pain and functional impairment associated with inflammation. The precise interplay among vascular changes, cellular infiltration, and molecular signaling pathways isolates and neutralizes harmful stimuli during tissue preparation for subsequent repair processes (Zabel et al., 2005).

The inflammatory response is involved in the onset and progression of various diseases in multiple organ systems. In infectious diseases, such as bacterial pneumonia, COVID-19, and candidiasis, inflammatory responses mediate protective immunity and pathological tissue damage (Sulicka-Grodzicka et al., 2022). Similarly, dysregulated inflammation drives the development and progression of autoimmune disorders including rheumatoid arthritis, psoriasis, systemic lupus erythematosus, asthma, and inflammatory bowel diseases (ulcerative colitis and Crohn’s disease) (Berg et al., 2010). Even in mechanical injuries such as fractures, localized inflammatory cascades initiate the healing process.

Vascular pathologies demonstrate the dual nature of inflammation: acute responses promote tissue repair, whereas chronic inflammation contributes to pathological processes such as post-angioplasty intimal hyperplasia and atherosclerotic plaque formation through endothelial dysfunction and lipid accumulation. Inflammation-associated chronic diseases include hypertension (McMillan and Kirabo, 2025), diabetic vasculopathy, Alzheimer’s disease, chronic obstructive pulmonary disease (COPD), obesity-related metabolic dysfunction, chronic cerebral hypoperfusion, ischemic stroke, and persistent hepatitis. These conditions share common inflammatory mechanisms characterized by sustained immune cell infiltration, persistent cytokine release, and maladaptive tissue remodeling, which collectively drive disease progression (Luangsay et al., 2009). The ubiquitous involvement of inflammatory pathways in diverse pathologies highlights their central role in both physiological defense and pathological processes.

3.2 Chemerin/ChemerinR1 axis in the initiation of inflammation

During the initiation phase of inflammation, the Chemerin/ChemerinR1 axis plays a critical role in two core pathological events: (1) inducing or inhibiting vascular endothelial dysfunction, and (2) mediating the early recruitment of inflammatory cells. Vascular ECs are essential as the primary barrier to the vascular wall for maintaining vascular homeostasis. Under physiological conditions, ECs sustain vasodilation, inhibit platelet aggregation and leukocyte adhesion, and ensure normal vascular function by secreting bioactive substances such as nitric oxide (NO) and prostacyclin (PGI2) (Bondue et al., 2011). However, exposure to pathological stimuli (e.g., oxidative stress, hyperlipidemia, and hypertension) disrupts this balance and triggers endothelial dysfunction.

In the inflammatory state, Chemerin inhibits the activity of endothelial nitric oxide synthase (eNOS) and reduces nitric oxide production, further impairing vascular diastolic function, increasing the risk of platelet aggregation and leukocyte adhesion, and promoting vascular inflammation (Lei et al., 2020). In vitro experiments show that ECs treated with Chemerin exhibit downregulated expression of intercellular junction proteins (e.g., occludin and claudin) (Shang et al., 2019), leading to widened gaps between ECs and increased permeability. This facilitates the entry of lipids and inflammatory cells from the bloodstream into the subendothelial space, thereby driving the onset of atherosclerosis.

Among various chemokines and cytokines released by activated ECs, Chemerin is a key regulator of inflammation. Its production marks the critical transition from endothelial dysfunction to active vascular inflammation. Secreted Chemerin rapidly binds to ChemerinR1 on the surface of vascular endothelial cells and circulating immune cells, initiating a series of inflammatory cascades (Bondue et al., 2011; Cash et al., 2010).

In the early stages of atherosclerosis, Chemerin released by vascular ECs forms a chemotactic signal via a concentration gradient, recruiting monocytes to migrate to the lesion sites (Tang et al., 2023). This chemoattractant signaling ensures the precise targeting of endothelial injury sites and serves as an initial link for inflammatory cell infiltration. Migrating monocytes undergo phenotypic transformation into macrophages in the subintimal space. Experimental evidence from animal models of atherosclerosis has demonstrated that exogenous Chemerin administration significantly enhances macrophage accumulation beneath the vascular intima, highlighting the central role of the Chemerin/ChemerinR1 axis in monocyte/macrophage trafficking (Bondue et al., 2011).

At the molecular level, the primary mediator of these effects is the active full-length Chemerin, generated by the protease-mediated hydrolysis of pro-Chemerin rather than the C15 fragment (Yoshimura and Oppenheim, 2008). In the early stages of inflammation, epithelial cells, adipocytes, and other cell types secrete inactive pro-Chemerin, which is hydrolyzed into active full-length Chemerin by enzymes such as cathepsin L and trypsin (Kulig et al., 2011). This active form binds with a high affinity to ChemerinR1 on the surface of immune cells (neutrophils and monocytes), triggering chemotactic recruitment signals. Upon binding, it activates the PI3K-Akt and MAPK pathways (ERK1/2 and p38) (Kaneko et al., 2011).

The PI3K-Akt pathway promotes actin cytoskeleton rearrangement in immune cells, enhancing their migratory capacity, and guiding neutrophils and monocytes to accumulate at inflammatory sites. The MAPK pathway activates downstream transcription factors (e.g., AP-1), inducing the expression of adhesion molecules (e.g., ICAM-1) (Kim et al., 2021; Xie and Liu, 2022). This finding further supports the idea of immune cell adhesion to the vascular endothelium and transendothelial migration, ultimately initiating an inflammatory response (Cash et al., 2010).

In addition to monocyte and macrophage recruitment, the Chemerin/ChemerinR1 axis also attracts other immune cell populations (e.g., dendritic cells and neutrophils) to migrate to vascular inflammation sites. Chemerin binding to ChemerinR1 significantly enhances the chemotactic responsiveness of dendritic cells and neutrophils during the initial inflammatory phase (Wittamer et al., 2003). Although the number of these infiltrating cells is relatively small in the early stage, they achieve “directional navigation” to the inflammatory site via the Chemerin/ChemerinR1 axis—laying the groundwork for massive accumulation in the subsequent inflammatory progression phase (Parolini et al., 2007). Collectively, these mechanisms constitute the fundamental initiating events of inflammatory cascades, underscoring the important role of this chemokine axis in vascular pathobiology (Cash et al., 2008) (Figure 3).

Schematic diagram of Chemerin/ChemerinR1 axis in different stages of inflammation. In the initial stage of inflammation, pathological stimuli (e.g. oxidative stress, hyperlipidemia) impair EC function. Chemerin binding to ChemerinR1 on ECs reduces tight junction proteins (e.g. occludin, claudin) and promote inffammatory cells enter the subendothelial space. Chemerin-S157 released from activated ECs binds to ChemerinR1 on the monocyte/macrophages, and activates PI3K/Akt/MAPK pathways. In the progressing stage of inflammation, macrophages phagocytose ox-LDL to become foam cells. The foam cells secrete Chemerin and upregulate ChemerinR1, forming a cycle to recruit neutrophils, T lymphocytes, dendritic cells. Additionally, activated macrophages, neutrophils and T lymphocytes release TNF-α, IL-6, and MMPs via NF-κB pathway. These inflammatory cytokines and cells contribute to chronic inflammation. ECs, endothelial cells; ox-LDL, oxidized low density lipoprotein; MMPs, matrix metalloproteinases.

3.3 Impact of the Chemerin/ChemerinR1 axis on inflammation progression

After vascular inflammation progresses from the initiation stage to the progression stage, the Chemerin/ChemerinR1 axis drives the progressive exacerbation of the inflammatory response through multiple mechanisms, including establishing a positive feedback regulatory network, expanding the range of inflammatory cell infiltration, promoting the release of inflammatory mediators, and impairing vascular structural integrity. This accelerates the progression of vascular lesions and promotes vascular inflammation to more complex pathological stages (Eichelmann et al., 2019).

A core feature of the inflammatory progression stage is “excessive recruitment” of inflammatory cells, driven by positive feedback regulation of the Chemerin/ChemerinR1 axis. Residual and recruited cells at injured lesions continuously secrete Chemerin and upregulate ChemerinR1 expression on their surface, forming a “secretion–binding–re-secretion” positive feedback loop (Helfer and Wu, 2018). This loop increases Chemerin concentration at the inflammatory site, strengthens chemotactic signals, and attracts more types of immune cells (e.g., T-lymphocytes, neutrophils, and dendritic cells) to accumulate in the vascular wall. Their massive infiltration spreads the inflammatory response from local to broader vascular areas (Ge et al., 2018).

The Chemerin/ChemerinR1 axis exerts precise regulatory effects on different cell types. Chemerin binds to ChemerinR1 on its surface to guide chemotaxis to the inflammatory site, with active full-length Chemerin as the primary mediator. This not only sustains activation of the PI3K-Akt and MAPK pathways but also additionally activates the NF-κB pathway via the ChemerinR1 axis (Dimitriadis et al., 2018). NF-κB activation promotes neutrophils to express and release large amounts of inflammatory mediators and proteases (e.g., myeloperoxidase [MPO] and elastase). MPO catalyzes the production of substantial amounts of ROS, causing oxidative stress damage, further disrupting vascular endothelial integrity, directly degrading extracellular matrix components, loosening the vascular wall structure, and creating conditions for deeper inflammatory cell infiltration (Rosales et al., 2016). Excessive neutrophil activation triggers the release of neutrophil extracellular traps (NETs). While NETs capture pathogens in normal immunity, their excessive release in the progressive stages of vascular inflammation directly damages vascular ECs and induces platelet aggregation (Thiam et al., 2020).

The activation and proliferation of T-lymphocytes are pivotal for inflammatory progression. In the vascular inflammatory microenvironment,