An overview of the role of chemokine CX3CL1 (Fractalkine) and CX3C chemokine receptor 1 in systemic sclerosis.

INTRODUCTION: Systemic sclerosis (SSc) is a complex autoimmune disease characterized by fibrosis, vascular damage, and immune dysregulation. Fractalkine or chemokine (C-X3-C motif) ligand 1 (CX3CL1), a chemokine and adhesion molecule, along with its receptor CX3CR1, have been implicated in the inflammatory processes of SSc. CX3CL1 functions as both a chemoattractant and an adhesion molecule, guiding immune cell trafficking. This systematic review examines the role of CX3CL1 and its receptor CX3CR1 in the pathogenesis of SSc, with a focus on pulmonary and vascular complications. METHODS: A systematic literature search was conducted across databases including PubMed, Scopus, and Web of Science from inception to November 2020. The search focused on studies investigating the CX3CL1/CX3CR1 axis in the context of SSc. RESULTS: The review identified elevated CX3CL1 expression in SSc patients, particularly in the skin and lungs, where CX3CR1 is expressed on infiltrating immune cells. Higher levels of CX3CL1 were correlated with the severity of interstitial lung disease in SSc patients, indicating a potential predictive marker for disease progression. CX3CR1-positive monocytes and NK cells were recruited to inflamed tissues, contributing to fibrosis and tissue damage. Animal studies showed that inhibition of the CX3CL1/CX3CR1 axis reduced fibrosis and improved vascular function. CONCLUSION: The CX3CL1/CX3CR1 axis plays a key role in immune cell recruitment and fibrosis in SSc. Elevated CX3CL1 levels are associated with lung and vascular complications, making it a potential biomarker for disease progression and a promising therapeutic target.

Fractalkine/CX3CR1 axis is critical for neuroprotection induced by hypoxic postconditioning against cerebral ischemic injury.

Microglial activation-mediated neuroinflammation is a major contributor to neuronal damage after cerebral ischemia. The Fractalkine (FKN)/CX3C chemokine receptor 1 (CX3CR1) axis plays a critical role in regulating microglial activation and neuroinflammation. The aim of this study is to ascertain the role and mechanism of FKN/CX3CR1 axis in hypoxic postconditioning (HPC)-induced anti-inflammatory and neuroprotective effects on transient global cerebral ischemia (tGCI). We found that HPC suppressed microglial activation and alleviated neuroinflammation in hippocampal CA1 after tGCI. Meanwhile, HPC upregulated the expression of FKN and CX3CR1 in neurons, but it downregulated the expression of CX3CR1 in glial cells after tGCI. In addition, the overexpression of FKN induced by the administration of FKN-carried lentivirus reduced microglial activation and inhibited neuroinflammation in CA1 after tGCI. Furthermore, silencing CX3CR1 with CX3CRi-carried lentivirus in CA1 after tGCI suppressed microglial activation and neuroinflammation and exerted neuroprotective effects. Finally, the overexpression of FKN caused a marked increase of neuronal CX3CR1 receptors, upregulated the phosphorylation of Akt, and reduced neuronal loss of rats in CA1 after tGCI. These findings demonstrated that HPC protected against neuronal damage in CA1 of tGCI rats through inhibiting microglial activation and activating Akt signaling pathway via FKN/CX3CR1 axis.

The Role of the CX3CR1-CX3CL1 Axis in Respiratory Syncytial Virus Infection and the Triggered Immune Response.

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.

YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8+ T cell recruitment.

Peritumoral hepatocytes are critical components of the liver cancer microenvironment, However, the role of peritumoral hepatocytes in the local tumor immune interface and the underlying molecular mechanisms have not been elucidated. YTHDF2, an RNA N6-methyladenosine (m6A) reader, is critical for liver tumor progression. The function and regulatory roles of YTHDF2 in peritumoral hepatocytes are unknown. This study demonstrated that oxaliplatin (OXA) upregulated m6A modification and YTHDF2 expression in hepatocytes. Studies using tumor-bearing liver-specific Ythdf2 knockout mice revealed that hepatocyte YTHDF2 suppresses liver tumor growth through CD8+ T cell recruitment and activation. Additionally, YTHDF2 mediated the response to immunotherapy. Mechanistically, OXA upregulated YTHDF2 expression by activating the cGAS-STING signaling pathway and consequently enhanced the therapeutic outcomes of immunotherapeutic interventions. Ythdf2 stabilized Cx3cl1 transcripts in an m6A-dependent manner, regulating the interplay between CD8+ T cells and the progression of liver malignancies. Thus, this study elucidated the novel role of hepatocyte YTHDF2, which promotes therapy-induced antitumor immune responses in the liver. The findings of this study provide valuable insights into the mechanism underlying the therapeutic benefits of targeting YTHDF2.

Causal association between circulating inflammatory proteins and peripheral artery disease: a bidirectional two-sample Mendelian randomization study.

Introduction: A growing body of research has shown a strong connection between circulating inflammatory proteins and Peripheral artery disease (PAD). However, the causal relationship between circulating inflammatory proteins and PAD is still not fully understood. To investigate this association, we conducted a bidirectional Mendelian randomization study. Materials and methods: Our study utilized genetic variation data obtained from genome-wide association studies (GWAS) datasets. Specifically, the GWAS dataset related to PAD (identifier: finn-b-I9_PAD) included 7,098 cases and 206,541 controls. Additionally, we extracted data on 91 inflammatory proteins from another GWAS dataset (identifiers: GCST90274758-GCST90274848), involving 14,824 participants. To assess the causal relationship between circulating inflammatory proteins and PAD development, we employed methodologies such as inverse variance weighting (IVW), MR Egger regression, and the weighted median approach. Furthermore, sensitivity analyses were conducted to ensure the reliability and robustness of our findings. Results: Two inflammatory proteins were found to be significantly associated with PAD risk: Natural killer cell receptor 2B4 levels (OR, 1.219; 95% CI,1.019~1.457; P=0.03), Fractalkine levels (OR, 0.755; 95% CI=0.591~0.965; P=0.025). PAD had statistically significant effects on 12 inflammatory proteins: C-C motif chemokine 19 levels (OR, 0.714; 95% CI, 0.585 to 0.872; P=0.001), T-cell surface glycoprotein CD5 levels (OR, 0.818; 95% CI, 0.713 to 0.938; P=0.004), CUB domain-containing protein 1 levels (OR, 0.889; 95% CI, 0.809 to 0.977; P=0.015), Fibroblast growth factor 23 levels (OR, 1.129; 95% CI, 1.009 to 1.264; P=0.034), Interferon gamma levels (OR, 1.124; 95% CI, (1.011 to 1.250); P=0.031),Interleukin-15 receptor subunit alpha levels (OR, 1.183; 95% CI,(1.005 to 1.392); P=0.044), Interleukin-17C levels (OR,1.186; 95% CI, (1.048 to 1.342); P=0.007), Interleukin-1-alpha levels (OR, 1.349; 95% CI, (1.032 to 1.765); P=0.029), Interleukin-5 levels (OR, 1.119; 95% CI,(1.003 to 1.248); P=0.043), Latency-associated peptide transforming growth factor beta 1 levels (OR,1.123; 95% CI, (1.020 to 1.236); P=0.018), Matrix metalloproteinase-10 levels (OR, 1.119; 95% CI,(1.015 to 1.233); P=0.024), Signaling lymphocytic activation molecule levels (OR, 0.823; 95% CI, (0.693 to 0.978); P=0.027). Conclusion: Our research expands on genetic studies exploring the strong association between circulating inflammatory proteins and PAD. This discovery has the potential to inform and shape future clinical and basic research endeavors in this area.

Activated THP-1 Macrophage-Derived Factors Increase the Cytokine, Fractalkine, and EGF Secretions, the Invasion-Related MMP Production, and Antioxidant Activity of HEC-1A Endometrium Cells.

Endometrium receptivity is a multifactor-regulated process involving progesterone receptor-regulated signaling, cytokines and chemokines, and additional growth regulatory factors. In the female reproductive system, macrophages have distinct roles in the regulation of receptivity, embryo implantation, immune tolerance, and angiogenesis or oxidative stress. In the present study, we investigated the effects of PMA-activated THP-1 macrophages on the receptivity-related genes, cytokines and chemokines, growth regulators, and oxidative stress-related molecules of HEC-1A endometrium cells. We established a non-contact co-culture in which the culture medium of the PMA-activated macrophages exhibiting the pro-inflammatory phenotype was used for the treatment of the endometrial cells. In the endometrium cells, the expression of the growth-related factors activin and bone morphogenetic protein 2, the growth hormone EGF, and the activation of the downstream signaling molecules pERK1/2 and pAkt were analyzed by ELISA and Western blot. The secretions of cytokines and chemokines, which are involved in the establishment of endometrial receptivity, and the expression of matrix metalloproteinases implicated in invasion were also determined. Based on the results, the PMA-activated THP-1 macrophages exhibiting a pro-inflammatory phenotype may play a role in the regulation of HEC-1A endometrium cells. They alter the secretion of cytokines and chemokines, as well as the protein level of MMPs of HEC-1A cells. Moreover, activated THP-1 macrophages may elevate oxidative stress protection of HEC-1A endometrium cells. All these suggest that pro-inflammatory macrophages have a special role in the regulation of receptivity-related and implantation-related factors of HEC-1A cells.

CX3C chemokine: Hallmarks of fibrosis and ageing.

Fibrosis refers to the progressive tissue lesion process characterized by excessive secretion and deposition of extracellular matrix (ECM). Abnormal fibrous tissue deposition distorts tissue architecture and leads to the progressive loss of organ function. Notably, fibrosis is one of the primary pathological appearances of many end stage illnesses, and is considered as a lethal threat to human health, especially in the elderly with ageing-related diseases. CX3C ligand 1 (CX3CL1) is the only member of chemokine CX3C and binds specifically to CX3C receptor 1 (CX3CR1). Different from other chemokines, CX3CL1 possesses both chemotactic and adhesive activity. CX3CL1/CX3CR1 axis involves in various physiological and pathological processes, and exerts a critical role in cells from the immune system, vascular system, and nervous system etc. Notably, increasing evidence has demonstrated that CX3CL1/CX3CR1 signaling pathway is closely related to the pathological process of fibrosis in multiple tissue and organs. We reviewed the crucial role of CX3CL1/CX3CR1 axis in fibrosis and ageing and systematically summarized the underlying mechanism, which offers prospective strategies of targeting CX3C for the therapy of fibrosis and ageing-related diseases.

Concentration of IL-1ß, IL-7, IL-12, IL-17, CX3CL1, ITAC and relation with the seizure severity and sudden unexpected death in epilepsy patient.

OBJECTIVE: Inflammation plays an important role in epilepsy. There is evidence for the relationship between proinflammatory cytokines and epilepsy. We aimed to detect the serum levels of multiple cytokines in epilepsy patients, looking for biological indicators, and providing a theoretical basis for the clinical diagnosis, treatment, and prognosis of epilepsy. MATERIALS AND METHODS: In this study, 30 patients with drug-resistant epilepsy (DRE), 30 patients with well-controlled epilepsy (WCE), and 29 healthy controls (HC) were enrolled. Multi-proinflammatory cytokines were measured by LUMINX multi-factor detection. RESULTS: The levels of IL-1ß, IL-7, IL-12, and IL-17 were significantly elevated, and the levels of CX3CL1 and ITAC were significantly decreased in epilepsy patients compared with healthy controls. Furthermore, the level of IL-17 was significantly higher in the DRE group compared to WCE. We also found the ratio of IL-7/CX3CL discriminates accurately between patients and controls, with a ROC Area Under the Curve (AUC) of 0.963 (P<0.001). The levels of IL-1ß, IL-7, IL-12, and IL-17 in the DRE group were positively correlated with the National Hospital Seizure Severity Scale (NHS3) scores (IL-1ß, P = 0.029; IL-12, P = 0.039; IL-17, P = 0.004). IL-17 was positively correlated with seizure frequency (P = 0.050), while ITAC was negatively correlated with seizure frequency (P = 0.012) and Sudden Unexpected Death in Epilepsy-3 (SUDEP-3) scores (P = 0.023). CONCLUSIONS: IL-1ß, IL-12, and IL-17 may be used to predict seizure severity and the IL-7/CX3CL1 ratio may be a candidate biomarker for predicting epileptic seizures. While CX3CL1 and ITAC play anti-epileptic effects, ITAC may be used to assess the risk of SUDEP.

Non-classical monocytes scavenge the growth factor CSF1 from endothelial cells in the peripheral vascular tree to ensure survival and homeostasis.

Unlike sessile macrophages that occupy specialized tissue niches, non-classical monocytes (NCMs)-circulating phagocytes that patrol and cleanse the luminal surface of the vascular tree-are characterized by constant movement. Here, we examined the nature of the NCM's nurturing niche. Expression of the growth factor CSF1 on endothelial cells was required for survival of NCMs in the bloodstream. Lack of endothelial-derived CSF1 did not affect blood CSF1 concentration, suggesting that NCMs rely on scavenging CSF1 present on endothelial cells. Deletion of the transmembrane chemokine and adhesion factor CX3CL1 on endothelial cells impaired NCM survival. Mechanistically, endothelial-derived CX3CL1 and integrin subunit alpha L (ITGAL) facilitated the uptake of CSF1 by NCMs. CSF1 was produced by all tissular endothelial cells, and deletion of Csf1 in all endothelial cells except bone marrow sinusoids impaired NCM survival, arguing for a model where the full vascular tree acts as a niche for NCMs and where survival and patrolling function are connected.

Fractalkine in Health and Disease.

CX3CL1 is one of the 50 up-to-date identified and characterized chemokines. While other chemokines are produced as small, secreted proteins, CX3CL1 (fractalkine) is synthetized as a transmembrane protein which also leads to a soluble form produced as a result of proteolytic cleavage. The membrane-bound protein and the soluble forms exhibit different biological functions. While the role of the fractalkine/CX3CR1 signaling axis was described in the nervous system and was also related to the migration of leukocytes to sites of inflammation, its actions are controversial in cancer progression and anti-tumor immunity. In the present review, we first describe the known biology of fractalkine concerning its action through its cognate receptor, but also its role in the activation of different integrins. The second part of this review is dedicated to its role in cancer where we discuss its role in anti-cancer or procarcinogenic activities.

CX3CL1 release during immunogenic apoptosis is associated with enhanced anti-tumour immunity.

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 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. 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 TCGA-SKCM 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.

Chemokine CX3CL1 (Fractalkine) Signaling and Diabetic Encephalopathy.

Diabetes mellitus (DM) is the most common metabolic disease in humans, and its prevalence is increasing worldwide in parallel with the obesity pandemic. A lack of insulin or insulin resistance, and consequently hyperglycemia, leads to many systemic disorders, among which diabetic encephalopathy (DE) is a long-term complication of the central nervous system (CNS), characterized by cognitive impairment and motor dysfunctions. The role of oxidative stress and neuroinflammation in the pathomechanism of DE has been proven. Fractalkine (CX3CL1) has unique properties as an adhesion molecule and chemoattractant, and by acting on its only receptor, CX3CR1, it regulates the activity of microglia in physiological states and neuroinflammation. Depending on the clinical context, CX3CL1-CX3CR1 signaling may have neuroprotective effects by inhibiting the inflammatory process in microglia or, conversely, maintaining/intensifying inflammation and neurotoxicity. This review discusses the evidence supporting that the CX3CL1-CX3CR1 pair is neuroprotective and other evidence that it is neurotoxic. Therefore, interrupting the vicious cycle within neuron-microglia interactions by promoting neuroprotective effects or inhibiting the neurotoxic effects of the CX3CL1-CX3CR1 signaling axis may be a therapeutic goal in DE by limiting the inflammatory response. However, the optimal approach to prevent DE is simply tight glycemic control, because the elimination of dysglycemic states in the CNS abolishes the fundamental mechanisms that induce this vicious cycle.

Higher levels of IL-1ra, IL-6, IL-8, MCP-1, MIP-3α, MIP-3ß, and fractalkine are associated with 90-day mortality in 132 non-immunomodulated hospitalized patients with COVID-19.

INTRODUCTION: Immune dysregulation with an excessive release of cytokines has been identified as a key driver in the development of severe COVID-19. The aim of this study was to evaluate the initial cytokine profile associated with 90-day mortality and respiratory failure in a cohort of patients hospitalized with COVID 19 that did not receive immunomodulatory therapy. METHODS: Levels of 45 cytokines were measured in blood samples obtained at admission from patients with confirmed COVID-19. Logistic regression analysis was utilized to determine the association between cytokine levels and outcomes. The primary outcome was death within 90 days from admission and the secondary outcome was need for mechanical ventilation. RESULTS: A total of 132 patients were included during the spring of 2020. We found that one anti-inflammatory cytokine, one pro-inflammatory cytokine, and five chemokines were associated with the odds of 90-day mortality, specifically: interleukin-1 receptor antagonist, interleukin-6, interleukin-8, monocyte chemoattractant protein-1, macrophage inflammatory protein-3α, macrophage inflammatory protein-3ß, and fractalkine. All but fractalkine were also associated with the odds of respiratory failure during admission. Monocyte chemoattractant protein-1 showed the strongest estimate of association with both outcomes. CONCLUSION: We showed that one anti-inflammatory cytokine, one pro-inflammatory cytokine, and five chemokines were associated with 90-day mortality in patients hospitalized with COVID-19 that did not receive immunomodulatory therapy.

Expression and analysis of CX3CL1 chemokine and CD57+ lymphocytes in oral squamous cell carcinoma and their correlation with clinicopathologic features.

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.

Inflammatory response of leptomeninges to a single cortical spreading depolarization.

BACKGROUND: Neurogenic meningeal inflammation is regarded as a key driver of migraine headache. Multiple evidence show importance of inflammatory processes in the dura mater for pain generation but contribution of the leptomeninges is less clear. We assessed effects of cortical spreading depolarization (CSD), the pathophysiological mechanism of migraine aura, on expression of inflammatory mediators in the leptomeninges. METHODS: A single CSD event was produced by a focal unilateral microdamage of the cortex in freely behaving rats. Three hours later intact cortical leptomeninges and parenchyma of ipsi-lesional (invaded by CSD) and sham-treated contra-lesional (unaffected by CSD) hemispheres were collected and mRNA levels of genes associated with inflammation (Il1b, Tnf, Ccl2; Cx3cl1, Zc3h12a) and endocannabinoid CB2 receptors (Cnr2) were measured using qPCR. RESULTS: Three hours after a single unilateral CSD, most inflammatory factors changed their expression levels in the leptomeninges, mainly on the side of CSD. The meninges overlying affected cortex increased mRNA expression of all proinflammatory cytokines (Il1b, Tnf, Ccl2) and anti-inflammatory factors Zc3h12a and Cx3cl1. Upregulation of proinflammatory cytokines was found in both meninges and parenchyma while anti-inflammatory markers increased only meningeal expression. CONCLUSION: A single CSD is sufficient to produce pronounced leptomeningeal inflammation that lasts for at least three hours and involves mostly meninges overlying the cortex affected by CSD. The prolonged post-CSD inflammation of the leptomeninges can contribute to mechanisms of headache generation following aura phase of migraine attack.

Alirocumab boosts antioxidant status and halts inflammation in rat model of sepsis-induced nephrotoxicity via modulation of Nrf2/HO-1, PCSK9/HMGB1/NF-ᴋB/NLRP3 and Fractalkine/CX3CR1 hubs.

Acute kidney injury (AKI) is a devastating consequence of sepsis, accompanied by high mortality rates. It was suggested that inflammatory pathways are closely linked to the pathogenesis of lipopolysaccharide (LPS)-induced AKI. Inflammatory signaling, including PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-κB, NLRP3/caspase-1 and Fractalkine/CX3CR1 are considered major forerunners in this link. Alirocumab, PCSK9 inhibitor, with remarkable anti-inflammatory features. Accordingly, this study aimed to elucidate the antibacterial effect of alirocumab against E. coli in vitro. Additionally, evaluation of the potential nephroprotective effects of alirocumab against LPS-induced AKI in rats, highlighting the potential underlying mechanisms involved in these beneficial actions. Thirty-six adult male Wistar rats were assorted into three groups (n=12). Group I; was a normal control group, whereas sepsis-mediated AKI was induced in groups II and III through single-dose intraperitoneal injection of LPS on day 16. In group III, animals were given alirocumab. The results revealed that LPS-induced AKI was mitigated by alirocumab, evidenced by amelioration in renal function tests (creatinine, cystatin C, KIM-1, and NGAL); oxidative stress biomarkers (Nrf2, HO-1, TAC, and MDA); apoptotic markers and renal histopathological findings. Besides, alirocumab pronouncedly hindered LPS-mediated inflammatory response, confirmed by diminishing HMGB1, TNF-α, IL-1ß, and caspase-1 contents; the gene expression of PCSK9, RAGE, NF-ᴋB and Fractalkine/CX3CR1, along with mRNA expression of TLR4, MYD88, and NLRP3. Regarding the antibacterial actions, results showed that alirocumab displayed potential anti-bacterial activity against pathogenic gram-negative E. coli. In conclusion, alirocumab elicited nephroprotective activities against LPS-induced AKI via modulation of Nrf2/HO-1, PCSK9, HMGB1/RAGE/TLR4/MYD88/NF-ᴋB/NLRP3/Caspase-1, Fractalkine/CX3R1 and apoptotic axes.

Expression and significance of Fractalkine/CX3CL1 in MPO-AAV-associated glomerulonephritis rats.

OBJECTIVE: To investigate the expression and significance of Fractalkine (CX3CL1, FKN) in serum and renal tissue of myeloperoxidase and anti-neutrophil cytoplasmic antibody associated vasculitis (MPO-AAV) rats. METHODS: Thirty Wistar-Kyoto (WKY) rats were randomly divided into: Control group, MPO-AAV group (400 µg/kg MPO mixed with Freund's complete adjuvant i.p), MPO-AAV + Anti-FKN group (400 µg/kg MPO mixed with Freund's complete adjuvant i.p), anti-FKN group (1 µg/ rat /day, i.p) after 6 weeks. MPO-AAV associated glomerulonephritis model was established by intraperitoneal injection of MPO + Freund's complete adjuvant with 10 mice in each group. The concentration of MPO-ANCA and FKN in serum was detected by Enzyme-linked immunosorbent assay (ELISA). Hematoxylin-eosin (HE) staining was used to detect pathological changes of kidney tissue. Western blot and immunofluorescence staining were used to detect the expression and localization of FKN protein in kidney tissue. Renal function test indicators: 24-hour urinary protein (UAER), blood urea nitrogen (BUN), serum creatinine (Scr). The expression levels of p65NF-κB and IL-6 was detected by Immunohistochemical assays. RESULTS: Compared with the control group, the serum MPO-ANCA antibody expression level in the MPO-AAV group was significantly increased (P < 0.01), and the contents of UAER, BUN and Scr were significantly up-regulated at 24 h (P < 0.01). Compared with the control group, the glomeruli in the MPO-AAV group had different degrees of damage, infiltration of inflammatory cell, and membrane cell hyperplasia and renal tubule edema. Compared with the control group, rats in the MPO-AAV group had significantly higher levels of FKN in serum and renal tissues (P < 0.01), and high expression of p65NF-κB and IL-6 in renal tissues (P < 0.01) (P < 0.05), whereas anti-FKN reversed the expression of the above factors. In MPO-AAV renal tissue, FKN was mainly expressed in the cytoplasm of renal tubular epithelial cells and glomerular podocytes. In addition, the contents of 24 h UAER, BUN and Scr of renal function in MPO-AAV rats were significantly decreased (P < 0.01) and the damage of renal tissue was significantly ameliorated after the administration of antagonistic FKN. CONCLUSION: FKN may play a key role in the pathogenesis of MPO-AAV associated glomerulonephritis.

Diagnostic value of galectin-3, fractalkine, IL-6, miR-21 and cardiac troponin I in human ischemic cardiomyopathy.

OBJECTIVE: The primary objective of this study was to assess the diagnostic potential of galectin-3 (Gal-3), fractalkine (FKN), interleukin (IL)-6, microRNA(miR)-21, and cardiac troponin I (cTnI) in patients with ischemic cardiomyopathy (ICM). METHOD: A total of 78 ICM patients (Case group) and 80 healthy volunteers (Control group) admitted to our hospital for treatment or physical examination from Aug. 2018 to Feb. 2020 were included in the current study. The serum concentration of Gal-3, FKN, IL-6, miR-21, and plasma expression of cTnI of both groups were determined. The severity of ICM was classified using New York Heart Association (NYHA) scale. RESULTS: When compared with the control group, the case group had a significantly high blood concentration of Gal-3, FKN, IL-6, miR-21, and cTnI (P < 0.001). NYHA class II patients had lower blood levels of Gal-3, FKN, IL-6, miR-21, and cTnI than that in patients of NYHA class III and IV without statistical significance (P > 0.05). However, statistical significance could be achieved when comparing the above-analyzed markers in patients classified between class III and IV. Correlation analysis also revealed that serum levels of Gal-3, FKN, IL-6, miR-21, and cTnI were positively correlated with NYHA classification (R = 0.564, 0.621, 0.792, 0.981, P < 0.05). CONCLUSION: Our study revealed that up-regulated serum Gal-3, FKN, IL-6, miR-21, and cTnI levels were closely related to the progression of ICM. This association implies that these biomarkers have diagnostic potential, offering a promising avenue for early detection and monitoring of ICM progression.

Blood metabolites mediate the causal relationship between circulating CX3CL1 levels and prostate cancer: A 2-step Mendelian randomization study.

Chemokines influence the progression of prostate cancer (PCa) through multiple mechanisms. However, the effect of C-X3-C chemokine ligand 1 (CX3CL1) on PCa risk remains controversial. Our study aimed to investigate whether circulating CX3CL1 is causally associated with PCa and to identify metabolites that have mediating effects using the 2-step bidirectional Mendelian randomization (MR) analysis process. Inverse variance weighting (IVW) results were used as the primary observations, while additional sensitivity analyses were conducted. For each standard deviation increase exhibited by the circulating CX3CL1 levels, the risk of PCa was reduced by 0.4% (IVW: OR = 0.996, [95% CI = 0.994-0.998], P < .001), and blood alliin levels increased by 19% (IVW: OR = 1.185, [95% CI = 1.01-1.54], P = .003). For each standard deviation increase in the blood alliin levels, the risk of PCa was reduced by 0.1% (IVW: OR = 0.999, [95% CI = 0.997-0.999], P = .03). Therefore, the protective effect of circulating CX3CL1 on PCa may be mediated by blood alliin levels (mediated proportion = 6.7%). The results supported the notion that high levels of circulating CX3CL1 indicate a lower PCa risk and the idea that the food-derived antioxidant alliin may mediate this association. We emphasize that the use of CX3CL1 as a protective factor against PCa may provide new strategies for PCa prevention and care in the future.

Dynamics of Cellular Regulation of Fractalkine/CX3CL1 and Its Receptor CX3CR1 in the Rat Trigeminal Subnucleus Caudalis after Unilateral Infraorbital Nerve Lesion-Extended Cellular Signaling of the CX3CL1/CX3CR1 Axis in the Development of Trigeminal Neuropathic Pain.

The cellular distribution and changes in CX3CL1/fractalkine and its receptor CX3CR1 protein levels in the trigeminal subnucleus caudalis (TSC) of rats with unilateral infraorbital nerve ligation (IONL) were investigated on postoperation days 1, 3, 7, and 14 (POD1, POD3, POD7, and POD14, respectively) and compared with those of sham-operated and naïve controls. Behavioral tests revealed a significant increase in tactile hypersensitivity bilaterally in the vibrissal pads of both sham- and IONL-operated animals from POD1 to POD7, with a trend towards normalization in sham controls at POD14. Image analysis revealed increased CX3CL1 immunofluorescence (IF) intensities bilaterally in the TSC neurons of both sham- and IONL-operated rats at all survival periods. Reactive astrocytes in the ipsilateral TSC also displayed CX3CL1-IF from POD3 to POD14. At POD1 and POD3, microglial cells showed high levels of CX3CR1-IF, which decreased by POD7 and POD14. Conversely, CX3CR1 was increased in TSC neurons and reactive astrocytes at POD7 and POD14, which coincided with high levels of CX3CL1-IF and ADAM17-IF. This indicates that CX3CL1/CX3CR1 may be involved in reciprocal signaling between TSC neurons and reactive astrocytes. The level of CatS-IF in microglial cells suggests that soluble CX3CL1 may be involved in neuron-microglial cell signaling at POD3 and POD7, while ADAM17 allows this release at all studied time points. These results indicate an extended CX3CL1/CX3CR1 signaling axis and its role in the crosstalk between TSC neurons and glial cells during the development of trigeminal neuropathic pain.