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Introduction: Primary Sjögren syndrome (pSS) is a systemic autoimmune disease that is characterized by the infiltration of immune cells into the salivary glands. The re-establishment of salivary glands (SGs) function in pSS remains a clinical challenge. Myeloid-derived growth factor (MYDGF) has anti-inflammatory, immunomodulatory, and tissue-functional restorative abilities. However, its potential to restore SGs function during pSS has not yet been investigated. Methods: Nonobese diabetic (NOD)/LtJ mice (pSS model) were intravenously administered with adeno-associated viruses carrying MYDGF at 11 weeks of age. Salivary flow rates were determined before and after treatment. Mice were killed 5 weeks after MYDGF treatment, and submandibular glands were collected for analyses of histological disease scores, inflammatory cell infiltration, PCR determination of genes, and Western blotting of functional proteins. Furthermore, mRNA sequencing and bioinformatics were used to predict the mechanism underlying the therapeutic effect of MYDGF. Results: Treatment of NOD/LtJ mice with MYDGF alleviated pSS, as indicated by increased salivary flow rate, reduced lymphocyte infiltration, attenuated glandular inflammation, and enhanced AQP5 and NKCC1 expression. The gene expression levels of cytokines and chemokines, including Ccl12, Ccl3, Il1r1, Ccr2, Cx3cr1, Il7, Mmp2, Mmp14, Il1b, and Il7, significantly decreased after treatment with MYDGF, as determined by RNA sequencing. Meanwhile, MYDGF inhibits infiltration of macrophages (Mf) in SGs, induces polarization of M2f, and suppresses C-X3C motif ligand 1 (CX3CL1)/C-X3C motif receptor 1 (CX3CR1) axis. Conclusions: Our findings showed that MYDGF could revitalize the SGs function of pSS, inhibit infiltration of Mf, and promote M2f polarization via suppression of the CX3CL1/CX3CR1 axis, which has implications for potential therapy for pSS. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) is a common respiratory pathogen that causes respiratory illnesses, ranging from mild symptoms to severe lower respiratory tract infections in infants and older adults. This virus is responsible for one-third of pneumonia deaths in the pediatric population; however, there are currently only a few effective vaccines. A better understanding of the RSV–host relationship at the molecular level may lead to a more effective management of RSV-related symptoms. The fractalkine (CX3CL1) receptor (CX3CR1) is a co-receptor for RSV expressed by airway epithelial cells and diverse immune cells. RSV G protein binds to the CX3CR1 receptor via a highly conserved amino acid motif (CX3C motif), which is also present in CX3CL1. The CX3CL1-CX3CR1 axis is involved in the activation and infiltration of immune cells into the infected lung. The presence of the RSV G protein alters the natural functions of the CX3CR1-CX3CL1 axis and modifies the host's immune response, an aspects that need to be considered in the development of an efficient vaccine and specific pharmacological treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Melanoma progression is based on a close interaction between cancer cells and immune cells in the tumor microenvironment (TME). Thus, a better understanding of the mechanisms controlling TME dynamics and composition will help improve the management of this dismal disease. Work from our and other groups has reported the requirement of an active Hedgehog-GLI (HH-GLI) signaling for melanoma growth and stemness. However, the role of the downstream GLI1 transcription factor in melanoma TME remains largely unexplored. Methods The immune-modulatory activity of GLI1 was evaluated in a syngeneic B16F10 melanoma mouse model assessing immune populations by flow cytometry. Murine polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were differentiated from bone marrow cells and their immunosuppressive ability was assessed by inhibition of T cells. Conditioned media (CM) from GLI1-overexpressing mouse melanoma cells was used to culture PMN-MDSCs, and the effects of CM were evaluated by Transwell invasion assay and T cell inhibition. Cytokine array analysis, qPCR and chromatin immunoprecipitation were performed to explore the regulation of CX3CL1 expression by GLI1. Human monocyte-derived dendritic cells (moDCs) were cultured in CM from GLI1-silenced patient-derived melanoma cells to assess their activation and recruitment. Blocking antibodies anti-CX3CL1, anti-CCL7 and anti-CXCL8 were used for in vitro functional assays. Results Melanoma cell-intrinsic activation of GLI1 promotes changes in the infiltration of immune cells, leading to accumulation of immunosuppressive PMN-MDSCs and regulatory T cells, and to decreased infiltration of dendric cells (DCs), CD8 + and CD4 + T cells in the TME. In addition, we show that ectopic expression of GLI1 in melanoma cells enables PMN-MDSC expansion and recruitment, and increases their ability to inhibit T cells. The chemokine CX3CL1, a direct transcriptional target of GLI1, contributes to PMN-MDSC expansion and recruitment. Finally, silencing of GLI1 in patient-derived melanoma cells promotes the activation of human monocyte-derived dendritic cells (moDCs), increasing cytoskeleton remodeling and invasion ability. This phenotype is partially prevented by blocking the chemokine CCL7, but not CXCL8. Conclusion Our findings highlight the relevance of tumor-derived GLI1 in promoting an immune-suppressive TME, which allows melanoma cells to evade the immune system, and pave the way for the design of new combination treatments targeting GLI1.

Abstract Phagocytosis, a vital defense mechanism, involves the recognition and elimination of foreign substances by cells. Phagocytes, such as neutrophils and macrophages, rapidly respond to invaders; macrophages are especially important in later stages of the immune response. They detect “find me” signals to locate apoptotic cells and migrate toward them. Apoptotic cells then send “eat me” signals that are recognized by phagocytes via specific receptors. “Find me” and “eat me” signals can be strategically harnessed to modulate antitumor immunity in support of cancer therapy. These signals, such as calreticulin and phosphatidylserine, mediate potent pro‐phagocytic effects, thereby promoting the engulfment of dying cells or their remnants by macrophages, neutrophils, and dendritic cells and inducing tumor cell death. This review summarizes the phagocytic “find me” and “eat me” signals, including their concepts, signaling mechanisms, involved ligands, and functions. Furthermore, we delineate the relationships between “find me” and “eat me” signaling molecules and tumors, especially the roles of these molecules in tumor initiation, progression, diagnosis, and patient prognosis. The interplay of these signals with tumor biology is elucidated, and specific approaches to modulate “find me” and “eat me” signals and enhance antitumor immunity are explored. Additionally, novel therapeutic strategies that combine “find me” and “eat me” signals to better bridge innate and adaptive immunity in the treatment of cancer patients are discussed.

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Background: Melanoma progression is based on a close interaction between cancer cells and immune cells in the tumor microenvironment (TME). Thus, a better understanding of the mechanisms controlling TME dynamics and composition will help improve the management of this dismal disease. Work from our and other groups has reported the requirement of an active Hedgehog-GLI (HH-GLI) signaling for melanoma growth and stemness. However, the role of the downstream GLI1 transcription factor in melanoma TME remains largely unexplored. Methods: The immune-modulatory activity of GLI1 was evaluated in a syngeneic B16F10 melanoma mouse model assessing immune populations by flow cytometry. Murine polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) were differentiated from bone marrow cells and their immunosuppressive ability was assessed by inhibition of T cells. Conditioned media (CM) from GLI1-overexpressing mouse melanoma cells was used to culture PMN-MDSCs, and the effects of CM were evaluated by Transwell invasion assay and T cell inhibition. Cytokine array analysis, qPCR and chromatin immunoprecipitation were performed to explore the regulation of CX3CL1 expression by GLI1. Human monocyte-derived dendritic cells (moDCs) were cultured in CM from GLI1-silenced patient-derived melanoma cells to assess their activation and recruitment. Blocking antibodies anti-CX3CL1, anti-CCL7 and anti-CXCL8 were used for in vitro functional assays. Results: Melanoma cell-intrinsic activation of GLI1 promotes changes in the infiltration of immune cells, leading to accumulation of immunosuppressive PMN-MDSCs and regulatory T cells, and to decreased infiltration of dendric cells (DCs), CD8 + and CD4 + T cells in the TME. In addition, we show that ectopic expression of GLI1 in melanoma cells enables PMN-MDSC expansion and recruitment, and increases their ability to inhibit T cells. The chemokine CX3CL1, a direct transcriptional target of GLI1, contributes to PMN-MDSC expansion and recruitment. Finally, silencing of GLI1 in patient-derived melanoma cells promotes the activation of human monocyte-derived dendritic cells (moDCs), increasing cytoskeleton remodeling and invasion ability. This phenotype is partially prevented by blocking the chemokine CCL7, but not CXCL8. Conclusion: Our findings highlight the relevance of tumor-derived GLI1 in promoting an immune-suppressive TME, which allows melanoma cells to evade the immune system, and pave the way for the design of new combination treatments targeting GLI1. [ABSTRACT FROM AUTHOR]

Introduction: Immunogenic cell death (ICD) has emerged as a novel option for cancer immunotherapy. The key determinants of ICD encompass antigenicity (the presence of antigens) and adjuvanticity, which involves the release of damageassociated molecular patterns (DAMPs) and various cytokines and chemokines. CX3CL1, also known as neurotactin or fractalkine, is a chemokine involved in cellular signalling and immune cell interactions. CX3CL1 has been denoted as a "find me" signal that stimulates chemotaxis of immune cells towards dying cells, facilitating efferocytosis and antigen presentation. However, in the context of ICD, it is uncertain whether CX3CL1 is an important mediator of the effects of ICD. Methods: In this study, we investigated the intricate role of CX3CL1 in immunogenic apoptosis induced by mitoxantrone (MTX) in cancer cells. The Luminex xMAP technology was used to quantify murine cytokines, chemokines and growth factors to identify pivotal regulatory cytokines released by murine fibrosarcoma MCA205 and melanoma B16-F10 cells undergoing ICD. Moreover, a murine tumour prophylactic vaccination model was employed to analyse the effect of CX3CL1 on the activation of an adaptive immune response against MCA205 cells undergoing ICD. Furthermore, thorough analysis of the TCGASKCM public dataset from 98 melanoma patients revealed the role of CX3CL1 and its receptor CX3CR1 in melanoma patients. Results: Our findings demonstrate enhanced CX3CL1 release from apoptotic MCA205 and B16-F10 cells (regardless of the cell type) but not if they are undergoing ferroptosis or accidental necrosis. Moreover, the addition of recombinant CX3CL1 to non-immunogenic doses of MTX-treated, apoptotically dying cancer cells in the murine prophylactic tumour vaccination model induced a robust immunogenic response, effectively increasing the survival of the mice. Furthermore, analysis of melanoma patient data revealed enhanced survival rates in individuals exhibiting elevated levels of CD8+ T cells expressing CX3CR1. Conclusion: These data collectively underscore the importance of the release of CX3CL1 in eliciting an immunogenic response against dying cancer cells and suggest that CX3CL1 may serve as a key switch in conferring immunogenicity to apoptosis. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to explore the expression of CX3CL1 induced by lipopolysaccharide (LPS) in oral squamous cell carcinoma (OSCC) and its impact on biological characteristics such as invasion and migration, taking the foundation for new targets for the treatment and prognosis of OSCC. Methods: This study utilized a variety of techniques, including bioinformatics, molecular biology, and cell experiments, to investigate the expression of CX3CL1 and its receptor CX3CR1 in OSCC patients' cancer tissues or OSCC cell lines. Extracting, organizing, and analyzing the TCGA database on the expression of CX3CL1 and its receptor CX3CR1 in cancer tissues and corresponding paracancerous normal tissues of OSCC patients by bioinformatics methods. The expression of CX3CL1 in cancerous and normal tissues of OSCC patients was verified by IHC, and the changes inmRNA and protein expression of CX3CL1 and its receptor CX3CR1 in OSCC cell lines were detected before and after lipopolysaccharide LPS stimulation by RT-PCR, ELISA, and WB. Changes in cell biological behavior by overexpression of CX3CL1 in OSCC cell lines were detected by CCK-8, Transwell, scratch healing assay, and cloning assay. The effects of overexpressing cell lines on the AKT pathway and Epithelial-mesenchymal Transition (EMT)-related protein expression before and after LPS stimulation were detected by Western Blot. Results: (1) CX3CL1 and its receptor CX3CR1 were found to be downregulated in OSCC tissues of patients or OSCC cell lines. (2) After LPS stimulation, CX3CL1 gene expression increased in both OSCC cell lines, while CX3CR1 expression remained unchanged. (3) OSCC cell lines overexpressing CX3CL1 showed changes in cell biological characteristics, including decreased proliferation, invasion, migration, and stemness, which were more pronounced after LPS stimulation. (4) Overexpression of CX3CL1 in OSCC cell lines decreased EMT-related protein expression and AKT phosphorylation. On the contrary were promoted by LPS stimulation. Conclusion: CX3CL1 and CX3CR1 are downregulated in OSCC cancer tissues and cell lines compared to adjacent normal tissues and cells. LPS stimulation increases CX3CL1 expression in OSCC cell lines, suggesting that inflammation may induce CX3CL1 expression and that the CX3CL1 gene may play an important role in OSCC progression. Overexpression of CX3CL1 inhibits OSCC cell proliferation, migration, invasion, and stemness, suggesting that CX3CL1 plays a critical role in suppressing OSCC development. CX3CL1 suppresses OSCC invasion and migration by affecting EMT progression and AKT phosphorylation, and partially reverse the process that LPS causes and affects the development of OSCC. [ABSTRACT FROM AUTHOR]

Background: Severe asthma, characterized by inflammation and airway remodeling, involves fibroblast differentiation into myofibroblasts expressing α-SMA. This process leads to the production of fibronectin and connective tissue growth factor (CTGF), driven by factors such as transforming growth factor (TGF)-β. Furthermore, the persistent presence of myofibroblasts is associated with resistance to apoptosis and mitochondrial dysfunction. The chemokine (C-X3-C motif) ligand 1 (CX3CL1) plays a role in tissue fibrosis. However, it is currently unknown whether neutralization of CX3CL1 decreases TGF-β-induced fibroblast differentiation and mitochondrial dysfunction in normal human lung fibroblasts (NHLFs). Methods: CX3CL1/C-X3-C motif chemokine receptor 1 (CX3CR1), CX3CL1 was analyzed by immunofluorescence (IF) or immunohistochemical (IHC) staining of ovalbumin-challenged mice. CX3CL1 release was detected by ELISA. TGF-β-induced CTGF, fibronectin, and α-SMA expression were evaluated in NHLFs following neutralization of CX3CL1 (TP213) treatment for the indicated times by Western blotting or IF staining. Mitochondrion function was detected by a JC-1 assay and seahorse assay. Cell apoptosis was observed by a terminal uridine nick-end labeling (TUNEL) assay. Results: An increase in CX3CL1 expression was observed in lung tissues from mice with ovalbumin-induced asthma by IF staining. CX3CR1 was increased in the subepithelial layer of the airway by IHC staining. Moreover, CX3CR1 small interfering (si)RNA downregulated TGF-β-induced CTGF and fibronectin expression in NHLFs. CX3CL1 induced CTGF and fibronectin expression in NHLFs. TGF-β-induced CX3CL1 secretion from NHLFs. Furthermore, TP213 decreased TGF-β-induced CTGF, fibronectin, and α-SMA expression in NHLFs. Mitochondrion-related differentially expressed genes (DEGs) were examined after CX3CL1 neutralization in TGF-β-treated NHLFs. TP213 alleviated TGF-β-induced mitochondrial dysfunction and apoptosis resistance in NHLFs. CX3CL1 induced p65, IκBα, and IKKα phosphorylation in a time-dependent manner. Furthermore, CX3CL1-induced fibronectin expression and JC-1 monomer were decreased by p65 siRNA. TP213 reduced TGF-β-induced p65 and α-SMA expression in NHLFs. Conclusions: These findings suggest that neutralizing CX3CL1 attenuates lung fibroblast activation and mitochondrial dysfunction. Understanding the impacts of CX3CL1 neutralization on fibroblast mitochondrial function could contribute to the development of therapeutic strategies for managing airway remodeling in severe asthma. [ABSTRACT FROM AUTHOR]

Abstract Background Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and inflammation, followed by excessive fibrosis of the skin and other internal organs, including the lungs. CX3CL1 (fractalkine), a chemokine expressed on endothelial cells, supports the migration of macrophages and T cells that express its specific receptor CX3CR1 into targeted tissues. We previously reported that anti-CX3CL1 monoclonal antibody (mAb) treatment significantly inhibited transforming growth factor (TGF)-β1-induced expression of type I collagen and fibronectin 1 in human dermal fibroblasts. Additionally, anti-mouse CX3CL1 mAb efficiently suppressed skin inflammation and fibrosis in bleomycin- and growth factor-induced SSc mouse models. However, further studies using different mouse models of the complex immunopathology of SSc are required before the initiation of a clinical trial of CX3CL1 inhibitors for human SSc. Methods To assess the preclinical utility and functional mechanism of anti-CX3CL1 mAb therapy in skin and lung fibrosis, a sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) mouse model was analyzed with immunohistochemical staining for characteristic infiltrating cells and RNA sequencing assays. Results On day 42 after bone marrow transplantation, Scl-cGVHD mice showed increased serum CX3CL1 level. Intraperitoneal administration of anti-CX3CL1 mAb inhibited the development of fibrosis in the skin and lungs of Scl-cGVHD model, and did not result in any apparent adverse events. The therapeutic effects were correlated with the number of tissue-infiltrating inflammatory cells and α-smooth muscle actin (α-SMA)-positive myofibroblasts. RNA sequencing analysis of the fibrotic skin demonstrated that cGVHD-dependent induction of gene sets associated with macrophage-related inflammation and fibrosis was significantly downregulated by mAb treatment. In the process of fibrosis, mAb treatment reduced cGVHD-induced infiltration of macrophages and T cells in the skin and lungs, especially those expressing CX3CR1. Conclusions Together with our previous findings in other SSc mouse models, the current results indicated that anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.

The objective of our study was to evaluate serum CX3CL1/Fractalkine, a monocyte/macrophage chemoattractant expressed in cytotrophoblasts and decidual cells, as a predictive biomarker for the occurrence of preterm premature rupture of membranes (PPROM). A case-control study of 438 pregnancies including 82 PPROM cases and 64 preterm labor with intact membranes cases with blood samples collected at first trimester, second trimester and delivery was conducted. The predictive ability of CX3CL1 and maternal risk factors for the occurrence of PPROM was assessed by receiver operating characteristic curve analysis. A second, independent cohort was prospectively constituted to confirm the case-control study results. First trimester CX3CL1 was significantly increased in PPROM cases when compared to matched controls. Multivariate regression analysis highlighted a significant difference for CX3CL1 measured during the first trimester (p<0.001). Alone, CX3CL1 predicts PPROM with a 90 % sensitivity and a specificity around 40 %. The area under the receiver operating characteristic curve for PPROM prediction were 0.64 (95% confidence interval: 0.57–0.71) for first trimester CX3CL1, and 0.61 (95% confidence interval: 0.54–0.68) for maternal risk factors (body mass index<18.5 kg/m2, nulliparity, tobacco use and the absence of high school diploma). The combination of CX3CL1 and maternal risk factors significantly improved the area under the curve: 0.72 (95% confidence interval: 0.66–0.79) (p<0.001). The results were confirmed on a second independent cohort. CX3CL1 is a promising blood biomarker in the early (first trimester) prediction of PPROM. [ABSTRACT FROM AUTHOR]

Introduction: CX3CL1 exhibits chemoattraction for T-cells, monocytes, and CD57+ natural killer cells mediating antitumor immunity. The role of CX3CL1 has been studied in tumors of the breast, lung, colon, pancreas, prostate, etc. The current study was undertaken to understand the importance of CX3CL1 and its correlation with CD57+ cells in oral squamous cell carcinoma (OSCC). Material and Methods: Seventy-five primary OSCC were staged and histopathologically graded, followed by immunohistochemistry for CX3CL1 and CD57. Mann-Whitney U-test, Kruskal-Wallis test, Post hoc Bonferroni test, and Pearson's correlation coefficient were applied. Results: CX3CL1 assessment within the tumor cells was high in 62.66% of cases, and the CD57 Labeling Index (LI) varied over a wide range of 8.2-111.6. A statistically significant reduction in expression of both CX3CL1 and CD57 was observed with an increase in histologic grade (p = 0.021 and 0.038, respectively). Discussion: It is concluded that CX3CL1 and CD57 may be important players in the immune surveillance of OSCC. Further studies with detailed follow-up for the overall survival of patients will help in studying the diagnostic, prognostic, and therapeutic roles of CX3CL1 in OSCC. [ABSTRACT FROM AUTHOR]

CX3CL1, also named fractalkine or neurotactin, is the only known member of the CX3C chemokine family that can chemoattract several immune cells. CX3CL1 exists in both membrane-anchored and soluble forms, with each mediating distinct biological activities. CX3CL1 signals are transmitted through its unique receptor, CX3CR1, primarily expressed in the microglia of the central nervous system (CNS). In the CNS, CX3CL1 acts as a regulator of microglia activation in response to brain disorders or inflammation. Recently, there has been a growing interest in the role of CX3CL1 in regulating cell adhesion, chemotaxis, and host immune response in viral infection. Here, we provide a comprehensive review of the changes and function of CX3CL1 in various viral infections, such as human immunodeficiency virus (HIV), SARS-CoV-2, influenza virus, and cytomegalovirus (CMV) infection, to highlight the emerging roles of CX3CL1 in viral infection and associated diseases. [ABSTRACT FROM AUTHOR]

Aim: To evaluate i) the relationship between epilepsy and inflammation by analyzing the levels of thymus activation-regulated chemokine (TARC), and interferon regulatory factor 5 (IRF5) in healthy controls, patients with epilepsy on monotherapy and polytherapy, ii) the levels of sICAM5, chemokine (c-x3-c motif) ligand 1 (CX3CL1), and septin 7 (SEPT7) which are important in both inflammation and synaptic formation. Methods: Patients who were seizure-free with monotherapy (epilepsy group-1), patients with drug-resistant epilepsy (epilepsy group-2), and healthy controls were included. Demographical data, disease durations, and medications were noted. Measurements were made by commercial ELISA kits. Results: The numbers of epilepsy group-1, epilepsy group-2, and healthy controls were 23, 20, and 21, respectively. TARC levels were significantly lower in healthy controls than in both epilepsy groups. Higher TARC levels than 0.58 pg/ml indicated epilepsy with a sensitivity of 81.8% and specificity of 84.0%. SEPT7 levels were significantly higher in epilepsy group-1 than in those epilepsy group-2. A negative correlation was found between SEPT7 levels and disease duration as is the case for the correlation between SEPT7 and average seizure duration. A positive correlation was found between IRF5 and CX3CL1 levels, SEPT7 and IRF5 levels, and IRF5 and sICAM5 levels. Conclusions: We suggest that TARC is a promising biomarker, even in a heterogeneous epilepsy group not only for drug-resistance epilepsy but also for seizure-free epilepsy with monotherapy. Additionally, drug resistance, longer disease, and longer seizure durations are related to lower levels of SEPT7, which has an essential role in immunological functions and dendritic morphology. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common form of dementia, characterized by the accumulation of β-amyloid plaques, tau tangles, neuroinflammation, and synaptic/neuronal loss, the latter being the strongest correlating factor with memory and cognitive impairment. Through an in vitro study on a neurons–astrocytes–microglia (NAM) co-culture system, we analyzed the effects of cerebrospinal fluid (CSF) samples from AD and non-AD patients (other neurodegenerative pathologies). Treatment with CSF from AD patients showed a loss of neurofilaments and spheroids, suggesting the presence of elements including CX3CL1 (soluble form), destabilizing the neurofilaments, cellular adhesion processes, and intercellular contacts. The NAM co-cultures were analyzed in immunofluorescence assays for several markers related to AD, such as through zymography, where the expression of proteolytic enzymes was quantified both in cell extracts and the co-cultures' conditioned medium (CM). Through qRT-PCR assays, several genes involved in the formation of β-amyloid plaque, in phosphorylation of tau, and in inflammation pathways and MMP expression were investigated. [ABSTRACT FROM AUTHOR]

IntroductionImmunogenic cell death (ICD) has emerged as a novel option for cancer immunotherapy. The key determinants of ICD encompass antigenicity (the presence of antigens) and adjuvanticity, which involves the release of damage-associated molecular patterns (DAMPs) and various cytokines and chemokines. CX3CL1, also known as neurotactin or fractalkine, is a chemokine involved in cellular signalling and immune cell interactions. CX3CL1 has been denoted as a “find me” signal that stimulates chemotaxis of immune cells towards dying cells, facilitating efferocytosis and antigen presentation. However, in the context of ICD, it is uncertain whether CX3CL1 is an important mediator of the effects of ICD.MethodsIn this study, we investigated the intricate role of CX3CL1 in immunogenic apoptosis induced by mitoxantrone (MTX) in cancer cells. The Luminex xMAP technology was used to quantify murine cytokines, chemokines and growth factors to identify pivotal regulatory cytokines released by murine fibrosarcoma MCA205 and melanoma B16-F10 cells undergoing ICD. Moreover, a murine tumour prophylactic vaccination model was employed to analyse the effect of CX3CL1 on the activation of an adaptive immune response against MCA205 cells undergoing ICD. Furthermore, thorough analysis of the TCGA-SKCM public dataset from 98 melanoma patients revealed the role of CX3CL1 and its receptor CX3CR1 in melanoma patients.ResultsOur findings demonstrate enhanced CX3CL1 release from apoptotic MCA205 and B16-F10 cells (regardless of the cell type) but not if they are undergoing ferroptosis or accidental necrosis. Moreover, the addition of recombinant CX3CL1 to non-immunogenic doses of MTX-treated, apoptotically dying cancer cells in the murine prophylactic tumour vaccination model induced a robust immunogenic response, effectively increasing the survival of the mice. Furthermore, analysis of melanoma patient data revealed enhanced survival rates in individuals exhibiting elevated levels of CD8+ T cells expressing CX3CR1.ConclusionThese data collectively underscore the importance of the release of CX3CL1 in eliciting an immunogenic response against dying cancer cells and suggest that CX3CL1 may serve as a key switch in conferring immunogenicity to apoptosis.

Objective To explore the effect and mechanism of chemokine CX3CL1 on mouse liver fibrosis model. Methods C57BL/6 mice were randomly divided into CCl-4 model group and normal control group with 8 animals in each group. The model group was injected with 10% CCl-4 intra peritoneally for 6 weeks. After 6 weeks, the mice were sacrificed, and the pathological changes of the mouse liver were observed by HE staining. The level of CX3CL1 in peripheral blood of the mice was measured, and the expression level of CX3CL1 mRNA in the liver tissue of the mice was detected. In addition, in order to explore the mechanism of CX3CL1, the level of IFN-γ in mouse serum was detected as well. Results After the 6-week modeling, the liver pathology microscopy showed a successful modeling of liver fibrosis. The serum CX3CL1 level and liver tissue CX3CL1 expression in the model group were found to be significantly up-regulated, which suggested a potential impact on the pathogenesis of liver fibrosis. In addition, the level of IFN-γ in the serum of mice in the model group increased significantly. Conclusions CX3CL1 is related to liver fibrosis in mice, and its mechanism might be explained by promoting the production of IFN-γ so to prevent liver fibrosis.

Respiratory syncytial virus (RSV) is a common respiratory pathogen that causes respiratory illnesses, ranging from mild symptoms to severe lower respiratory tract infections in infants and older adults. This virus is responsible for one-third of pneumonia deaths in the pediatric population; however, there are currently only a few effective vaccines. A better understanding of the RSV–host relationship at the molecular level may lead to a more effective management of RSV-related symptoms. The fractalkine (CX3CL1) receptor (CX3CR1) is a co-receptor for RSV expressed by airway epithelial cells and diverse immune cells. RSV G protein binds to the CX3CR1 receptor via a highly conserved amino acid motif (CX3C motif), which is also present in CX3CL1. The CX3CL1-CX3CR1 axis is involved in the activation and infiltration of immune cells into the infected lung. The presence of the RSV G protein alters the natural functions of the CX3CR1-CX3CL1 axis and modifies the host’s immune response, an aspects that need to be considered in the development of an efficient vaccine and specific pharmacological treatment.

Objective: This systematic review aimed to investigate the role of the C-X3-C motif ligand 1/chemokine receptor 1 C-X3-C motif (CX3CL1/CX3CR1) axis in the pathogenesis of periodontitis. Furthermore, as a secondary objective, we determine whether the CX3CL1/CX3CR1 axis could be considered complementary to clinical parameters to distinguish between periodontitis and rheumatoid arthritis (RA) and/or systemically healthy subjects. Methods: The protocol used for this review was registered in OSF (10.17605/OSF.IO/KU8FJ). This study was designed following Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Records were identified using different search engines (PubMed/MEDLINE, Scopus, Science Direct, and Web of Science) from August 10, 2006, to September 15, 2023. The observational studies on human subjects diagnosed with periodontitis and RA and/or systemically healthy were selected to analyze CX3CL1 and CX3CR1 biomarkers. The methodological validity of the selected articles was assessed using NIH. Results: Six articles were included. Biological samples (gingival crevicular fluid [GCF], saliva, gingival tissue biopsies, serum) from 379 subjects (n = 275 exposure group and n = 104 control group) were analyzed. Higher CX3CL1 and CX3CR1 chemokine levels were found in subjects with periodontitis and RA compared with periodontal and systemically healthy subjects. Conclusion: Very few studies highlight the role of the CX3CL1/CX3CR1 axis in the pathogenesis of periodontitis; however, increased levels of these chemokines are observed in different biological samples (GCF, gingival tissue, saliva, and serum) from subjects with periodontitis and RA compared with their healthy controls. Future studies should focus on long-term follow-up of subjects and monitoring changes in cytokine levels before and after periodontal therapy to deduce an appropriate interval in health and disease conditions. [ABSTRACT FROM AUTHOR]

Introduction: The healing of tendon-bone injuries is very difficult, often resulting in poor biomechanical performance and unsatisfactory functional recovery. The tendon-bone insertion has a complex four distinct layers structure, and previous studies have often focused on promoting the regeneration of the fibrocartilage layer, neglecting the role of its bone end repair in tendon-bone healing. This study focuses on the role of treadmill training in promoting bone regeneration at the tendon-bone insertion and its related mechanisms. Methods: After establishing the tendon-bone insertion injury model, the effect of treadmill training on tendon-bone healing was verified by Micro CT and HE staining; then the effect of CX3CL1 on osteoclast differentiation was verified by TRAP staining and cell culture; and finally the functional recovery of the mice was verified by biomechanical testing and behavioral test. Results: Treadmill training suppresses the secretion of CX3CL1 and inhibits the differentiation of local osteoclasts after tendon-bone injury, ultimately reducing osteolysis and promoting tendon bone healing. Discussion: Our research has found the interaction between treadmill training and the CX3CL1-C3CR1 axis, providing a certain theoretical basis for rehabilitation training. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to investigate the role of plasmacytoma variant translocation 1 (PVT1), a long non‐coding RNA, in glioblastoma multiforme (GBM) and its impact on the tumor microenvironment (TME). Methods: We assessed aberrant PVT1 expression in glioma tissues and its impact on GBM cell growth in vitro and in vivo. Additionally, we investigated PVT1's role in influencing glioma‐associated macrophages. To understand PVT1's role in cell growth and the immunosuppressive TME, we performed a series of comprehensive experiments. Results: PVT1 was overexpressed in GBM due to copy number amplification, correlating with poor prognosis. Elevated PVT1 promoted GBM cell proliferation, while its downregulation inhibited growth in vitro and in vivo. PVT1 inhibited type I interferon‐stimulated genes (ISGs), with STAT1 as the central hub. PVT1 correlated with macrophage enrichment and regulated CX3CL1 expression, promoting recruitment and M2 phenotype polarization of macrophages. PVT1 localized to the cell nucleus and bound to DHX9, enriching at the promoter regions of STAT1 and CX3CL1, modulating ISGs and CX3CL1 expression. Conclusion: PVT1 plays a significant role in GBM, correlating with poor prognosis, promoting cell growth, and shaping an immunosuppressive TME via STAT1 and CX3CL1 regulation. Targeting PVT1 may hold therapeutic promise for GBM patients. [ABSTRACT FROM AUTHOR]

Expression levels of the chemokine receptor CX3CR1 serve as high‐resolution marker delineating functionally distinct antigen‐experienced T‐cell states. The factors that influence CX3CR1 expression in T cells are, however, incompletely understood. Here, we show that in vitro priming of naïve CD8+ T cells failed to robustly induce CX3CR1, which highlights the shortcomings of in vitro priming settings in recapitulating in vivo T‐cell differentiation. Nevertheless, in vivo generated memory CD8+ T cells maintained CX3CR1 expression during culture. This allowed us to investigate whether T‐cell receptor ligation, cell death, and CX3CL1 binding influence CX3CR1 expression. T‐cell receptor stimulation led to downregulation of CX3CR1. Without stimulation, CX3CR1+ CD8+ T cells had a selective survival disadvantage, which was enhanced by factors released from necrotic but not apoptotic cells. Exposure to CX3CL1 did not rescue their survival and resulted in a dose‐dependent loss of CX3CR1 surface expression. At physiological concentrations of CX3CL1, CX3CR1 surface expression was only minimally reduced, which did not hamper the interpretability of T‐cell differentiation states delineated by CX3CR1. Our data further support the broad utility of CX3CR1 surface levels as T‐cell differentiation marker and identify factors that influence CX3CR1 expression and the maintenance of CX3CR1 expressing CD8+ T cells. [ABSTRACT FROM AUTHOR]

In addition to regulating the antiviral response, increased expression of Toll-like receptor 3 (TLR3) in resident renal cells plays a role in developing some forms of glomerulonephritis. TLR3 activation leads to type I interferon (IFN) production, which induces the expression of IFN-stimulated genes (ISGs). However, the role of ISG20 expression in resident renal cells remains unclear. Cultured normal human glomerular endothelial cells (GECs) were treated with polyinosinic-polycytidylic acid (poly IC), Escherichia coli lipopolysaccharide (LPS), R848, and CpG (TLR3, TLR4, TLR7, and TLR9 agonists, respectively). The mRNA levels of ISG20, CX3CL1/fractalkine, and CXCL10/IP-10 were measured by quantitative reverse transcription-polymerase chain reaction. ISG20 protein expression was assessed by Western blotting. RNA interference was used to knockdown IFN-β and ISG20 expression. CX3CL1 protein levels were assessed by enzyme-linked immunosorbent assay. We performed immunofluorescence to examine endothelial ISG20 expression in biopsy specimens from patients with lupus nephritis (LN). In GECs, the expression of ISG20 mRNA and protein was increased by polyIC, not by LPS, R848, or CpG treatment. Moreover, ISG20 knockdown prevented poly IC-induced CX3CL1 expression but had no effect on CXCL10 expression. Intense endothelial ISG20 immunoreactivity was observed in biopsy specimens obtained from patients with proliferative LN. In GECs, ISG20 was regulated via TLR3 but not via TLR4, TLR7, or TLR9 signaling. Moreover, ISG20 was involved in regulating CX3CL1 production. In addition to regulating antiviral innate immunity, ISG20 may act as a mediator of CX3CL1 production, thereby inducing glomerular inflammation, particularly in patients with LN. [ABSTRACT FROM AUTHOR]

To explore the effect and mechanism of chemokine CX3CLI on mouse liver fibrosis model. Methods C57BL/6 mice were randomly divided into CCI-4 model group and normal control group with 8 animals in each group. The model group was injected with 10% CCl-4 intra peritoneally for 6 weeks. After 6 weeks, the mice were sacrificed, and the pathological changes of the mouse liver were observed by HE staining. The level of CX3CLI in peripheral blood of the mice was measured, and the expression level of CX3CL1 mRNA in the liver tis- sue of the mice was detected. In addition, in order to explore the mechanism of CX3CLI, the level of IFN-y in mouse serum was detected as well. Results After the 6-week modeling, the liver pathology microscopy showed a successful modeling of liver fibrosis. The serum CX3CLI level and liver tissue CX3CLI expression in the model group were found to be significantly up-regulated, which suggested a potential impact on the pathogenesis of liver fibrosis. In addition, the level of IFN-y in the serum of mice in the model group increased significantly. Conclusions CX3CLI is related to liver fibrosis in mice, and its mechanism might be explained by promoting the production of IFN-y so to prevent liver fibrosis. [ABSTRACT FROM AUTHOR]

C-X3-C motif chemokine ligand 1 (CX3CL1) is a transmembrane protein, and the membranal and soluble forms of CX3CL1 exhibit different functions, although both bind to the CX3CR1 chemokine receptor. The CX3CL1/CX3CR1 axis induces many cellular responses relevant to cancer, such as proliferation, migration, invasion, and apoptosis resistance. Here we attempt to elucidate whether CX3CL1/CX3CR1 is associated with paclitaxel (PTX) resistance in gastric cancer (GC). The Gene Expression Omnibus database was queried to screen for differentially expressed genes in GC cells caused by drug resistance, and CX3CL1 was selected as a candidate. CX3CL1 was overexpressed in PTX-resistant cells and tissues. CX3CL1 loss sensitized GC cells to PTX, promoted apoptosis and DNA damage, and inhibited cell proliferation, migration, and invasion. CX3CR1 reversed the ameliorative effect of CX3CL1 silencing on PTX sensitivity in GC cells. The promotion of PTX resistance by CX3CL1/CX3CR1 was inhibited by impairment of the small GTPase Ras homolog gene family member A (RhoA) pathway in vitro and in vivo. These findings indicate that the CX3CL1/CX3CR1 expedites PTX resistance through the RhoA signaling in GC cells.

Abstract Background It is widely acknowledged that cisplatin-induced nephrotoxicity hinders its efficacy during clinical therapy. Effective pharmaceutical interventions for cisplatin-induced acute kidney injury (Cis-AKI) are currently lacking. Prior studies have implicated the chemokine CX3CL1 in the development of lipopolysaccharide-induced AKI; however, its specific role in Cis-AKI remains uncertain. This research aimed to comprehensively characterize the therapeutic impact and mechanism of CX3CL1 inhibition on Cis-AKI. Methods This study employed an in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes. Kidney pathological changes were assessed using hematoxylin–eosin (HE) and Periodic-Schiff (PAS) staining. Transcriptome changes in mouse kidney tissue post-cisplatin treatment were analyzed through RNA sequencing (RNA-seq) datasets. Evaluation parameters included the expression of inflammatory markers, intracellular free iron levels, ferroptosis-related proteins—solute carrier family 7 member 11 (SLC7A11/XCT) and glutathione peroxidase 4 (GPX4)—as well as lipid peroxidation markers and mitochondrial function proteins. Mitochondrial morphological changes were visualized through transmission electron microscopy. The impact of CX3CL1 on the glucose-regulated protein 78/eukaryotic translation initiation factor 2A/CCAAT enhancer binding protein-homologous protein (GRP78/eIF2α/CHOP) and hypoxia-inducible factor 1-alpha/heme oxygenase-1 (HIF1A/HO-1) pathways in Cis-AKI was assessed via Western Blot and Immunofluorescence experiments, both in vivo and in vitro. Results Kidney CX3CL1 levels were elevated following cisplatin injection in wild-type (WT) mice. Cisplatin-treated CX3CL1-Knockout mice exhibited reduced renal histological changes, lowered blood creatinine (Cre) and blood urea nitrogen (BUN) levels, and decreased expression of inflammatory mediators compared to cisplatin-treated WT mice. RNA-seq analysis revealed the modulation of markers associated with oxidative stress and lipid metabolism related to ferroptosis in the kidneys of mice with Cis-AKI. Both the in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes demonstrated that CX3CL1 inhibition could mitigate ferroptosis. This effect was characterized by alleviated intracellular iron overload, malondialdehyde (MDA) content, and reactive oxygen species (ROS) production, alongside increased glutathione/glutathione disulfide ratio, superoxide dismutase (SOD), XCT, and GPX4 activity. CX3CL1 inhibition also ameliorated mitochondrial dysfunction and upregulated expression of mitochondrial biogenesis proteins-uncoupling protein (UCP), mitofusin 2 (Mfn2), and peroxisome proliferators-activated receptor γ coactivator l-alpha (PGC1α)-both in vivo and in vitro. Furthermore, CX3CL1 inhibition attenuated cisplatin-induced endoplasmic reticulum (ER) stress in podocytes. Notably, CX3CL1 inhibition reduced cisplatin-induced expression of HIF-1α and HO-1 in vivo and in vitro. Conclusion Our findings suggest that CX3CL1 inhibition exerts therapeutic effects against Cis-AKI by suppressing podocyte ferroptosis.

Abstract Background Ankylosing spondylitis (AS) is an autoimmune disease with a genetic correlation and is characterized by inflammation in the axial skeleton and sacroiliac joints. Many AS patients also have inflammatory bowel diseases (IBD), but the underlying causes of intestinal inflammation and osteoporosis in AS are not well understood. CX3CL1, a protein involved in inflammation, has been found to be up-regulated in AS patients and AS-model mice. Methods The authors investigated the effects of CX3CL1 on AS by studying its impact on macrophage polarization, inflammation factors, and osteoclast differentiation. Furthermore, the effects of inhibiting the NF-κB pathway and blocking CX3CL1 were assessed using BAY-117082 and anti-CX3CL1 mAb, respectively. AS model mice were used to evaluate the effects of anti-CX3CL1 mAb on limb thickness, spine rupture, and intestinal tissue damage. Results The authors found that CX3CL1 increased the expression of M1-type macrophage markers and inflammation factors, and promoted osteoclast differentiation. This effect was mediated through the NF-κB signaling pathway. Inhibition of the NF-κB pathway prevented M1-type macrophage polarization, reduced inflammation levels, and inhibited osteoclast differentiation. Injection of anti-CX3CL1 mAb alleviated limb thickness, spine rupture, and intestinal tissue damage in AS model mice by inhibiting M1-type macrophage polarization and reducing intestinal tissue inflammation. Conclusions The study demonstrated that up-regulated CX3CL1 promotes M1-type macrophage polarization and osteoclast differentiation through the NF-κB signaling pathway. Inhibition of this pathway and blocking CX3CL1 can alleviate inflammation and bone destruction in AS. These findings contribute to a better understanding of the pathogenesis of AS and provide a basis for clinical diagnosis and treatment.

Abstract Objective This systematic review aimed to investigate the role of the C‐X3‐C motif ligand 1/chemokine receptor 1 C‐X3‐C motif (CX3CL1/CX3CR1) axis in the pathogenesis of periodontitis. Furthermore, as a secondary objective, we determine whether the CX3CL1/CX3CR1 axis could be considered complementary to clinical parameters to distinguish between periodontitis and rheumatoid arthritis (RA) and/or systemically healthy subjects. Methods The protocol used for this review was registered in OSF (10.17605/OSF.IO/KU8FJ). This study was designed following Preferred Reporting Items for Systematic Review and Meta‐Analysis guidelines. Records were identified using different search engines (PubMed/MEDLINE, Scopus, Science Direct, and Web of Science) from August 10, 2006, to September 15, 2023. The observational studies on human subjects diagnosed with periodontitis and RA and/or systemically healthy were selected to analyze CX3CL1 and CX3CR1 biomarkers. The methodological validity of the selected articles was assessed using NIH. Results Six articles were included. Biological samples (gingival crevicular fluid [GCF], saliva, gingival tissue biopsies, serum) from 379 subjects (n = 275 exposure group and n = 104 control group) were analyzed. Higher CX3CL1 and CX3CR1 chemokine levels were found in subjects with periodontitis and RA compared with periodontal and systemically healthy subjects. Conclusion Very few studies highlight the role of the CX3CL1/CX3CR1 axis in the pathogenesis of periodontitis; however, increased levels of these chemokines are observed in different biological samples (GCF, gingival tissue, saliva, and serum) from subjects with periodontitis and RA compared with their healthy controls. Future studies should focus on long‐term follow‐up of subjects and monitoring changes in cytokine levels before and after periodontal therapy to deduce an appropriate interval in health and disease conditions.

AbstractBackground In addition to regulating the antiviral response, increased expression of Toll-like receptor 3 (TLR3) in resident renal cells plays a role in developing some forms of glomerulonephritis. TLR3 activation leads to type I interferon (IFN) production, which induces the expression of IFN-stimulated genes (ISGs). However, the role of ISG20 expression in resident renal cells remains unclear.Methods Cultured normal human glomerular endothelial cells (GECs) were treated with polyinosinic-polycytidylic acid (poly IC), Escherichia coli lipopolysaccharide (LPS), R848, and CpG (TLR3, TLR4, TLR7, and TLR9 agonists, respectively). The mRNA levels of ISG20, CX3CL1/fractalkine, and CXCL10/IP-10 were measured by quantitative reverse transcription-polymerase chain reaction. ISG20 protein expression was assessed by Western blotting. RNA interference was used to knockdown IFN-β and ISG20 expression. CX3CL1 protein levels were assessed by enzyme-linked immunosorbent assay. We performed immunofluorescence to examine endothelial ISG20 expression in biopsy specimens from patients with lupus nephritis (LN).Results In GECs, the expression of ISG20 mRNA and protein was increased by polyIC, not by LPS, R848, or CpG treatment. Moreover, ISG20 knockdown prevented poly IC-induced CX3CL1 expression but had no effect on CXCL10 expression. Intense endothelial ISG20 immunoreactivity was observed in biopsy specimens obtained from patients with proliferative LN.Conclusion In GECs, ISG20 was regulated via TLR3 but not via TLR4, TLR7, or TLR9 signaling. Moreover, ISG20 was involved in regulating CX3CL1 production. In addition to regulating antiviral innate immunity, ISG20 may act as a mediator of CX3CL1 production, thereby inducing glomerular inflammation, particularly in patients with LN.

Objective: To investigate the effect of calcium hydroxide combined with early myelotomy decompression and drainage surgery on serum leukocyte differentiation antigen-14 (CD14), hypoxia inducible factor-1α (HIF-1α) and CX3C chemokine ligand 1 (CX3CL1) levels and masticatory function in patients with pulpitis. Methods: 174 patients with pulpitis who were treated in Lianyungang Hospital affiliated to Xuzhou Medical University were selected from January 2020 to April 2022, the patients were divided into control group and study group according to the double chromosphere method, 87 cases each. Both groups underwent early myelotomy decompression and drainage surgery, the control group was filled with zinc oxide eugenol cement, the study group was filled with calcium hydroxide paste filling. The efficacy, visual analog score of pain (VAS), bite force, chewing efficiency, CD14, HIF-1α and CX3CL1 levels in two groups were observed. Results: Compared with the control group, the clinical total effective rate was further increased in the study group (P＜0.05) . Compared with the control group, the VAS score decreased, bite force increased, chewing efficiency increased and serum CD14, HIF-1α and CX3CL1 levels decreased in the study group 7 d after treatment (P＜0.05) . Conclusion: Early pulp opening decompression and drainage of pulpitis was treated with calcium hydroxide filling, can effectively reduce the pain in the patient, improve the chewing function, lift the bite force, regulation of the serum CD14, HIF-1α and CX3CL1 levels, improve the clinical treatment effect. [ABSTRACT FROM AUTHOR]

Background: It is widely acknowledged that cisplatin-induced nephrotoxicity hinders its efficacy during clinical therapy. Effective pharmaceutical interventions for cisplatin-induced acute kidney injury (Cis-AKI) are currently lacking. Prior studies have implicated the chemokine CX3CL1 in the development of lipopolysaccharide-induced AKI; however, its specific role in Cis-AKI remains uncertain. This research aimed to comprehensively characterize the therapeutic impact and mechanism of CX3CL1 inhibition on Cis-AKI. Methods: This study employed an in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes. Kidney pathological changes were assessed using hematoxylin–eosin (HE) and Periodic-Schiff (PAS) staining. Transcriptome changes in mouse kidney tissue post-cisplatin treatment were analyzed through RNA sequencing (RNA-seq) datasets. Evaluation parameters included the expression of inflammatory markers, intracellular free iron levels, ferroptosis-related proteins—solute carrier family 7 member 11 (SLC7A11/XCT) and glutathione peroxidase 4 (GPX4)—as well as lipid peroxidation markers and mitochondrial function proteins. Mitochondrial morphological changes were visualized through transmission electron microscopy. The impact of CX3CL1 on the glucose-regulated protein 78/eukaryotic translation initiation factor 2A/CCAAT enhancer binding protein-homologous protein (GRP78/eIF2α/CHOP) and hypoxia-inducible factor 1-alpha/heme oxygenase-1 (HIF1A/HO-1) pathways in Cis-AKI was assessed via Western Blot and Immunofluorescence experiments, both in vivo and in vitro. Results: Kidney CX3CL1 levels were elevated following cisplatin injection in wild-type (WT) mice. Cisplatin-treated CX3CL1-Knockout mice exhibited reduced renal histological changes, lowered blood creatinine (Cre) and blood urea nitrogen (BUN) levels, and decreased expression of inflammatory mediators compared to cisplatin-treated WT mice. RNA-seq analysis revealed the modulation of markers associated with oxidative stress and lipid metabolism related to ferroptosis in the kidneys of mice with Cis-AKI. Both the in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes demonstrated that CX3CL1 inhibition could mitigate ferroptosis. This effect was characterized by alleviated intracellular iron overload, malondialdehyde (MDA) content, and reactive oxygen species (ROS) production, alongside increased glutathione/glutathione disulfide ratio, superoxide dismutase (SOD), XCT, and GPX4 activity. CX3CL1 inhibition also ameliorated mitochondrial dysfunction and upregulated expression of mitochondrial biogenesis proteins-uncoupling protein (UCP), mitofusin 2 (Mfn2), and peroxisome proliferators-activated receptor γ coactivator l-alpha (PGC1α)-both in vivo and in vitro. Furthermore, CX3CL1 inhibition attenuated cisplatin-induced endoplasmic reticulum (ER) stress in podocytes. Notably, CX3CL1 inhibition reduced cisplatin-induced expression of HIF-1α and HO-1 in vivo and in vitro. Conclusion: Our findings suggest that CX3CL1 inhibition exerts therapeutic effects against Cis-AKI by suppressing podocyte ferroptosis. [ABSTRACT FROM AUTHOR]

The chemokine fractalkine (FKN, CX3CL1), a member of the CX3C subfamily, contributes to neuron--glia interaction and the regulation of microglial cell activation. Fractalkine is expressed by neurons as a membrane-bound protein (mCX3CL1) that can be cleaved by extracellular proteases generating several sCX3CL1 forms. sCX3CL1, containing the chemokine domain, and mCX3CL1 have high affinity by their unique receptor (CX3CR1) which, physiologically, is only found in microglia, a resident immune cell of the CNS. The activation of CX3CR1contributes to survival and maturation of the neural network during development, glutamatergic synaptic transmission, synaptic plasticity, cognition, neuropathic pain, and inflammatory regulation in the adult brain. Indeed, the various CX3CL1 forms appear in some cases to serve an anti-inflammatory role of microglia, whereas in others, they have a pro-inflammatory role, aggravating neurological disorders. In the last decade, evidence points to the fact that sCX3CL1 and mCX3CL1 exhibit selective and differential effects on their targets. Thus, the balance in their level and activity will impact on neuron--microglia interaction. This review is focused on the description of factors determining the emergence of distinct fractalkine forms, their age-dependent changes, and how they contribute to neuroinflammation and neurodegenerative diseases. Changes in the balance among various fractalkine forms may be one of the mechanisms on which converge aging, chronic CNS inflammation, and neurodegeneration. [ABSTRACT FROM AUTHOR]

CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration. We generated a novel monoclonal antibody against mouse CX3CR1 that binds to CX3CR1 and blocks the CX3CL1-CX3CR1 interaction. We next explored the immune evasion strategies implemented by the CX3CL1-CX3CR1 axis and find that it initiates a resistance program in cancer cells that results in 1) facilitation of tumor cell migration, 2) secretion of soluble mediators to generate a pro-metastatic niche, 3) secretion of soluble mediators to attract myeloid populations, and 4) generation of tumor-inflammasome. The CX3CR1 monoclonal antibody reduces migration of tumor cells and decreases secretion of immune suppressive soluble mediators by tumor cells. In combination with anti-PD-1 immunotherapy, this CX3CR1 monoclonal antibody enhances survival in an immunocompetent mouse colon carcinoma model through a decrease in tumor-promoting myeloid populations. Thus, this axis is involved in the mechanisms of resistance to anti-PD-1 immunotherapy and the combination therapy can overcome a portion of the resistance mechanisms to anti-PD-1. [ABSTRACT FROM AUTHOR]

In addition to amyloid and tau pathology in the central nervous system (CNS), inflammatory processes and synaptic dysfunction are highly important mechanisms involved in the development and progression of dementia diseases. In the present study, we conducted a comparative analysis of selected pro-inflammatory proteins in the CNS with proteins reflecting synaptic damage and core biomarkers in mild cognitive impairment (MCI) and early Alzheimer's disease (AD). To our knowledge, no studies have yet compared CXCL12 and CX3CL1 with markers of synaptic disturbance in cerebrospinal fluid (CSF) in the early stages of dementia. The quantitative assessment of selected proteins in the CSF of patients with MCI, AD, and non-demented controls (CTRL) was performed using immunoassays (single- and multiplex techniques). In this study, increased CSF concentration of CX3CL1 in MCI and AD patients correlated positively with neurogranin (r = 0.74; p < 0.001, and r = 0.40; p = 0.020, respectively), ptau181 (r = 0.49; p = 0.040), and YKL-40 (r = 0.47; p = 0.050) in MCI subjects. In addition, elevated CSF levels of CXCL12 in the AD group were significantly associated with mini-mental state examination score (r = −0.32; p = 0.040). We found significant evidence to support an association between CX3CL1 and neurogranin, already in the early stages of cognitive decline. Furthermore, our findings indicate that CXCL12 might be a useful marker for tract severity of cognitive impairment. [ABSTRACT FROM AUTHOR]

Ursodeoxycholic acid (UDCA) is the primary treatment for primary biliary cholangitis (PBC), but its mechanism of action remains unclear. Studies suggest that UDCA enhances NF erythroid 2-related factor 2 (NFE2L2) expression and that the interaction between IFN-γ and C-X3-C motif chemokine ligand 1 (CX3CL1) facilitates biliary inflammation in PBC. Therefore, we examined the effects of UDCA on the expression of IFN-γ and CX3CL1 in in vitro and in vivo PBC models such as human liver tissue, a murine model, cell lines, and isolated human intrahepatic biliary epithelial cells (IHBECs). We observed a significant decrease in IFN-γ mRNA levels and positive correlations between IFN-γ and CX3CL1 mRNA levels post-UDCA treatment in PBC livers. NFE2L2-mediated transcriptional activation was significantly enhanced in UDCA-treated Jurkat cells. In 2-octynoic acid-immunized mice, IFN-γ production by liver-infiltrating T cells was dependent on NFE2L2 activation. IFN-γ significantly and dose-dependentlyinduced CX3CL1 expression, which was significantly decreased in HuCC-T1 cells and IHBECs upon UDCA treatment. These results suggest that UDCA-induced suppression of IFN-γ and CX3CL1 production attenuates the chemotactic and adhesive abilities of liver-infiltrating T cells in PBC.

Abstract Background Long-term smoking is a risk factor for chronic pain, and chronic nicotine exposure induces pain-like effects in rodents. The anterior cingulate cortex (ACC) has been demonstrated to be associated with pain and substance abuse. This study aims to investigate whether ACC microglia are altered in response to chronic nicotine exposure and their interaction with ACC neurons and subsequent nicotine-induced allodynia in mice. Methods We utilized a mouse model that was fed nicotine water for 28 days. Brain slices of the ACC were collected for morphological analysis to evaluate the impacts of chronic nicotine on microglia. In vivo calcium imaging and whole-cell patch clamp were used to record the excitability of ACC glutamatergic neurons. Results Compared to the vehicle control, the branch endpoints and the length of ACC microglial processes decreased in nicotine-treated mice, coinciding with the hyperactivity of glutamatergic neurons in the ACC. Inhibition of ACC glutamatergic neurons alleviated nicotine-induced allodynia and reduced microglial activation. On the other hand, reactive microglia sustain ACC neuronal excitability in response to chronic nicotine, and pharmacological inhibition of microglia by minocycline or liposome-clodronate reduces nicotine-induced allodynia. The neuron-microglia interaction in chronic nicotine-induced allodynia is mediated by increased expression of neuronal CX3CL1, which activates microglia by acting on CX3CR1 receptors on microglial cells. Conclusion Together, these findings underlie a critical role of ACC microglia in the maintenance of ACC neuronal hyperactivity and resulting nociceptive hypersensitivity in chronic nicotine-treated mice.

CX3CL1, also named fractalkine or neurotactin, is the only known member of the CX3C chemokine family that can chemoattract several immune cells. CX3CL1 exists in both membrane-anchored and soluble forms, with each mediating distinct biological activities. CX3CL1 signals are transmitted through its unique receptor, CX3CR1, primarily expressed in the microglia of the central nervous system (CNS). In the CNS, CX3CL1 acts as a regulator of microglia activation in response to brain disorders or inflammation. Recently, there has been a growing interest in the role of CX3CL1 in regulating cell adhesion, chemotaxis, and host immune response in viral infection. Here, we provide a comprehensive review of the changes and function of CX3CL1 in various viral infections, such as human immunodeficiency virus (HIV), SARS-CoV-2, influenza virus, and cytomegalovirus (CMV) infection, to highlight the emerging roles of CX3CL1 in viral infection and associated diseases.

Purpose: To assess the systemic effects of an acute bout of moderate-intensity exercise on factors that are known to regulate muscle and bone growth in prepubertal girls and women. Methods: A total of 12 prepubertal girls (8–10 y) and 12 women (20–30 y) cycled at 60% maximal oxygen uptake for 1 hour followed by 1 hour recovery. Blood samples were collected at rest, mid-exercise, end of exercise, mid-recovery, and end of recovery. Plasma was analyzed for interleukin-6, chemokine ligand 1, fibroblast growth factor-2, total insulin growth factor-1 (IGF-1), and free IGF-1 using enzyme-linked immunosorbent assays assays. Results: Both groups had similar concentrations of systemic factors at baseline with the exception of free IGF-1, which was higher in girls (P =.001). Interleukin-6 response was lower in girls versus women (P =.04), with a difference of +105.1% at end of exercise (P <.001), +113.5% at mid-recovery (P =.001), and +93.2% at end of recovery (P =.02). Girls and women exhibited significant declines in chemokine ligand 1, fibroblast growth factor-2, and total IGF-1 during recovery. Conclusion: Compared with women, an acute bout of moderate-intensity exercise in girls elicits a lower inflammatory response, suggesting that other mechanisms may be more important for driving the anabolic effects of exercise on muscle and bone in girls. [ABSTRACT FROM AUTHOR]

Chorea-acanthocytosis (ChAc) is an inherited neurodegenerative movement disorder caused by VPS13A gene mutations leading to the absence of protein expression. The striatum is the most affected brain region in ChAc patients. However, the study of the VPS13A function in the brain has been poorly addressed. Here we generated a VPS13A knockdown (KD) model and aimed to elucidate the contribution of VPS13A to synaptic plasticity and neuronal communication in the corticostriatal circuit. First, we infected primary cortical neurons with miR30-shRNA against VPS13A and analyzed its effects on neuronal plasticity. VPS13A-KD neurons showed a higher degree of branching than controls, accompanied by decreased BDNF and PSD-95 levels, indicative of synaptic alterations. We then injected AAV-KD bilaterally in the frontal cortex and two different regions of the striatum of mice and analyzed the effects of VPS13A-KD on animal behavior and synaptic plasticity. VPS13A-KD mice showed modification of the locomotor behavior pattern, with increased exploratory behavior and hyperlocomotion. Corticostriatal dysfunction in VPS13A-KD mice was evidenced by impaired striatal long-term depression (LTD) after stimulation of cortical afferents, which was partially recovered by BDNF administration. VPS13A-KD did not lead to neuronal loss in the cortex or the striatum but induced a decrease in the neuronal release of CX3CL1 and triggered a microglial reaction, especially in the striatum. Notably, CX3CL1 administration partially restored the impaired corticostriatal LTD in VPS13A-KD mice. Our results unveil the involvement of VPS13A in neuronal connectivity modifying BDNF and CX3CL1 release. Moreover, the involvement of VPS13A in synaptic plasticity and motor behavior provides key information to further understand not only ChAc pathophysiology but also other neurological disorders.

The chemokine fractalkine (FKN, CX3CL1), a member of the CX3C subfamily, contributes to neuron–glia interaction and the regulation of microglial cell activation. Fractalkine is expressed by neurons as a membrane-bound protein (mCX3CL1) that can be cleaved by extracellular proteases generating several sCX3CL1 forms. sCX3CL1, containing the chemokine domain, and mCX3CL1 have high affinity by their unique receptor (CX3CR1) which, physiologically, is only found in microglia, a resident immune cell of the CNS. The activation of CX3CR1contributes to survival and maturation of the neural network during development, glutamatergic synaptic transmission, synaptic plasticity, cognition, neuropathic pain, and inflammatory regulation in the adult brain. Indeed, the various CX3CL1 forms appear in some cases to serve an anti-inflammatory role of microglia, whereas in others, they have a pro-inflammatory role, aggravating neurological disorders. In the last decade, evidence points to the fact that sCX3CL1 and mCX3CL1 exhibit selective and differential effects on their targets. Thus, the balance in their level and activity will impact on neuron–microglia interaction. This review is focused on the description of factors determining the emergence of distinct fractalkine forms, their age-dependent changes, and how they contribute to neuroinflammation and neurodegenerative diseases. Changes in the balance among various fractalkine forms may be one of the mechanisms on which converge aging, chronic CNS inflammation, and neurodegeneration.

CX3CL1 secreted in the tumor microenvironment serves as a chemoattractant playing a critical role in metastasis of CX3CR1 expressing cancer cells. CX3CR1 can be expressed in both cancer and immune-inhibitory myeloid cells to facilitate their migration. We generated a novel monoclonal antibody against mouse CX3CR1 that binds to CX3CR1 and blocks the CX3CL1-CX3CR1 interaction. We next explored the immune evasion strategies implemented by the CX3CL1-CX3CR1 axis and find that it initiates a resistance program in cancer cells that results in 1) facilitation of tumor cell migration, 2) secretion of soluble mediators to generate a pro-metastatic niche, 3) secretion of soluble mediators to attract myeloid populations, and 4) generation of tumor-inflammasome. The CX3CR1 monoclonal antibody reduces migration of tumor cells and decreases secretion of immune suppressive soluble mediators by tumor cells. In combination with anti-PD-1 immunotherapy, this CX3CR1 monoclonal antibody enhances survival in an immunocompetent mouse colon carcinoma model through a decrease in tumor-promoting myeloid populations. Thus, this axis is involved in the mechanisms of resistance to anti-PD-1 immunotherapy and the combination therapy can overcome a portion of the resistance mechanisms to anti-PD-1.

Background: Ankylosing spondylitis (AS) is an autoimmune disease with a genetic correlation and is characterized by inflammation in the axial skeleton and sacroiliac joints. Many AS patients also have inflammatory bowel diseases (IBD), but the underlying causes of intestinal inflammation and osteoporosis in AS are not well understood. CX3CL1, a protein involved in inflammation, has been found to be up-regulated in AS patients and AS-model mice. Methods: The authors investigated the effects of CX3CL1 on AS by studying its impact on macrophage polarization, inflammation factors, and osteoclast differentiation. Furthermore, the effects of inhibiting the NF-κB pathway and blocking CX3CL1 were assessed using BAY-117082 and anti-CX3CL1 mAb, respectively. AS model mice were used to evaluate the effects of anti-CX3CL1 mAb on limb thickness, spine rupture, and intestinal tissue damage. Results: The authors found that CX3CL1 increased the expression of M1-type macrophage markers and inflammation factors, and promoted osteoclast differentiation. This effect was mediated through the NF-κB signaling pathway. Inhibition of the NF-κB pathway prevented M1-type macrophage polarization, reduced inflammation levels, and inhibited osteoclast differentiation. Injection of anti-CX3CL1 mAb alleviated limb thickness, spine rupture, and intestinal tissue damage in AS model mice by inhibiting M1-type macrophage polarization and reducing intestinal tissue inflammation. Conclusions: The study demonstrated that up-regulated CX3CL1 promotes M1-type macrophage polarization and osteoclast differentiation through the NF-κB signaling pathway. Inhibition of this pathway and blocking CX3CL1 can alleviate inflammation and bone destruction in AS. These findings contribute to a better understanding of the pathogenesis of AS and provide a basis for clinical diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Aims: Integrating bioinformatics and experimental validation to explore the mechanisms of inflammaging in the Brain. Method: After dividing the GSE11882 dataset into aged and young groups, we identified co-expressed differentially expressed genes (DEGs) in different brain regions. Enrichment analysis revealed that the co-expressed DEGs were mainly associated with inflammatory responses. Subsequently, we identified 12 DEGs that were related to the inflammatory response and used the DGIdb website for drug prediction. By using both the least absolute shrinkage and selection operator (LASSO) and random forest (RF), four biomarkers were screened and an artificial neural network (ANN) was developed for diagnosis. Subsequently, the biomarkers were validated through animal studies. Then we utilized AgeAnno to investigate the roles of biomarkers at the single cell level. Next, a consensus clustering approach was used to classify the aging samples and perform differential analysis to identify inflammatory response-related genes. After conducting a weighted gene co-expression network analysis (WGCNA), we identified the genes that are correlated with both four brain regions and aging. Wayne diagrams were used to identify seven inflammaging-related genes in different brain regions. Finally, we performed immuno-infiltration analysis and identified macrophage module genes. Key findings: Inflammaging may be a major mechanism of brain aging, and the regulation of macrophages by CX3CL1 may play a role in the development of inflammaging. Significance: In summary, targeting CX3CL1 can potentially delay inflammaging and immunosenescence in the brain. [ABSTRACT FROM AUTHOR]

Background: Persistent liver damage contributes to the development of liver fibrosis, marked by an accumulation of extracellular matrix. Macrophages play a pivotal role in this process, with the CCL2-CCR2 and CX3CR1-CX3CL1 axes serving as key regulators of macrophage recruitment, liver infiltration, and differentiation. In this study, utilizing a rat model of carbon tetrachloride (CCL4)-induced liver fibrosis, we aimed to investigate the impact of imatinib and bone marrow-derived mesenchymal stem cells (BM-MSCs) on the expression of these axis. Methods: Sixteen Sprague-Dawley rats were divided into four groups: healthy, liver fibrosis, imatinibrecipient, and BM-MSC-recipient. Treatment effects were evaluated using histopathology and Sirus-red staining. Quantitative real-time PCR was employed to analyze changes in the expression of the genes CCL2, CCR2, CX3CL1, and CX3CR1. Results: Histopathological assessments revealed the efficacy of imatinib and BM-MSCs in mitigating liver fibrosis. Our findings demonstrated a significant reduction in CCL2 and CCR2 expression in both imatinib and BM-MSCs treatment groups compared to the liver fibrosis group. Conversely, the gene expression of CX3CL1 and CX3CR1 increased in both therapeutic groups compared to the liver fibrosis groups. Conclusion: Conclusion: The notable decrease in CCL2-CCR2 genes in both therapeutic groups suggests that BM-MSCs and imatinib may contribute to a decline in inflammatory macrophages within the liver. The lower CCL2-CCR2 expression in imatinib-recipient rats indicates better efficacy in modulating the recruitment of inflammatory macrophages. The elevated expression of CX3CL1 in BM-MSC-recipient rats suggests a greater impact on the polarization of LY6Chigh (inflammatory) to LY6Clow (anti-inflammatory) macrophages, warranting further investigation. [ABSTRACT FROM AUTHOR]

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Human oral squamous cell carcinoma (OSCC) has been associated with a relatively low survival rate over the years and is characterized by a poor prognosis. C‐X3‐C motif chemokine ligand 1 (CX3CL1) has been involved in advanced migratory cells. Overexpressed CX3CL1 promotes several cellular responses related to cancer metastasis, including cell movement, migration and invasion in tumour cells. However, CX3CL1 controls the migration ability, and its molecular mechanism in OSCC remains unknown. The present study confirmed that CX3CL1 increased cell movement, migration and invasion. The CX3CL1‐induced cell motility is upregulated through intercellular adhesion molecule‐1 (ICAM‐1) expression in OSCC cells. These effects were significantly suppressed when OSCC cells were pre‐treated with CX3CR1 monoclonal antibody (mAb) and small‐interfering RNA (siRNA). The CX3CL1‐CX3CR1 axis activates promoted PLCβ/PKCα/c‐Src phosphorylation. Furthermore, CX3CL1 enhanced activator protein‐1 (AP‐1) activity. The CX3CR1 mAb and PLCβ, PKCα, c‐Src inhibitors reduced CX3CL1‐induced c‐Jun phosphorylation, c‐Jun translocation into the nucleus and c‐Jun binding to the ICAM‐1 promoter. The present results reveal that CX3CL1 induces the migration of OSCC cells by promoting ICAM‐1 expression through the CX3CR1 and the PLCβ/PKCα/c‐Src signal pathway, suggesting that CX3CL1‐CX3CR1‐mediated signalling is correlated with tumour motility and appealed to be a precursor for prognosis in human OSCC. [ABSTRACT FROM AUTHOR]

Abstract Background An increasing number of studies have demonstrated that CX3CL1 is involved in the development of tumors and may thus be considered a new potential therapeutic target for them. However, the function of CX3CL1 in clear cell renal cell carcinoma (ccRCC) remains poorly defined. Methods The pan-cancer expression pattern and prognostic value of CX3CL1 were evaluated in this study. Moreover, the relationship of CX3CL1 expression with the tumor microenvironment, especially the tumor immune microenvironment, was analyzed. Our analyses employed public repository data. Additionally, we generated stable CX3CL1-overexpressing 786-O cells to determine the role of CX3CL1 in vitro via cell viability and transwell assays. A xenograft tumor model was used to determine the role of CX3CL1 in vivo. The association between CX3CL1 and ferroptosis sensitivity of tumor cells was assessed using Ferrostatin-1. Results Our findings indicated the involvement of CX3CL1 in the occurrence and development of ccRCC by acting as a tumor suppressor. We also found that ccRCC patients with high CX3CL1 expression showed better clinical outcomes than those with low CX3CL1 expression. The findings of our epigenetic study suggested that the expression of CX3CL1 in ccRCC is correlated with its DNA methylation level. Furthermore, the CX3CL1 expression level was closely related to the infiltration level of CD8+ T cells into the tumor microenvironment (TME). CX3CL1 showed different predictive values in different immunotherapy cohorts. Finally, CX3CL1 overexpression inhibited tumor cell proliferation and metastasis and promoted tumor ferroptosis sensitivity in ccRCC. Conclusions This study revealed the role of CX3CL1 as a tumor suppressor in ccRCC. Our findings indicated that CX3CL1 plays a crucial role in regulating the ccRCC TME and is a potential predictor of immunotherapy outcomes in ccRCC. We also found that CX3CL1 can promote ferroptosis sensitivity in ccRCC cells.