Search Results (49)

Background/Objectives: Chronic neuropathic ocular pain (NOP) can manifest concurrently with dry eye (DE) symptoms following ocular surgical procedures. Due to its low prevalence, NOP remains an underrecognized and underdiagnosed postoperative complication, leading to suboptimal management. This study evaluated the long-term evolution of symptoms, signs, and tear biomarkers in patients with NOP and DE after corneal refractive surgery (RS). Methods: Patients with chronic NOP and persistent DE-related symptoms after corneal RS were assessed in two visits (V1 and V2), at least two years apart. Symptoms (DE, pain, anxiety, and depression) were measured with specific questionnaires. Clinical examination included a slit-lamp ocular surface evaluation, corneal sensitivity measurement, and subbasal corneal nerve plexus evaluation. Basal tear samples were collected, and a 20-plex cytokine panel and Substance P (SP) were assayed. Results: Twenty-three patients (35.57 ± 8.43 years) were included, with a mean time between visits of 4.83 ± 1.10 years. DE symptoms, measured with the Ocular Surface Disease Index questionnaire, improved at V2 (p < 0.001), along with a reduction in anxiety and depression levels, measured with the Hospital Anxiety and Depression Scale (p = 0.027). Corneal staining also decreased (p < 0.001), while subbasal nerve plexus parameters and corneal sensitivity remained unchanged. Tear analysis revealed increased concentrations of fractalkine/CX3CL1 (p = 0.039), interleukin (IL)-1 receptor antagonist (Ra) (p = 0.025), IL-10 (p = 0.002), and SP (p < 0.001). Conclusions: Symptom improvement may result from better control of underlying pathologies or natural disease progression. However, the increased levels of SP and fractalkine/CX3CL1 suggest sustained neurogenic inflammation, while elevated IL-1Ra and IL-10 indicate a potential compensatory anti-inflammatory response. Full article

Diabetic retinopathy (DR) causes vision loss due to sustained inflammation and vascular damage. The vascular damage is evident by fibrinogen leakage, angiogenesis, and hypoxia. Neuronal regulation of microglia via the CX3CL1 (Fractalkine or FKN)-CX3CR1 pathway plays a significant role in retinal pathology. Defects in FKN or CX3CR1 exacerbate inflammation, vascular damage, and vision impairment. However, the contribution of hypoxic astrocytes to the pathological process of DR is unclear. A hypoxic model (7 days of systemic 7.5% O₂) was utilized to induce retinal damage in adult mice in the absence of systemic inflammatory signals. This model induced vascular and microglial responses similar to 10 weeks of STZ-induced hyperglycemia. The goal of this study is to characterize retinal damage in WT and mice with defects in the FKN-CX3CR1 signaling axis and hence assess the impact of the microglial inflammatory responses to hypoxic retinopathy. Tissues were analyzed by immunostaining, RNA sequencing, and cytokine quantification. We found that CX3CR1 deficiency in hypoxic animals induced reactive astrogliosis and that Müller glial responses to hypoxia and systemic inflammation were dependent on FKN signaling. Exacerbated microglial reactivity to hypoxic conditions significantly altered the expression of HIF transcripts. Microglial dysregulation was found to reduce the anti-inflammatory response to hypoxic conditions, downregulate hypoxia-responsive gene expression, and restrained LPS-induced inflammatory responses. We found that microglia dysregulation alters the hypoxic response by inhibiting the upregulation of HIF2α/3α, increasing CD31 immunoreactivity, and altering the expression of ECM-associated transcripts such as type I, III, and XVIII collagens to hypoxic conditions. Full article

Among the different chemokines, C-X3-C motif chemokine ligand 1 or CX3CL1, also named fractalkine, is one of the most interesting due to its characteristics, including its unique structure, not shared by any other chemokine, and its ability to function both in a membrane-bound form and in a soluble form, among others. However, undoubtedly, its most relevant characteristic from the neuroscientific point of view is its role as a messenger used by neurons to communicate with microglia. The study of the interaction between both cell types and the key role that CX3CL1 seems to play has facilitated the identification of CX3CL1 as a crucial modulator of microglial activation and a promising target in the fight against neuroinflammation. As a result, numerous studies have contributed to elucidate the involvement of CX3CL1 and its specific receptor CCX3CR1 in the progression of different neuroinflammatory and neurodegenerative processes, with Alzheimer’s and Parkinson’s diseases being the most studied ones. However, the different animal and cellular models used to reproduce the pathological conditions to be analyzed, as well as the difficulties inherent to studies performed on human samples, have hindered the collection of compatible results in many cases. In this review, we summarize some of the most relevant data describing the alterations found for the CX3CL1/CX3CR1 signaling axis in different neurodegenerative conditions in which neuroinflammation is known to play a relevant role. Full article

Diabetic retinopathy (DR) is a complication of diabetes, characterized by progressive microvascular dysfunction that can result in vision loss. Chronic hyperglycemia drives oxidative stress, endothelial dysfunction, and inflammation, leading to retinal damage and complications such as neovascularization. Current treatments, including anti-VEGF agents, have limitations, necessitating the exploration of alternative therapeutic strategies. Fractalkine (CX3CL1), a chemokine with dual roles as a membrane-bound adhesion molecule and a soluble chemoattractant, has emerged as a potential therapeutic target. Its receptor, CX3CR1, is expressed on immune cells and mediates processes such as immune cell recruitment and microglial activation through intracellular signaling pathways. In DR, soluble fractalkine plays critical roles in retinal inflammation, angiogenesis, and neuroprotection, balancing tissue damage and repair. In DR, elevated fractalkine levels are associated with retinal inflammation and endothelial dysfunction. Experimental studies suggest that fractalkine deficiency exacerbates the severity of diabetic retinopathy (DR), whereas exogenous fractalkine appears to reduce inflammation, oxidative stress, and neuronal damage. However, its role in pathological angiogenesis within DR remains unclear and warrants further investigation. Preclinical evidence indicates that fractalkine may hold therapeutic potential, particularly in mitigating tissue injury and inflammation associated with early-stage DR. Full article

Background/Objectives: Nurse-like cells (NLCs) derived from monocytes in the tumor microenvironment support the growth of chronic lymphocytic leukemia (CLL) cells. Here, we investigated the effects of a CX3CR1 (fractalkine receptor) antagonist (KAND567) on autologous monocytes and their pro-survival effects on CLL cells in vitro. Methods: Plasma concentration of CX3CL1 was determined by ELISA and CX3CR1 expression by flow cytometry. CD19⁺ cells and autologous monocytes from patients with CLL and healthy donors were treated with KAND567 either in co-culture or alone. The apoptosis of CD19⁺ cells and monocytes was determined by Annexin V/PI staining and live-cell imaging. Results: Plasma concentration of CX3CL1 (fractalkine) was significantly higher in patients with CLL (n = 88) than in healthy donors (n = 32) (p < 0.0001), with higher levels in patients with active compared to non-active disease (p < 0.01). CX3CR1 was found on monocytes but not B cells in patients and controls. Levels of intermediate and non-classical CX3CR1⁺ monocytes were higher in patients with CLL than in controls (p < 0.001), particularly in those with active disease (p < 0.0001). Co-culture experiments revealed that autologous monocytes promoted the survival of both malignant and normal B cells and that KAND567 selectively inhibited the growth of CLL cells in a dose-dependent manner but only in the presence of autologous monocytes (p < 0.05). Additionally, KAND567 inhibited the transition of monocytes to NLCs in CLL (p < 0.05). Conclusions: Our data suggest that the CX3CR1/CX3CL1 axis is activated in CLL and may contribute to the NLC-driven growth-promoting effects of CLL cells. KAND567, which is in clinical trials in other disorders, should also be explored in CLL. Full article

Background/Objectives: Acute myeloid leukemia (AML) is a type of leukemia with a very poor prognosis. Consequently, this neoplasm is extensively researched to discover new therapeutic strategies. One area of investigation is the study of intracellular communication and the impact of the bone marrow microenvironment on AML cells, with chemokines being a key focus. The roles of β-chemokines, γ-chemokines, and δ-chemokines in AML processes have not yet been sufficiently characterized. Methods: This publication summarizes all available knowledge about these chemotactic cytokines in AML and myelodysplastic neoplasm (MDS) processes and presents potential therapeutic strategies to combat the disease. The significance of β-chemokines, γ-chemokines, and δ-chemokines is detailed, including CCL2 (MCP-1), CCL3 (MIP-1α), CCL5 (RANTES), CCL23, CCL28, and CX3CL1 (fractalkine). Additionally, the importance of atypical chemokine receptors in AML is discussed, specifically ACKR1, ACKR2, ACKR4, and CCRL2. Results/Conclusions: The focus is on the effects of these chemokines on AML cells, particularly their influence on proliferation and resistance to anti-leukemic drugs. Intercellular interactions with non-AML cells, such as mesenchymal stem cells (MSC), macrophages, and regulatory T cells (T_reg), are also characterized. The clinical aspects of chemokines are thoroughly explained, including their effect on overall survival and the relationship between their blood levels and AML characteristics. Full article

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. Full article

A hepatitis B virus (HBV) infection can progress to chronic hepatitis, leading to liver fibrosis, cirrhosis, and hepatocellular carcinoma. CX3CL1/Fractalkine plays a crucial role in recruiting immune cells that are responsible for protecting against HBV infection. The aim of this study was to measure CX3CL1/Fractalkine concentrations in the blood plasma of individuals infected with HBV and to evaluate the role of this chemokine in the development of liver tissue fibrosis. Our study included patients infected with HBV, patients infected with HCV, autoimmune hepatitis, and healthy donors. We analyzed the CX3CL1/Fractalkine concentrations in blood plasma using the xMAP technology. Our results showed that HBV-infected patients had lower concentrations of CX3CL1/Fractalkine. Furthermore, in HBV-infected patients with severe fibrosis/cirrhosis, we observed significantly lower concentrations of CX3CL1/Fractalkine compared to those with no/mild fibrosis. Our study revealed that CX3CL1/Fractalkine concentrations are significantly associated with the stage of fibrosis in HBV infection. We demonstrated that lowered CX3CL1/Fractalkine concentrations might have prognostic value for predicting fibrosis development in liver tissue. Our findings suggest that decreased concentrations of CX3CL1/Fractalkine are associated with an increased risk of progressive liver fibrosis, indicating the potential of this chemokine as a prognostic biomarker for the development of liver fibrosis. Full article

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. Full article

This study investigates the impact of allopregnanolone ([3α,5α]3-hydroxypregnan-20-one or 3α,5α-tetrahydroprogesterone (3α,5α-THP); 10 mg/kg, IP) on fractalkine/CX3-C motif chemokine ligand 1 (CX3CL1) levels, associated signaling components, and markers for microglial and astrocytic cells in the nucleus accumbens (NAc) of male and female alcohol-preferring (P) rats. Previous research suggested that 3α,5α-THP enhances anti-inflammatory interleukin-10 (IL-10) cytokine production in the brains of male P rats, with no similar effect observed in females. This study reveals that 3α,5α-THP elevates CX3CL1 levels by 16% in the NAc of female P rats, with no significant changes observed in males. The increase in CX3CL1 levels induced by 3α,5α-THP was observed in females across multiple brain regions, including the NAc, amygdala, hypothalamus, and midbrain, while no significant effect was noted in males. Additionally, female P rats treated with 3α,5α-THP exhibited notable increases in CX3CL1 receptor (CX3CR1; 48%) and transforming growth factor-beta 1 (TGF-β1; 24%) levels, along with heightened activation (phosphorylation) of signal transducer and activator of transcription 1 (STAT1; 85%) in the NAc. Conversely, no similar alterations were observed in male P rats. Furthermore, 3α,5α-THP decreased glial fibrillary acidic protein (GFAP) levels by 19% in both female and male P rat NAc, without affecting microglial markers ionized calcium-binding adaptor molecule 1 (IBA1) and transmembrane protein 119 (TMEM119). These findings indicate that 3α,5α-THP enhances the CX3CL1/CX3CR1 pathway in the female P rat brain but not in males, primarily influencing astrocyte reactivity, with no observed effect on microglial activation. Full article

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. Full article

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. Full article

The chemotactic cytokine fractalkine (FKN, chemokine CX3CL1) has unique properties resulting from the combination of chemoattractants and adhesion molecules. The soluble form (sFKN) has chemotactic properties and strongly attracts T cells and monocytes. The membrane-bound form (mFKN) facilitates diapedesis and is responsible for cell-to-cell adhesion, especially by promoting the strong adhesion of leukocytes (monocytes) to activated endothelial cells with the subsequent formation of an extracellular matrix and angiogenesis. FKN signaling occurs via CX3CR1, which is the only known member of the CX3C chemokine receptor subfamily. Signaling within the FKN-CX3CR1 axis plays an important role in many processes related to inflammation and the immune response, which often occur simultaneously and overlap. FKN is strongly upregulated by hypoxia and/or inflammation-induced inflammatory cytokine release, and it may act locally as a key angiogenic factor in the highly hypoxic tumor microenvironment. The importance of the FKN/CX3CR1 signaling pathway in tumorigenesis and cancer metastasis results from its influence on cell adhesion, apoptosis, and cell migration. This review presents the role of the FKN signaling pathway in the context of angiogenesis in inflammation and cancer. The mechanisms determining the pro- or anti-tumor effects are presented, which are the cause of the seemingly contradictory results that create confusion regarding the therapeutic goals. Full article

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. Full article

Non-obstructive coronary artery disease (NO-CAD) constitutes a heterogeneous group of conditions collectively characterized by less than 50% narrowing in at least one major coronary artery with a fractional flow reserve (FFR) of ≤0.80 observed in coronary angiography. The pathogenesis and progression of NO-CAD are still not fully understood, however, inflammatory processes, particularly atherosclerosis and microvascular dysfunction are known to play a major role in it. Chemokine fractalkine (FKN/CX3CL1) is inherently linked to these processes. FKN/CX3CL1 functions predominantly as a chemoattractant for immune cells, facilitating their transmigration through the vessel wall and inhibiting their apoptosis. Its concentrations correlate positively with major cardiovascular risk factors. Moreover, promising preliminary results have shown that FKN/CX3CL1 receptor inhibitor (KAND567) administered in the population of patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), inhibits the adverse reaction of the immune system that causes hyperinflammation. Whereas the link between FKN/CX3CL1 and NO-CAD appears evident, further studies are necessary to unveil this complex relationship. In this review, we critically overview the current data on FKN/CX3CL1 in the context of NO-CAD and present the novel clinical implications of the unique structure and function of FKN/CX3CL1 as a compound which distinctively contributes to the pathomechanism of this condition. Full article