Fact-checked by Grok 2 weeks ago

CX3CL1

CX3CL1, also known as fractalkine, is the sole member of the CX3C chemokine subfamily and serves as both a chemoattractant and an adhesion molecule for immune cells such as monocytes, T lymphocytes, natural killer cells, and mast cells.^[1]^[2] It is synthesized as a type I transmembrane protein featuring a chemokine domain connected to a mucin-like stalk, a transmembrane region, and a short cytoplasmic tail, with the soluble form generated through proteolytic cleavage by enzymes like ADAM10 and ADAM17.^[3] Discovered in 1997, CX3CL1 binds exclusively to its G protein-coupled receptor, CX3CR1, which is predominantly expressed on microglia, monocytes, and subsets of T and NK cells, thereby mediating leukocyte adhesion, migration, and survival in inflammatory contexts.^[4]^[5]^[3] CX3CL1 is constitutively expressed in tissues including the brain, heart, lung, and colon, while its production in endothelial cells and fibroblasts is upregulated by proinflammatory cytokines such as TNF-α and IFN-γ.^[3] In the central nervous system, it plays a critical role in maintaining microglial homeostasis and promoting neurogenesis, whereas in peripheral immunity, it facilitates the recruitment and activation of effector cells during inflammation.^[3] The CX3CL1-CX3CR1 axis exhibits dual functionality in diseases: it exerts antitumor effects by enhancing cytotoxic responses from NK and CD8+ T cells in contexts like colorectal cancer, but it also promotes tumor progression, invasion, and metastasis in solid malignancies such as pancreatic and ovarian cancers through pathways involving proliferation and apoptosis resistance.^[3] Additionally, dysregulation of this axis contributes to neuroinflammatory conditions like stroke and osteoarthritis, highlighting its broader involvement in chronic inflammatory pathologies.^[1]

Introduction

Discovery and Nomenclature

CX3CL1 was discovered in 1997 through a bioinformatics approach involving searches of expressed sequence tag (EST) and genomic databases for novel chemokines with atypical cysteine motifs. The molecule was first reported by Bazan et al., who identified it as a unique, membrane-bound protein derived from non-hematopoietic cells, featuring a novel CX₃C cysteine arrangement that distinguished it from previously known chemokine families.^[6] Independently, several months later, Pan et al. confirmed the discovery by isolating the same chemokine from brain tissue, highlighting its neuronal expression.^[7] Bazan et al. named the protein fractalkine to evoke its distinctive structural features—a chemokine domain perched atop a long, heavily glycosylated mucin-like stalk that resembles a fractal tree—and its functional resemblance to cytokines in promoting leukocyte adhesion and chemotaxis.^[6] Pan et al. alternatively termed it neurotactin, emphasizing its prominent expression in neural cells. Though fractalkine and neurotactin became the most commonly used non-systematic names. Under standardized chemokine nomenclature established by the Chemokine Nomenclature Subcommittee, it was officially designated CX3CL1, denoting chemokine (C-X₃-C motif) ligand 1.^[8] CX3CL1 remains the sole member of the CX3C (or δ) subfamily, uniquely defined by three amino acids separating the first two conserved cysteine residues in its motif, setting it apart from the CXC, CC, and XC subfamilies.^[6]

General Overview

CX3CL1, also known as fractalkine, is a unique member of the CX3C chemokine subfamily, encoded by the CX3CL1 gene located on the long arm of human chromosome 16 at position 16q21.^[9] The gene produces a precursor protein of 397 amino acids, which, after removal of a 24-amino-acid signal peptide, yields the mature 373-amino-acid protein.^[9] Discovered in 1997, CX3CL1 stands out due to its distinctive structure, featuring a chemokine domain separated by three amino acids from the second cysteine, unlike the single intervening amino acid in CXC chemokines or none in CC chemokines. This protein exhibits dual functionality that distinguishes it from other chemokines: in its membrane-bound form, it acts as an adhesion molecule, promoting firm adhesion and migration of leukocytes across endothelial barriers through interactions with its receptor CX3CR1.^[10] Upon proteolytic cleavage by enzymes such as ADAM10 or ADAM17, the extracellular domain is released as a soluble chemokine, serving as a potent chemoattractant for CX3CR1-expressing cells, including monocytes, T lymphocytes, and natural killer cells.^[11] This versatility allows CX3CL1 to mediate both adhesive and chemotactic processes in immune responses. CX3CL1 plays a critical role in bridging innate and adaptive immunity, particularly by facilitating communication between neurons and microglia in the central nervous system (CNS), where it helps regulate neuroinflammation and maintain homeostasis.^[12] In peripheral tissues, it supports immune cell recruitment and modulates inflammatory responses, contributing to processes such as vascular integrity and antimicrobial defense.^[13]

Gene and Structure

Gene Characteristics

The CX3CL1 gene is located on the long arm of human chromosome 16 at cytogenetic band 16q21, specifically spanning genomic coordinates 16:57,372,490-57,385,044 (GRCh38).^[14] This region encompasses approximately 12.6 kb of genomic DNA and consists of three exons, with the first exon encoding the signal peptide and the subsequent exons contributing to the chemokine domain, mucin-like stalk, and transmembrane regions.^[9] The gene's organization reflects its role in producing a type I transmembrane protein, distinguishing it from typical soluble chemokines.^[15] The promoter region of CX3CL1 is highly responsive to proinflammatory signals, enabling rapid transcriptional activation during inflammation. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) bind to upstream regulatory elements, activating transcription factors like nuclear factor-kappa B (NF-κB) to induce CX3CL1 expression in endothelial and epithelial cells.^[3] This mechanism ensures context-dependent upregulation in response to immune challenges, contributing to the gene's involvement in acute inflammatory processes.^[16] CX3CL1 demonstrates strong evolutionary conservation across mammalian species, with orthologs exhibiting high sequence identity in the chemokine domain and overall genomic structure. The murine ortholog, Cx3cl1, shares this organization and has been instrumental in knockout models that reveal the gene's essential roles in leukocyte trafficking and neuroinflammation. For instance, Cx3cl1-null mice exhibit impaired microglial function and altered immune responses, underscoring the conserved physiological importance of this chemokine axis.^[17]

Protein Structure and Isoforms

CX3CL1 is synthesized as a type I transmembrane glycoprotein with a calculated molecular mass of approximately 42 kDa, but due to extensive post-translational modifications, particularly O-linked glycosylation in the mucin-like stalk, the mature protein exhibits an apparent molecular weight of about 95 kDa on SDS-PAGE. The protein structure comprises several distinct domains: an N-terminal signal peptide of 24 amino acids (residues 1-24) that directs translocation into the endoplasmic reticulum and is cleaved during maturation; a globular chemokine domain (residues 25-100) at the extracellular terminus featuring the characteristic CX3C motif; an extended mucin-like stalk (residues 102-342) rich in serine and threonine residues that undergo heavy O-glycosylation, contributing to the protein's rigidity and length of up to 60 nm; a hydrophobic transmembrane domain (residues 343-363) anchoring the protein to the cell membrane; and a short cytoplasmic tail (residues 364-397) of 34 amino acids lacking known signaling motifs.^[18]^[10]^[19] The CX3C motif in the chemokine domain is defined by two conserved cysteine residues separated by three intervening amino acids (Ala-Ile-Val, residues 50-54), setting CX3CL1 apart from other chemokine families such as CXC or CC, where cysteines are adjacent or separated by one residue. This structural feature enables the domain to adopt a conformation that supports both firm adhesion to leukocytes via direct interaction with integrins and CX3CR1, as well as soluble chemotactic activity. The mucin stalk's high glycosylation density (over 90 potential sites) not only increases the apparent size but also positions the chemokine domain optimally for intercellular engagement, while protecting it from premature proteolytic shedding.^[18]^[19]^[20] CX3CL1 exists primarily in two isoforms: the full-length membrane-bound form, which functions as an adhesion molecule, and a soluble form generated by ectodomain shedding. The soluble isoform (~80 kDa) is produced through proteolytic cleavage just proximal to the transmembrane domain by the metalloproteases ADAM10 (constitutive shedding) and ADAM17 (induced shedding), releasing the extracellular portion comprising the chemokine domain and mucin stalk. This cleavage site is located between residues 341 and 342, allowing regulated release in response to inflammatory stimuli, with the soluble form retaining chemotactic properties but lacking adhesive capacity. No additional splice variants altering the core structure have been widely reported in humans.^[21]^[22]^[23]

Expression and Distribution

Tissue and Cellular Expression

CX3CL1 exhibits high basal expression in several human tissues, including the brain, heart, kidney, lung, and skeletal muscle. In the central nervous system (CNS), CX3CL1 is predominantly produced by neurons, with notable levels in regions such as the cerebral cortex, hippocampus, and thalamus.^[24] Endothelial cells in non-CNS tissues also display constitutive CX3CL1 expression, contributing to its baseline distribution.^[24] Microglia maintain low basal CX3CL1 levels in the healthy brain.^[24] Under inflammatory conditions, CX3CL1 expression is induced in activated endothelial cells, fibroblasts, and epithelial cells. Proinflammatory cytokines such as TNF-α, IFN-γ, and IL-1β stimulate CX3CL1 production in vascular endothelial cells, enhancing its role in leukocyte interactions.^[22] Similarly, airway epithelial and smooth muscle cells upregulate CX3CL1 in response to inflammatory signals, while fibroblast-like synoviocytes express it in inflamed synovial tissues.^[25]^[26] In the CNS, CX3CL1 expression in hippocampal neurons increases following spatial learning tasks, as observed in rat models where levels rise temporally post-training to support memory formation.^[27] In pathological states, such as experimental autoimmune encephalomyelitis, CX3CL1 is upregulated in astrocytes within inflammatory lesions.^[24]

Regulation of Expression

The expression of CX3CL1 is primarily regulated at the transcriptional level by pro-inflammatory cytokines through the activation of key transcription factors such as NF-κB and AP-1. Tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) synergistically induce CX3CL1 mRNA and protein expression in various cell types, including osteoblasts and endothelial cells, by promoting NF-κB nuclear translocation and DNA binding to the CX3CL1 promoter.^[28] This induction is enhanced in inflammatory contexts, where TNF-α alone upregulates CX3CL1 via NF-κB-dependent pathways, leading to increased transcription rates as confirmed by nuclear run-on assays. Similarly, the CX3CL1 promoter contains functional AP-1 binding sites that respond to TNF-α and interleukin-1β (IL-1β) stimulation, contributing to chemokine expression in vascular smooth muscle cells during atherosclerosis.^[29] Post-transcriptional regulation of CX3CL1 involves microRNAs (miRNAs) that target its 3' untranslated region (UTR), thereby modulating mRNA stability and translation. For instance, miR-29a, which is upregulated in the aging brain along with miR-29b, directly binds the CX3CL1 3'UTR, reducing mRNA levels and luciferase reporter activity by approximately 30%, resulting in decreased CX3CL1 expression as an adaptive response to limit microglial activation.^[30] Additionally, mRNA stability is controlled by AU-rich elements (AREs) in the 3'UTR, where proteins like KSRP bind to promote decay; IFN-γ-induced upregulation of KSRP via miR-27b enhances CX3CL1 mRNA destabilization, fine-tuning expression during immune responses.^[31] At the protein level, CX3CL1 expression is further regulated by proteolytic shedding of its membrane-bound form into a soluble chemokine. This process is mediated by a disintegrin and metalloproteinase (ADAM) proteases, primarily ADAM10 and ADAM17, which cleave the extracellular domain in both constitutive and stimulated conditions, such as in hepatic stellate cells and endothelial cells.^[32]^[33] Shedding is enhanced by protein kinase C (PKC) activation, as phorbol 12-myristate 13-acetate (PMA), a PKC agonist, increases ADAM10/17 activity and soluble CX3CL1 release, thereby modulating its bioavailability for leukocyte chemotaxis.^[34]

Receptor and Signaling

CX3CR1 Receptor

CX3CR1 is a G protein-coupled receptor (GPCR) belonging to the chemokine receptor family, featuring seven α-helical transmembrane domains that span the plasma membrane, coupled to heterotrimeric G proteins for signal transduction.^[35] The gene encoding CX3CR1 is located on the short arm of human chromosome 3 at position 3p22.2, spanning approximately 29 kb and consisting of six exons.^[36] This receptor was first identified as the specific binding partner for the chemokine CX3CL1 (fractalkine), distinguishing it as the sole receptor for this unique CX3C motif ligand. CX3CR1 is predominantly expressed on cells of the immune system, including monocytes, macrophages, dendritic cells, natural killer (NK) cells, and subsets of T cells, as well as on microglia in the central nervous system and, to a lesser extent, on certain neurons such as those in the hippocampus and CA1 region.^[26]^[37]^[38] Alternative splicing of the CX3CR1 transcript produces multiple isoforms, with four known variants encoding two primary protein forms: a canonical full-length isoform of 355 amino acids and truncated or extended N-terminal variants (e.g., with additions of 7 or 32 amino acids) that modulate receptor surface expression and signaling efficiency.^[36]^[39]^[35] The receptor exhibits high-affinity binding to the chemokine domain of CX3CL1, with a dissociation constant (Kd) of approximately 1 nM, enabling potent and selective interaction.^[19] This binding is particularly enhanced by the membrane-tethered form of CX3CL1, which facilitates direct cell-cell adhesion between CX3CR1-expressing leukocytes and endothelial or neuronal cells, bypassing traditional selectin-mediated rolling steps.^[19] Binding of CX3CL1 to CX3CR1 initiates downstream signaling, as detailed in subsequent sections.

Downstream Signaling Pathways

The interaction between CX3CL1 and its receptor CX3CR1, a G protein-coupled receptor, primarily activates Gi/o proteins, leading to the dissociation of the Gαi/o subunit from the Gβγ complex. This coupling inhibits adenylate cyclase activity, reducing cyclic AMP levels, while the released Gβγ subunits directly stimulate downstream effectors such as phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK), and phospholipase Cβ (PLCβ).^[40]^[41] The PI3K/Akt pathway, activated via Gβγ, promotes cell survival and anti-apoptotic responses by phosphorylating Akt, which in turn inhibits pro-apoptotic proteins like FOXO and Bad.^[41] Similarly, the MAPK/ERK cascade is engaged through Ras/Raf activation, facilitating transcriptional regulation via Elk-1 and CREB for processes such as proliferation and cytoskeletal reorganization.^[41] The PLCβ pathway hydrolyzes phosphatidylinositol 4,5-bisphosphate to generate inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), elevating intracellular calcium and activating protein kinase C (PKC), which supports rapid signaling events.^[42]^[43] In addition to G protein-dependent signaling, CX3CR1 recruits β-arrestin upon CX3CL1 binding, initiating G protein-independent pathways that include MAPK activation through scaffold-mediated ERK phosphorylation.^[44] A truncated isoform of CX3CR1, such as the S319X variant lacking the C-terminal tail, exhibits altered β-arrestin recruitment, which attenuates receptor desensitization and internalization while preserving MAPK signaling but impairing typical G protein-mediated responses like calcium flux.^[43]^[44] Membrane-bound CX3CL1 engages CX3CR1 to crosstalk with integrin signaling, enhancing the activation of integrins such as α4β1 and α5β1 through inside-out signaling mechanisms that stabilize high-affinity conformations for firm leukocyte adhesion to extracellular matrix components like fibronectin.^[45] This synergy involves CX3CR1-mediated PLCβ and PI3K activation, which phosphorylate integrin regulatory proteins like talin and kindlin, without requiring prior selectin interactions.^[45]^[41]

Biological Functions

Leukocyte Recruitment and Adhesion

CX3CL1, also known as fractalkine, plays a pivotal role in leukocyte recruitment through its unique dual functionality as both an adhesion molecule and a chemoattractant, primarily interacting with its receptor CX3CR1 expressed on various immune cells. The membrane-bound form of CX3CL1, anchored via a mucin-like stalk, enables rapid and firm adhesion of leukocytes to endothelial cells under physiological shear flow conditions, bypassing the traditional selectin-mediated rolling and integrin-dependent firm arrest steps. This direct capture mechanism facilitates the immobilization of rolling CX3CR1-expressing leukocytes, such as monocytes, promoting their subsequent crawling and transmigration across the endothelium. Studies have demonstrated that this adhesion is critically dependent on the chemokine domain and the mucin stalk's glycosylation, which extends the ligand to engage CX3CR1 effectively.^[46] Upon proteolytic cleavage by ADAM10 and ADAM17 metalloproteinases, the soluble form of CX3CL1 is released and acts as a potent chemoattractant, directing the haptotactic migration of CX3CR1-positive immune cells including monocytes, CD8+ T cells, and natural killer (NK) cells. This soluble variant induces directed migration without requiring additional G-protein-coupled signaling for initial adhesion, allowing efficient leukocyte navigation along CX3CL1 gradients on extracellular matrices or cell surfaces. In vitro assays have shown that soluble CX3CL1 preferentially attracts CD16+ monocytes, enhancing their transendothelial migration in response to inflammatory stimuli. This process underscores CX3CL1's role in fine-tuning immune cell trafficking to sites of potential antigen encounter.^[47]^[46] In immune surveillance, CX3CL1 contributes to the precise positioning and activation of leukocytes within tissues, exemplified by its guidance of microglia to neuronal synapses in the central nervous system (CNS). Neuronal-derived CX3CL1 signals through microglial CX3CR1 to regulate timely recruitment during brain development, supporting synaptic pruning and neuronal survival while maintaining a surveilling, non-inflammatory state. Similarly, endothelial CX3CL1 promotes the transmigration of monocytes into tissues, enabling their differentiation into macrophages or dendritic cells for local immune monitoring. These functions highlight CX3CL1's essential contribution to homeostatic leukocyte patrolling without eliciting overt inflammation.^[48]

Non-Immune Roles

CX3CL1, also known as fractalkine, plays a critical role in neuron-microglia communication within the central nervous system, facilitating bidirectional signaling that maintains microglial homeostasis independent of immune activation. Through tonic signaling via its receptor CX3CR1 on microglia, CX3CL1 exerts an inhibitory effect that preserves microglial quiescence under physiological conditions, preventing excessive activation and promoting a surveilling state essential for neuronal support.^[49] This ongoing, low-level interaction allows microglia to monitor neuronal health without inflammatory responses, as evidenced by studies showing that disruption of this axis leads to heightened microglial reactivity.^[50] Additionally, CX3CL1 guides microglial-mediated synaptic pruning during brain development, where microglia engulf and eliminate unnecessary synaptic elements to refine neural circuits, a process dependent on CX3CL1 expression in neurons.^[51]^[52] In skeletal muscle, CX3CL1 modulates metabolic processes by enhancing insulin sensitivity and regulating lipid handling, contributing to energy homeostasis in non-immune contexts. It synergizes with insulin to promote glucose uptake, particularly during exercise-induced states, by influencing GLUT4 translocation and mitochondrial function without independently mobilizing glucose transporters.^[53] CX3CL1 also upregulates genes involved in fatty acid oxidation, thereby reducing lipid accumulation and improving substrate flexibility in muscle fibers.^[53] In models of obesity and type 2 diabetes, circulating and tissue levels of CX3CL1 are elevated, where it acts protectively against insulin resistance; genetic deficiency of the CX3CL1-CX3CR1 axis exacerbates inflammation and impairs glucose tolerance in high-fat diet-fed mice.^[53]^[54] Regarding bone homeostasis, CX3CL1 influences osteoclast differentiation by promoting M1-like polarization in macrophage precursors, thereby priming them for bone-resorbing activity through pathways such as NF-κB signaling.^[55] This process enhances the survival and differentiation potential of osteoclast precursors, contributing to balanced bone remodeling under steady-state conditions. Studies demonstrate that CX3CL1 upregulation accelerates M1 polarization and osteoclastogenesis via epigenetic modifications like m5C RNA methylation mediated by NSUN5, underscoring its regulatory role in skeletal integrity.^[56]

Role in Disease

Neurological and Neurodegenerative Disorders

CX3CL1, also known as fractalkine, plays a significant role in neuroinflammation within the central nervous system (CNS), particularly in neurodegenerative disorders where it modulates microglial activation and immune cell recruitment. In the context of Alzheimer's disease (AD), elevated levels of CX3CL1 have been observed in association with amyloid-β (Aβ) plaques, suggesting its involvement in the inflammatory response surrounding these pathological structures.^[57] This elevation correlates with microglial activation aimed at Aβ clearance, as the CX3CL1/CX3CR1 axis regulates the phagocytic activity of microglia to mitigate plaque accumulation.^[57] However, CX3CR1 deficiency exacerbates AD pathology; studies in mouse models demonstrate that loss of CX3CR1 leads to impaired microglial function, resulting in accelerated tau hyperphosphorylation, increased neurodegeneration, and synaptic dysregulation.^[58] Conversely, partial CX3CR1 deficiency has been shown to reduce Aβ levels and senile plaque load in the brain, highlighting a complex balance in CX3CL1 signaling for neuroprotection.^[59] In ischemic stroke, the CX3CL1/CX3CR1 axis exerts neuroprotective effects by modulating microglial activation and the inflammatory response in the post-ischemic brain. Higher plasma CX3CL1 levels after stroke are associated with better 6-month functional outcomes and reduced inflammatory markers such as white blood cells and C-reactive protein.^[60] Dysregulation, including reduced CX3CL1 signaling, can aggravate neuronal damage and exacerbate neuroinflammation in stroke models.^[61] In Parkinson's disease (PD), CX3CL1 exerts neuroprotective effects on dopaminergic neurons, primarily through its interaction with CX3CR1 on microglia, which helps maintain a controlled inflammatory environment in the substantia nigra. Administration of CX3CL1 in rat models of PD induced by 6-hydroxydopamine (6-OHDA) reduces neurotoxicity and attenuates microglial activation, preserving dopaminergic neuron integrity.^[62] Reduced CX3CL1 expression in the substantia nigra is linked to heightened microglial overactivation and neuroinflammation, contributing to dopaminergic neurodegeneration in PD models.^[63] Specifically, the soluble isoform of CX3CL1 is essential for this neuroprotection, as demonstrated in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD models where it prevents neuronal loss without relying on the membrane-bound form.^[64] Disruption of CX3CR1 signaling further influences dopaminergic neuron survival, underscoring CX3CL1's role in modulating glial responses to limit progressive damage.^[65] Regarding multiple sclerosis (MS), CX3CL1 facilitates the infiltration of pro-inflammatory Th1 cells into the CNS, exacerbating demyelination through enhanced immune cell recruitment during early disease stages. Expression of CX3CL1 and its receptor CX3CR1 is elevated in the blood and brain tissue of MS patients, correlating with disease activity and severity, and is associated with the infiltration of activated Th1 cells that drive inflammatory lesions. CX3CL1 specifically induces the migration of CX3CR1-expressing CD4+ T cells, including Th1 subsets, into the CNS, promoting the initial inflammatory response in experimental autoimmune encephalomyelitis (EAE) models of MS. Therapeutic modulation of the CX3CL1/CX3CR1 pathway shows promise in reducing demyelination; for instance, infusion of CX3CL1 in demyelinated murine models enhances oligodendrocyte regeneration and remyelination by promoting microglial support for repair processes.^[66] Defective CX3CL1 signaling, conversely, aggravates regional demyelination in MS models, indicating that targeted enhancement of this axis could mitigate pathological progression.^[67]

Inflammatory and Cardiovascular Diseases

CX3CL1, also known as fractalkine, plays a pivotal role in atherosclerosis by facilitating the recruitment of monocytes to the vascular endothelium, where they differentiate into foam cells that contribute to plaque formation. Expressed primarily on lesional smooth muscle cells in atherosclerotic lesions, CX3CL1 interacts with its receptor CX3CR1 on monocytes to promote adhesion and migration under shear stress conditions.^[68] In experimental models, such as apolipoprotein E-deficient (apoE^{-/-}) mice, genetic deletion of CX3CR1 results in a 40% reduction in macrophage accumulation in the vessel wall and significantly smaller atherosclerotic lesions, with aortic root lesion areas decreased by 32% after 10 weeks on a high-fat diet.^[68] Blockade of the CX3CL1-CX3CR1 axis has been shown to ameliorate plaque severity in hyperlipidemic mouse models, highlighting its pro-atherogenic effects.^[69] In osteoarthritis (OA), CX3CL1 levels are elevated in the synovial fluid (1.4–3.17 ng/ml) and serum (up to 226 pg/ml) of patients compared to controls, correlating with disease severity and promoting synovial inflammation through chemoattraction of fibroblasts, chondrocytes, and immune cells.^[1] This contributes to cartilage degradation and joint pathology, with CX3CL1 expressed on synovial cells driving the inflammatory milieu in OA. In rheumatoid arthritis (RA), CX3CL1 is upregulated in the synovial tissue, particularly on fibroblast-like synoviocytes and endothelial cells, driving the infiltration of CX3CR1-expressing T cells and monocytes into the inflamed joint. This chemokine's adhesive and chemotactic properties enhance leukocyte crawling and firm adhesion, exacerbating synovial inflammation and pannus formation.^[70] Serum levels of CX3CL1 are elevated in RA patients and positively correlate with disease activity scores, such as the Disease Activity Score 28 (DAS28), reflecting its association with clinical severity.^[70] In rat models of adjuvant-induced arthritis, inhibition of CX3CL1 signaling reduces joint swelling and immune cell infiltration, suggesting a proinflammatory role that parallels human RA pathology.^[71] CX3CL1 contributes to chronic kidney disease (CKD) progression by promoting macrophage recruitment and activation in the renal interstitium and glomeruli, leading to fibrosis and tubular damage. In glomerular diseases like diabetic nephropathy and lupus nephritis, CX3CL1 expression is induced in mesangial cells and podocytes under inflammatory stimuli such as TNF-α or high glucose, facilitating the influx of CX3CR1-positive macrophages that release profibrotic cytokines like TGF-β.^[72] Studies in unilateral ureteric obstruction (UUO) and folic acid nephropathy models demonstrate that CX3CL1-CX3CR1 blockade attenuates macrophage accumulation and collagen deposition, reducing interstitial fibrosis by up to 50% in knockout mice.^[72] In human CKD cohorts, elevated circulating CX3CL1 levels are associated with declining glomerular filtration rates, underscoring its role in amplifying renal inflammation and scarring.^[73]

Cancer and Metabolic Disorders

CX3CL1 plays a dual role in cancer progression, exhibiting both pro-tumor and anti-tumor effects depending on the cancer type and context. In breast and prostate cancers, CX3CL1 promotes metastasis by enhancing tumor cell migration and invasion through activation of the Src/FAK signaling pathway.^[74]^[75] Specifically, in breast cancer, elevated CX3CL1 in spinal bone attracts CX3CR1-expressing cancer cells, facilitating spinal metastasis, as evidenced by overexpression of CX3CR1 in metastatic lesions compared to primary tumors.^[74] Similarly, in prostate cancer, CX3CL1 drives bone metastasis by increasing cell adhesion to bone marrow endothelium and stimulating proliferation, with dihydrotestosterone further amplifying these effects via CX3CR1.^[75] In contrast, CX3CL1 demonstrates anti-tumor activity in melanoma by recruiting natural killer (NK) cells to tumor sites through the CX3CL1-CX3CR1 axis, thereby enhancing NK cell adhesion, infiltration, and cytotoxicity against cancer cells.^[76]^[75] Gene transfer of CX3CL1 into melanoma tumors significantly reduces growth by over 85% in mouse models, an effect dependent on NK cells, as depletion abolishes the response.^[76] CX3CR1 deficiency exacerbates lung metastasis and reduces NK cell recruitment in these models, underscoring the protective role of the pathway.^[77] In metabolic disorders, circulating CX3CL1 levels are elevated in patients with type 2 diabetes and serve as a predictor of insulin resistance, reflecting its involvement in adipose tissue inflammation.^[78] The CX3CL1-CX3CR1 signaling axis modulates monocyte adhesion to adipocytes and regulates macrophage polarization in obese adipose tissue; its deficiency worsens obesity-induced inflammation by increasing pro-inflammatory M1 macrophages and impairing glucose tolerance.^[78]^[79] Exogenous CX3CL1 administration mitigates these effects, highlighting its regulatory function in adipocyte-mediated insulin sensitivity.^[79] Systemic sclerosis (SSc) features elevated CX3CL1 expression in lung tissue and vascular endothelium, contributing to fibrosis and pulmonary hypertension.^[80]^[81] In SSc-associated interstitial lung disease, higher serum and pulmonary CX3CL1 levels correlate with fibrosis extent, annual progression exceeding 5%, and reduced lung function, as observed in patient cohorts.^[80] Additionally, increased CX3CL1 associates with pulmonary arterial hypertension and microvascular damage in SSc, potentially serving as a biomarker for vascular complications.^[81]

Therapeutic Potential

Targeting Strategies

Targeting the CX3CL1/CX3CR1 axis involves pharmacological interventions designed to inhibit ligand-receptor interactions, thereby modulating leukocyte recruitment, adhesion, and chemotaxis in pathological conditions such as inflammation and cancer.^[82] These strategies primarily focus on blocking CX3CL1 binding to CX3CR1 or reducing expression of the ligand to disrupt pro-inflammatory and pro-tumorigenic signaling.^[83] Monoclonal antibodies targeting CX3CL1 or CX3CR1 represent a key approach to inhibit adhesion and chemotaxis. For instance, anti-CX3CL1 monoclonal antibodies neutralize fractalkine activity, preventing its interaction with CX3CR1 and reducing immune cell migration in fibrotic and inflammatory contexts.^[84] Similarly, CX3CR1-specific monoclonal antibodies, such as those developed to block receptor function, impair tumor cell migration and suppress secretion of immunosuppressive mediators by cancer cells.^[83] Quetmolimab, a monoclonal antibody against the CX3CL1-CX3CR1 axis, has been explored for its potential to attenuate inflammatory responses.^[85] Small-molecule antagonists of CX3CR1 offer an alternative to antibody-based blockade, particularly for reducing inflammation. AZD8797 (also known as KAND567), a selective CX3CR1 antagonist, inhibits receptor-mediated calcium mobilization and chemotaxis without affecting other chemokine receptors, thereby dampening monocyte and microglial activation in inflammatory settings.^[86] This compound has demonstrated efficacy in preclinical models by blocking CX3CL1-induced signaling, highlighting its utility in targeting overactive immune responses.^[87] Gene therapy and RNA interference techniques, such as siRNA, enable downregulation of CX3CL1 in tissues exhibiting overexpression, including tumors. siRNA-mediated knockdown of CX3CL1 in pancreatic ductal adenocarcinoma cells disrupts onco-immuno crosstalk, potentially sensitizing tumors to immune surveillance by limiting ligand-driven recruitment of suppressive immune cells.^[88] In lung cancer models, CX3CL1 siRNA transfection reduces tumor cell invasion and tyrosine phosphorylation of focal adhesion kinase, indicating a role in curbing metastatic potential.^[89] These nucleic acid-based approaches provide tissue-specific modulation, avoiding systemic effects associated with protein-targeting agents.^[90]

Clinical and Preclinical Studies

Preclinical studies utilizing CX3CR1 knockout mice have demonstrated protective effects against atherosclerosis. In apolipoprotein E-deficient mice crossed with CX3CR1 knockouts, atherosclerotic lesion formation in the thoracic aorta was reduced by 59%, attributed to diminished monocyte recruitment to vascular walls.^[91] Similarly, in models of Alzheimer's disease, Cx3cr1 knockout prevented neuronal loss in 5xFAD mice and reduced beta-amyloid deposition in a gene dose-dependent manner in APP/PS1 mice, highlighting the role of fractalkine signaling in modulating microglial activation and neurotoxicity.^[92]^[93] Clinical investigations into CX3CL1/CX3CR1 axis modulation for rheumatoid arthritis (RA) have advanced to early-phase trials. Phase I and II studies of E6011 (also known as quetmolimab), an anti-CX3CL1 monoclonal antibody, in patients with active RA demonstrated favorable safety, pharmacokinetics, and modest efficacy in reducing disease activity over 24 weeks, with long-term extension data up to 102 weeks confirming tolerability in patients with inadequate response to methotrexate.^[94]^[95]^[96] This approach targets the fractalkine interaction to inhibit leukocyte infiltration in inflamed joints. In type 2 diabetes (T2D) cohorts, elevated CX3CL1 levels serve as a biomarker associated with metabolic dysregulation. Recent analyses of patient samples revealed higher circulating CX3CL1 in T2D individuals, correlating with impaired insulin sensitivity and altered skeletal muscle metabolism, where CX3CL1 influences macrophage polarization and glucose uptake.^[97]^[98] Emerging 2025 research has linked CX3CL1 to bone homeostasis and systemic sclerosis (SSc) pulmonary complications. In models of bone remodeling, CX3CL1 promoted M1 macrophage polarization and osteoclast differentiation via NSUN5-mediated m5C RNA modification, disrupting the balance of bone resorption and formation.^[99] For SSc, multi-omic profiling identified elevated CX3CL1 in fibrotic lung tissue, contributing to interstitial lung disease progression, while anti-CX3CL1 therapy in preclinical models attenuated pulmonary fibrosis, indicating anti-fibrotic therapeutic potential.^[100]^[84]

References

[1]
The Chemokine CX3CL1 (Fractalkine) and its Receptor CX3CR1
CX3CL1 is a unique chemokine that combines properties of chemoattractant and adhesion molecule. The main roles of CX3CL1 include promotion of leukocyte binding ...
[2]
Regulation and biological functions of the CX3CL1-CX3CR1 axis ...
Oct 11, 2020 · The CX3CL1-CX3CR1 axis induces several cellular responses relevant to cancer such as proliferation, migration, invasion and apoptosis resistance.
[3]
https://pmc.ncbi.nlm.nih.gov/articles/PMC7738983/
[4]
https://doi.org/10.1038/385640a0
[5]
A new class of membrane-bound chemokine with a CX 3 C motif
Feb 13, 1997 · We report here the identification and characterization of a fourth human chemokine type, derived from non-haemopoietic cells and bearing a new CX 3 C ...Missing: CX3CL1 discovery original
[6]
A new class of membrane-bound chemokine with a CX3C motif
We report here the identification and characterization of a fourth human chemokine type, derived from non-haemopoietic cells and bearing a new CX3C fingerprint.Missing: discovery original paper
[7]
CX3CL1 C-X3-C motif chemokine ligand 1 [Homo sapiens (human)] - Gene - NCBI
- **Official Symbol**: CX3CL1
[8]
CX3CL1 - Fractalkine - Homo sapiens (Human) | UniProtKB | UniProt
Recommended name. Fractalkine 1 publication. Alternative names. C-X3-C motif chemokine 1 1 publication. CX3C membrane-anchored chemokine 1 publication.
[9]
The Transmembrane Form of the CX3CL1 Chemokine Fractalkine Is ...
Fractalkine (CX3CL1) is synthesized as a type I transmembrane protein. Its unique CX3C chemokine domain is attached to a 241-amino acid mucin stalk, a 19-amino ...
[10]
The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders
Oct 13, 2020 · The reciprocal interaction between the microglial chemokine receptor and the neuronal ligand CX3CL1 allows precise and effective communication ...
[11]
Tissue-specific Role of CX 3 CR1 Expressing Immune Cells and ...
Jan 25, 2018 · CX 3 CR1 expressing immune cells have a main role in either pro-inflammatory or anti-inflammatory response depending on environmental condition.Chemokine (c-X3-C Motif)... · Bone Marrow And Immune... · Gut And Immune Tolerance
[12]
601880 - CHEMOKINE, CX3C MOTIF, LIGAND 1; CX3CL1 - OMIM
(1997) found that both human and murine neurotactin genes are located on different chromosomes from other chemokines. Using a panel of backcross progeny of ...<|control11|><|separator|>
[13]
Regulation and biological functions of the CX3CL1-CX3CR1 axis ...
The gene coding for human CX3CL1 is located on chromosome 16q13 [5], and has three exons. CX3CL1 is a type I membrane protein composed of 373 amino acids ...
[14]
Regulation of CX3CL1/Fractalkine Expression in Endothelial Cells
TNF- α, IL-1 and LPS stimulate a similar spectrum of signal transduction systems: both the nuclear factor-κB (NF-. κB) system and mitogen-activated protein ...
[15]
Two forms of CX3CL1 display differential activity and rescue ...
May 14, 2020 · These results are the first to demonstrate that CX3CL1 knockout causes significant cognitive deficits that can be rescued by treatment with sFKN and only ...Missing: ortholog | Show results with:ortholog
[16]
CX3CL1, a chemokine finely tuned to adhesion: critical roles of the ...
Nov 13, 2014 · Consistently, the w/o cyto CX3CL1 exhibited a molecular weight of 110 kDa, whereas the shCX3CL1 mutant had a weight of approximately 70 kDa ...
[17]
CX3CL1 homo-oligomerization drives cell-to-cell adherence - Nature
Jun 3, 2020 · LCX3CL1 clone cells were harvested from culture flasks through treatment with Cell Dissociation Buffer (Life Technologies, Thermo Fisher ...
[18]
Tumor necrosis factor-alpha-converting enzyme (ADAM17 ... - PubMed
Oct 12, 2001 · Fractalkine (CX3CL1) is an unusual member of the chemokine family that is synthesized with its chemokine domain at the end of a mucin-rich, ...Missing: ADAM10 isoforms
[19]
Fractalkine/CX3CL1: A Potential New Target for Inflammatory ...
Fractalkine/CX3CL1, with its unique functional and structural characteristics, has been found to participate in inflammation.Missing: original paper<|control11|><|separator|>
[20]
Opposing Effects of Membrane-Anchored CX3CL1 on Amyloid and ...
Sep 10, 2014 · CX3CL1 is a type I transmembrane protein with an extracellular chemokine domain that is anchored to the membrane by a mucin-like stalk (Bazan et ...
[21]
CX3CL1 (fractalkine) and CX3CR1 expression in myelin ...
Jul 29, 2005 · CX3CL1 (alternative names: fractalkine or neurotactin) was identified in 1997 ... Bazan et al. [2]. An alternative explanation would be if the ...
[22]
Allergenic proteases cleave the chemokine CX3CL1 directly from ...
Jul 5, 2017 · CX3CL1 (fractalkine) is a membrane-bound 373 amino-acid chemokine of ∼42 kDa, with extensive glycosylation increasing its mass to ∼95 kDa. The N ...
[23]
Tissue-specific Role of CX3CR1 Expressing Immune Cells and ...
CX3CL1 can be expressed by synovial tissue macrophages, DC, fibroblast-like synoviocytes as well as by vessel endothelial cells.
[24]
CX3CL1 is up-regulated in the rat hippocampus during memory ...
In the present study, we investigated if CX3CL1 expression is actively regulated in the hippocampus during a normal spatial learning event and also after the ...
[25]
Synergistic induction of CX3CL1 by TNF alpha and IFN gamma in ...
Oct 28, 2008 · Abstract. To explore the regulation of CX3CL1 in inflammatory bone diseases, CX3CL1 expression by osteoblasts (OB) was examined.
[26]
Functional analysis of the fractalkine gene promoter in human aortic ...
Fractalkine (Fk) and its receptor CX3C receptor 1 contribute effectively to the atherosclerotic process, mediating the recruitment of leukocytes and ...
[27]
Increased miR-29b in the aged brain correlates with the reduction of ...
Insulin-like growth factor-1 (IGF-1) and fractalkine ligand (CX3CL1) are negative modulators of microglial activation and were identified as targets of miR-29a ...
[28]
Upregulation of KSRP by miR-27b provides IFN-γ-induced post ...
Dec 3, 2015 · KSRP regulates the stabilization of CX3CL1 mRNA through targeting ARE. Both human and mouse CX3CL1 mRNA 3′UTR contain a single UUAUUUAUU ...
[29]
CX3CL1/fractalkine shedding by human hepatic stellate cells - NIH
We conclude that ADAM10, ADAM17 and MMP-2 synthesized by activated HSC mediate CX3CL1 shedding and release of chemotactic peptides.
[30]
The disintegrin-like metalloproteinase ADAM10 is involved in ...
Aug 15, 2003 · Transmembrane CX3CL1 is converted into its soluble form by defined proteolytic cleavage (shedding), which can be enhanced by stimulation with ...
[31]
Molecular and Cellular Mechanisms of Ectodomain Shedding - PMC
Phorbol esters induce shedding of the majority of protein ectodomains, suggesting that protein kinase C (PKC) is one of the key regulators. Indeed, chemically ...
[32]
601470 - CHEMOKINE, CX3C MOTIF, RECEPTOR 1; CX3CR1 - OMIM
Fractalkine (CX3CL1; 601880), a transmembrane molecule with a CX3C-motif chemokine domain atop a mucin stalk, induces both adhesion and migration of leukocytes.
[33]
CX3CR1 Gene - GeneCards | CX3C1 Protein
The protein encoded by this gene is a receptor for fractalkine. The encoded protein also is a coreceptor for HIV-1, and some variations in this gene lead to ...Missing: seven | Show results with:seven
[34]
CX3CR1 protein expression summary - The Human Protein Atlas
Cell type enhanced (NK-cells, Microglial cells, Macrophages, Langerhans cells).Missing: length truncated<|separator|>
[35]
Expression of CX3CR1 chemokine receptors on neurons ... - PubMed
Jul 5, 2000 · Central nervous system expression of CX(3)CR1, the only known receptor for fractalkine, has been demonstrated exclusively on microglia and ...
[36]
Two novel fully functional isoforms of CX3CR1 are potent HIV ...
We identified two novel isoforms of the human chemokine receptor CX3CR1, produced by alternative splicing and with N-terminal regions extended by 7 and 32 aa.
[37]
Activation of the human chemokine receptor CX3CR1 regulated by ...
Jun 29, 2022 · However, the Gi1-coupled CX3CR1 structures in both ligand-free and chemokine-bound states exhibit a much smaller outward movement of helix VI in ...
[38]
Fractalkine in Health and Disease - MDPI
Fractalkine was first identified by Pan and co-workers in the brain and was named neurotactin [3]. In parallel, it was identified by Bazan and colleagues ...
[39]
Requirements for leukocyte transmigration via the transmembrane ...
... β-arrestin and desensitization of the receptor towards its ligand [17]. ... We found that HEK293 cells expressing CX3CR1 or its truncated variant S319X ...
[40]
https://pmc.ncbi.nlm.nih.gov/articles/PMC9242592/
[41]
An overview of the role of chemokine CX3CL1 (Fractalkine) and ...
CX3CL1 functions as both a chemoattractant and an adhesion molecule, guiding immune cell trafficking. This systematic review examines the role of CX3CL1 and its ...
[42]
https://www.mdpi.com/1422-0067/25/15/8007/
[43]
https://pmc.ncbi.nlm.nih.gov/articles/PMC11115548/
[44]
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764977/
[45]
Fractalkine Attenuates Microglial Cell Activation Induced by Prenatal ...
These results suggest that tonic activation of CX3CR1 by endogenous fractalkine may serve as an anti-inflammatory signal that maintains the microglial cells in ...
[46]
Role of fractalkine–CX3CR1 pathway in seizure-induced microglial ...
It has also been suggested that during physiological conditions, tonic activation of CX3CR1 by fractalkine helps to keep the microglia in a quiescent state.
[47]
Microglia regulation of synaptic plasticity and learning and memory
The CX3CR1/CX3CL1 signaling contributes to synaptic pruning, allowing microglia to know which synapses need to be eliminated. The interaction between CX3CR1 and ...
[48]
CX3CL1 Pathway as a Molecular Target for Treatment Strategies in ...
May 4, 2023 · Shortly, neuron-to-microglia crosstalk has two main purposes: (i) maintaining microglia in an anti-inflammatory, quiescent state, and (ii) ...
[49]
Fractalkine is a key player in skeletal muscle metabolism and ...
Sep 25, 2025 · CX3CL1 has emerged as a significant modulator of skeletal muscle metabolism, exerting a profound influence on insulin sensitivity and resistance ...
[50]
CX3CL1-CX3CR1 Signaling Deficiency Exacerbates Obesity ...
The CX3CL1–CX3CR1 system plays an important role in disease progression by regulating inflammation both positively and negatively.
[51]
CX3CL1 promotes M1 macrophage polarization and osteoclast ...
Aug 25, 2023 · The study demonstrated that up-regulated CX3CL1 promotes M1-type macrophage polarization and osteoclast differentiation through the NF-κB signaling pathway.
[52]
Effects of CX3CR1 and Fractalkine Chemokines in Amyloid Beta ...
Thus, the CX3CR1/Fractalkine axis regulates microglial activation, the clearance of amyloid plaque and plays a role in p-Tau intraneuronal accumulation in ...
[53]
CX3CR1 deficiency aggravates amyloid driven neuronal pathology ...
Jun 28, 2022 · Our results indicate that Aβ-driven microglial dysfunction in Cx3cr1 -/- mice aggravates tau hyperphosphorylation, neurodegeneration, synaptic dysregulation ...Missing: CX3CL1 | Show results with:CX3CL1
[54]
Heterozygous CX3CR1 Deficiency in Microglia Restores Neuronal β ...
Dec 2, 2019 · We found that partial CX3CR1 deficiency was associated with a significant reduction in Aβ levels and in senile-like plaque load in the brain.<|separator|>
[55]
CX3CL1 reduces neurotoxicity and microglial activation in a rat ...
Conclusion: These findings demonstrated that CX3CL1 plays a neuroprotective role in 6-OHDA-induced dopaminergic lesion and it might be an effective therapeutic ...
[56]
New evidences for fractalkine/CX3CL1 involved in substantia nigral ...
New evidences for fractalkine/CX3CL1 involved in substantia nigral microglial activation and behavioral changes in a rat model of Parkinson's disease.
[57]
The soluble isoform of CX3CL1 is necessary for neuroprotection in a ...
Oct 17, 2012 · Our results reveal that the neuroprotective capacity of CX3CL1 resides solely upon the soluble isoform in an MPTP-induced model of Parkinson's disease.
[58]
CX3CR1 Disruption Differentially Influences Dopaminergic Neuron ...
Sep 24, 2015 · We hypothesized that CX3CR1 could play a role in neurotoxicity and glial activation. For this, we used CX3CR1 knock-in mice and compared results.<|separator|>
[59]
Fractalkine enhances oligodendrocyte regeneration and ... - PubMed
Feb 14, 2023 · We show that infusion of fractalkine (CX3CL1) into the demyelinated murine brain increases de novo oligodendrocyte formation and enhances remyelination.
[60]
Defective fractalkine-CX3CR1 signaling aggravates ... - PubMed - NIH
Our results show that defective fractalkine signaling contributes to regional differences in demyelination, and suggest that the CX3CR1 pathway activity may be ...
[61]
mice reveals a role for fractalkine in atherogenesis - PubMed - NIH
CX(3)CR1(-/-) mice have a significant reduction in macrophage recruitment to the vessel wall and decreased atherosclerotic lesion formation.
[62]
Fractalkine/CX3CR1 and atherosclerosis - PubMed
Jun 11, 2011 · Several studies have showed that fractalkine or CX3CR1 deficiency in atherosclerotic mice would ameliorate the severity of plaque. Population ...
[63]
Fractalkine/CX3CL1 in rheumatoid arthritis - PubMed
Aug 2, 2016 · Interaction between fractalkine and its unique receptor (CX3CR1) induces cell adhesion, chemotaxis, crawling, "accessory cell" activity, and ...
[64]
Fractalkine, a novel chemokine in rheumatoid arthritis and in rat ...
Objective: To examine the expression of the novel CX3C chemokine fractalkine (Fkn) and its receptor (CX3CR1) in rheumatoid arthritis (RA) and rat adjuvant- ...
[65]
Fractalkine (CX3CL1) and Its Receptor CX3CR1 - Frontiers
CX3CL1 was identified independently by two separate research groups in 1997 and termed neurotactin and fractalkine by the respective authors (1, 2). Neurotactin ...
[66]
A Promising Therapeutic Target in Chronic Kidney Disease? - PubMed
Jun 7, 2021 · A wealth of evidence has emerged linking CX3CL1-CX3CR1 signalling to renal pathologies in both acute and chronic kidney diseases (CKD).
[67]
CX3CL1 involves in breast cancer metastasizing to the spine via the ...
Sep 8, 2018 · In the present study, we found that the receptor CX3CR1 was overexpressed in the spinal metastases of breast cancer than in para-tumor tissue.
[68]
Fractalkine/CX3CL1 in Neoplastic Processes - MDPI
Fractalkine/CX3C chemokine ligand 1 (CX3CL1) is a chemokine involved in the anticancer function of lymphocytes—mainly NK cells, T cells and dendritic cells.Fractalkine/cx3cl1 In... · 2. Cx3cl1 Protein · 3. Cx3cr1: Signal...<|control11|><|separator|>
[69]
Antitumor immune response by CX3CL1 fractalkine gene transfer ...
This study suggests that fractalkine can be a suitable candidate for immunogene therapy of cancer because fractalkine induces both innate and adaptive immunity.Missing: original | Show results with:original
[70]
Defective antitumor responses in CX3CR1-deficient mice - PubMed
Jul 15, 2007 · We found that B16-treated CX3CR1-/- mice had increased lung tumor burden and cachexia. There was a selective reduction of monocytes and NK cells ...
[71]
Fractalkine is a novel human adipochemokine associated with type ...
Fractalkine (CX3CL1) and its receptor (CX3CR1) comprise a chemokine system involved in leukocyte recruitment and adhesion in atherosclerosis, but its role in ...
[72]
CX3CL1-CX3CR1 Signaling Deficiency Exacerbates Obesity-induced Inflammation and Insulin Resistance in Male Mice
### Summary of CX3CL1-CX3CR1 Signaling Effects on Obesity, Inflammation, and Insulin Resistance in Adipose Tissue
[73]
Augmented concentrations of CX 3 CL1 are associated with ...
Nov 20, 2018 · CX3CL1 was associated with annual progression of pulmonary fibrosis > 5% in univariable analyses (Table 3), no further analyses were performed ...
[74]
AB0203 Possible Role of Fractalkine/CX3CL1 (FKN) in the ...
In SSc it seems to be expressed on endothelial cells in the affected skin and in lung tissue and raised serum levels of FKN are associated with higher ...
[75]
Fractalkine Signalling (CX3CL1/CX3CR1 Axis) as an Emerging ...
Jul 21, 2023 · Here we review the cellular biology of fractalkine and its receptor, along with ongoing studies that introduce CX3CR1 as a future target in ...Missing: blockers siRNA
[76]
The CX3CL1-CX3CR1 chemokine axis can contribute to tumor ...
Sep 12, 2023 · The CX3CR1 monoclonal antibody reduces migration of tumor cells and decreases secretion of immune suppressive soluble mediators by tumor cells.
[77]
Anti-CX3CL1 (fractalkine) monoclonal antibody attenuates lung and ...
May 3, 2024 · Anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.
[78]
CX3CR1+ Monocytes/Macrophages Promote Regional Immune ...
Jun 2, 2025 · Recently, many small-molecule inhibitors and monoclonal antibodies targeting the CX3CL1–CX3CR1 axis have been developed [49]. Quetmolimab ...Missing: blockers | Show results with:blockers
[79]
CX3CL1/CX3CR1 Signaling Mediated Neuroglia Activation Is ... - IOVS
The CX3CL1/CX3CR1 signaling mediated neuroglia activation was implicated in the photoreceptor demise of an RD model.
[80]
[PDF] Targeting efferocytosis for tissue regeneration: From microenvironment
Pharmacological inhibition of CX3CR1 via an antagonist, AZD8797, attenuates hepatic. IRI severity, confirming it could be a therapeutic target [99]. In ...
[81]
TRAIL/NF-κB/CX3CL1 Mediated Onco-Immuno Crosstalk Leading to ...
Jun 4, 2018 · Furthermore, we were able to exclude a direct effect of siRNA mediated knockdown of CX3CL1 on proliferation or migration of PDAC cells.
[82]
CX3CL1 promotes tumour cell by inducing tyrosine phosphorylation ...
Nov 15, 2020 · Here, we showed that CX3CL1 can further invasion and migration of lung adenocarcinoma A549 and lung squamous cell carcinoma H520. In addition, ...2.4 Sirna Transfection · 3 Results · 4 Discussion<|separator|>
[83]
A miR-125b/CSF1-CX3CL1/tumor-associated macrophage ... - Nature
Sep 20, 2018 · It is well-demonstrated that CSF1 and CX3CL1 control the recruitment of TAMs into tumor microenvironment. CSF1 silencing in tumor cells reduces ...Tumor Cell Mir-125b... · Mir-125b Targets Chemokines... · Csf1 And Cx3cl1 Are Direct...
[84]
Decreased atherosclerotic lesion formation in CX3CR1 ... - PubMed
Here we show that the extent of lipid-stained lesions in the thoracic aorta was reduced by 59% in CX3CR1/apoE double knockout mice.Missing: Sheridan 2014
[85]
Microglial Cx3cr1 knockout prevents neuron loss in a mouse model ...
Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer's disease. Nat Neurosci. 2010 Apr;13(4):411-3. doi: 10.1038/nn.2511. Epub 2010 ...Missing: progression | Show results with:progression
[86]
CX3CR1 deficiency alters microglial activation and reduces beta ...
These results demonstrate that loss of neuron-microglial fractalkine signaling leads to reduced β-amyloid deposition in mouse models of AD.Missing: knockout progression
[87]
SAT0187 Safety, pharmacokinetics and efficacy of e6011, an anti ...
The results obtained suggest that a novel approach to target FKN/CX3CR1 interaction will be clinically beneficial for RA, and support to conduct phase 2 ...Missing: antagonist | Show results with:antagonist
[88]
Fractalkine is a key player in skeletal muscle metabolism ... - PubMed
Sep 25, 2025 · Notably, CX3CL1 appears to play a role in the pathogenesis of several chronic diseases, including type 2 diabetes (T2D), obesity, cardiovascular ...Missing: sensitivity | Show results with:sensitivity
[89]
Association of circulating inflammatory proteins with type 2 diabetes ...
Mar 27, 2024 · CX3CL1-CX3CR1 signaling deficiency exacerbates obesity-induced inflammation and insulin resistance in male mice. Endocrinology. (2021) 162 ...<|separator|>
[90]
CX3CL1 promotes M1 macrophage polarization and osteoclast ...
Jul 12, 2025 · CX3CL1 accelerates M1 macrophage polarization and promotes osteoclast differentiation, mechanistically regulated by m5C modification mediated by NSUN5.
[91]
Multi‐omic analysis identifies biological processes underlying ...
Jul 7, 2025 · In SSc patients, CX3CL1 is found in higher levels in endothelial cells of fibrotic skin and lung [[25]], and localized in reactive type II ...