Opposite effects of CX3CR1 receptor polymorphisms V249I and T280M on the development of acute coronary syndrome. A possible implication of fractalkine in inflammatory activation

Several lines of evidence suggest that the chemokine fractalkine (FKN) and its receptor CX3CR1 contribute to the accumulation of leukocytes in the atherosclerotic plaque. The M280 allele of the CX3CR1T280M polymorphism modulates leukocyte recruitment and is associated with lower prevalence of cardiovascular disease. The influence of V249I, another CX3CR1 polymorphism, is discussed controversially. We investigated the association of the alleles M280 and I249 of CX3CR1 with coronary artery disease (CAD) and with acute coronary syndrome (ACS). Additionally, we assessed their association with the soluble ligand FKN and inflammatory activation measured by high sensitivity C-reactive protein (hsCRP). The genotypes of the V249I and T280M polymorphisms were determined in 1152 patients with suspected CAD.720 (62.5%) individuals showed significant CAD with an ACS prevalence of 59.3%. Using multivariate regression, we found a harmful influence of I249 (adjusted OR=1.8, P<0.03) and a protective effect of M280 (adjusted OR=0.6, P<0.04) on the occurrence of ACS in patients with CAD. Correspondingly, patients with I249 but without M280 (17%) were at elevated risk of ACS (OR=1.6, P<0.04). During ACS these patients (carrying only I249) had significantly higher circulating concentrations of FKN and high sensitivity C-reactive protein (1.9- and 1.6-fold). We found no association of the I249 or the M280 allele with the occurrence of CAD. In conclusion, I249 and M280 have opposite effects on the occurrence of ACS. The presence of I249 not "balanced" by M280 confers an elevated risk of ACS. A FKN-mediated enhanced inflammatory activation might explain this increased risk.     

CX3CR1基因多态与颈动脉狭窄的相关性

目的 探讨fractalkine受体CX3CR1基因多态V249I和T280M与颈动脉狭窄的相关性.方法 经颈部彩色多普勒超声检查诊断颈动脉狭窄患者318例,通过聚合酶链反应-限制性片段长度多态性(PCR-RFLP)和基因测序确定CX3CR1基因V249I和T280M多态性,并与292例无颈动脉狭窄者比较.结果 CX3CR1基因T280M多态中基因型MM和TM在颈动脉狭窄组明显低于对照组(分别为22.6%和31.2%,OR=0.646,95%CI 0.451～0.928,P=0.017),颈动脉狭窄组M等位基因频率明显低于对照组(分别为13.8%和19.2%,OR=0.677,95%CI 0.499～0.918,P=0.010).CX3CR1基因V249I多态中基因型Ⅱ和Ⅵ在颈动脉狭窄组和对照组差异无统计学意义(分别为39.0%和43.8%,OR=1.012,95%CI 0.731～1.403,P=0.940),颈动脉狭窄组Ⅰ等位基因频率明显低于对照组(分别为28.6%和32.7%,OR=0.842,95%CI 0.660～1.076,P=0.034).颈动脉狭窄组Ⅵ和Ⅱ在稳定斑块组明显增高(OR=0.610,95%CI 0.387～0.962,P=0.033).多因素Logistic回归分析显示MM和TM基因型是颈动脉狭窄的独立危险因素(OR=1.847,95%CI 1.091～3.127,P=0.022).结论 CX3CR1基因T280M多态中MM和TM基因型是颈动脉狭窄的一个独立危险因素,而V249I多态中Ⅱ和Ⅵ基因型与颈动脉粥样硬化斑块稳定性有关.     

Effects of polymorphisms in chemokine ligands and receptors on susceptibility to coronary artery disease

INTRODUCTION: Atherosclerosis, the underlying disorder of coronary artery disease (CAD), is an inflammatory process involving multiple molecular pathways. Chemokine-mediated mechanisms are potent regulators of atherosclerosis. Genetic variations that alter such signaling pathways could affect susceptibility to CAD. We investigated the effect of 5 common variations of chemokine and chemokine receptor genes (SDF1-3'A, CCR5-delta32, CCR2-64I, CX3CR1-V249I and CX3CR1-T280M) on predisposition to CAD. MATERIALS AND METHODS: The hypothesis was tested by screening the prevalence of the above polymorphisms in 210 angiographically diagnosed CAD patients (152 with history of acute coronary syndromes, 58 with stable disease) in comparison to 165 selected controls with negative coronary angiography. Genotyping was performed by PCR/RFLP analysis. RESULTS: There were no significant differences among cases and controls concerning allelic and genotypic frequencies of SDF1-3'A, CCR5-delta32, CCR2-64I and CX3CR1-V249I variations. A borderline higher allelic frequency of the M280 variant was observed in controls compared to CAD group (adjusted OR=0.65, 95% CI: 0.35-0.99, p=0.05). Subjects carrying at least one copy of the M280 allele were significantly more common in the control group, suggesting an atheroprotective effect of this variant (adjusted OR=0.58, 95% CI: 0.35-0.97, p=0.04). CONCLUSIONS: The study confers additional data in the field of genetic predisposition to CAD: it confirms the atheroprotective effect of the M280 variant in a completely different population and supports the role of the fractalkine-CX3CR1 pathway in atherosclerosis.     

Fractalkine receptor polymorphisms V2491 and T280M as genetic risk factors for restenosis

The chemokine fractalkine (FKN) recruits leukocytes into lesions of the arterial wall, which may lead to restenosis after stenting. FKN also regulates proliferation of smooth muscle cells, another mechanism pivotal to neointimal thickening. We assessed the hypothesis that functionally important polymorphisms of the FKN receptor CX3CR1 influence restenosis after coronary stenting.Three hundred and sixty-five patients undergoing coronary stenting were genotyped for the CX3CR1 polymorphisms V2491 and T280M. Restenosis occurred in 25% of patients, and recurrent (> 1) restenosis at the target lesion in 8%. The allele 1249 was associated with an increased risk of restenosis (adjusted odds ratio 2.4, 95% confidence interval: 1.3-4.2, P = 0.003) and recurrent restenosis (odds ratio 2.7, 95% confidence interval: 1.3-5.9, P = 0.011). Particularly, patients with 1249 lacking the allele M280 were at an elevated risk of restenosis (P = 0.006) and, accordingly, the haplotype containing 1249 but not M280 was more frequent in patients with restenosis (P = 0.001). In conclusion, the CX3CR1 1249 allele is associated with an increased risk of restenosis while the CX3CR1 M280 allele might counteract the harmful influence of 1249. These findings show the importance of the chemokine FKN and genetic variations of its receptor for restenosis after coronary stenting. Recognition of these inherited risk modifiers may help to individualize treatment of coronary stenosis.     

Increased frequency of CD4+T cells expressing fractalkine receptor CX3CR1 in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), but its AIDS susceptible polymorphisms are not associated with the disease

To investigate whether fractalkine receptor CX3CR1 polymorphisms that have been associated with rapid progression to AIDS among HIV-1 positive individuals also affects the risk of human T cell lymphotropic virus type 1 (HTLV-1) associated myelopathy/tropical spastic paraparesis (HAM/TSP), we compared the allele frequencies of V249I and T280M between 233 HAM/TSP patients and 213 HTLV-1 seropositive asymptomatic carriers (HCs). Although the frequency and absolute number of peripheral blood CX3CR1+CD4+T cells were significantly increased in HAM/TSP patients compared to HCs and uninfected controls independent of HTLV-1 trans-activator protein Tax, we could not observe any association between the two polymorphisms and the risk of HAM/TSP in our cohort.     

Common polymorphisms of chemokine (C‐X3‐C motif) receptor 1 gene modify amyotrophic lateral sclerosis outcome: A population‐based study

Introduction: In the brain, the chemokine (C‐X3‐C motif) receptor 1 (1CX3CR1) gene is expressed only by microglia, where it acts as a key mediator of the neuron–microglia interactions. We assessed whether the 2 common polymorphisms of the CX3CR1 gene (V249I and T280M) modify amyotrophic lateral sclerosis (ALS) phenotype. Methods: The study included 755 ALS patients diagnosed in Piemonte between 2007 and 2012 and 369 age‐matched and sex‐matched controls, all genotyped with the same chips. Results: Neither of the variants was associated with an increased risk of ALS. Patients with the V249I V/V genotype had a 6‐month‐shorter survival than those with I/I or V/I genotypes (dominant model, P = 0.018). The T280M genotype showed a significant difference among the 3 genotypes (additive model, P = 0.036). Cox multivariable analysis confirmed these findings. Discussion: We found that common variants of the CX3CR1 gene influence ALS survival. Our data provide further evidence for the role of neuroinflammation in ALS. Muscle Nerve 57 : 212–216, 2018     

Polymorphisms in the microglial marker molecule CX3CR1 affect the blood volume of the human brain

Aim

CX3CR1 , a G‐protein‐coupled receptor, is involved in various inflammatory processes. Two non‐synonymous single nucleotide polymorphisms, V249I (rs3732379) and T280M (rs3732378), are located in the sixth and seventh transmembrane domains of the CX3CR1 protein, respectively. Previous studies have indicated significant associations between T280M and leukocyte functional characteristics, including adhesion, signaling, and chemotaxis, while the function of V249I is unclear. In the brain, microglia are the only proven and widely accepted CX3CR1‐expressing cells. This study aimed to specify whether there were specific brain regions on which these two single nucleotide polymorphisms exert their biological impacts through their functional effects on microglia.

Methods

Associations between the single nucleotide polymorphisms and brain characteristics, including gray and white matter volumes, white matter integrity, resting arterial blood volume, and cerebral blood flow, were evaluated among 1300 healthy Japanese individuals.

Results

The major allele carriers (V249 and T280) were significantly associated with an increased total arterial blood volume of the whole brain, especially around the bilateral precuneus, left posterior cingulate cortex, and left posterior parietal cortex. There were no significant associations between the genotypes and other brain structural indicators.

Conclusion

This finding suggests that the CX3CR1 variants may affect arterial structures in the brain, possibly via interactions between microglia and brain microvascular endothelial cells.

     

CX3CL1 and CX3CR1 expression in human brain tissue: noninflammatory control versus multiple sclerosis

An important role for CX3CL1 in neuroinflammation and neurodegeneration has been suggested in recent publications. In this study, we compared the expression of CX3CL1 and its receptor CX3CR1 in human brain tissue derived from control patients without neurological complications and in multiple sclerosis (MS) patients. Results from this study demonstrate that CX3CL1 is constitutively expressed in human central nervous system (CNS) astrocytes in vivo and under basal conditions in human adult astrocyte cultures. CX3CR1 is expressed on astrocytes and microglial cells both in vivo and in vitro. Chemotaxis assay shows a functional response upon CX3CR1 signaling in microglial cells. Although CX3CL1 expression is upregulated in cultured astrocytes in response to proinflammatory cytokines, no evidence for expression differences of CX3CL1 between control patients and MS patients was found. Our data suggest that CX3CL1 has more general physiological functions, which occur also in the absence of proinflammatory conditions.     

Baseline T cell reactivity in multiple sclerosis is correlated to efficacy of interferon-beta

BACKGROUND: Measuring proliferative responses of T lymphocytes is a simple, reproducible and widely used assay of immune competence. Evidence suggests a role of T cell reactivity in autoimmune diseases. Interferon (IFN)-beta blocks in vitro proliferation of human T cells. OBJECTIVES: To assess (i) the relation between T cell proliferation and disease characteristics of MS patients, (ii) differences in T cell proliferation between subgroups and HC, and (iii) the predictive value of T cell proliferation for efficacy of IFN-beta. METHODS: Proliferative responses were measured in phytohaemagglutinin (PHA), anti-CD2/CD28 and anti-CD3 stimulated whole blood of 189 MS patients and 249 healthy controls (HC). Forty-eight patients started treatment with IFN-beta. Based on EDSS progression, number of relapses and steroid interventions, patients were classified as either clinical responder or nonresponder to IFN-beta. RESULTS: Significant differences between MS subgroups and HC were found in T cell responses upon both PHA stimulation (RR>HC: p=0.001 and SP>HC: p=0.001) and CD2/CD28 stimulation (RR>HC, SP>HC and PP>HC: all p values <0.001). No significant differences were found between the MS subgroups. A probability of 88% (95% CI, 71-95%) for a favorable response to IFN-beta was found with increased baseline proliferative T cell responses to PHA; a probability of only 16% (95% CI, 7-33%) with decreased values. CONCLUSION: Our results suggest that the level of T cell proliferation in whole blood predicts efficacy of IFN-beta in MS.     

The role of parental psychopathology and family environment for social phobia in the first three decades of life

Background: To examine the role of parental psychopathology and family environment for the risk of social phobia (SP) in offspring from childhood to early adulthood, encompassing the high risk period for SP. Methods: A community sample of 1,395 adolescents was prospectively followed‐up over 10 years. Offspring and parental psychopathology were assessed according to the Diagnostic and Statistical Manual of Mental Disorders (DSM‐IV) using the Munich Composite International Diagnostic Interview (M‐CIDI), and direct diagnostic interviews in parents were supplemented by family history reports. Parental rearing was assessed by the Questionnaire of Recalled Rearing Behavior administered to offspring. Family functioning was assessed by the McMaster Family Assessment Device administered to parents. Results: Parental SP was associated with offspring's risk to develop SP (OR=3.3, 95%CI:1.4–8.0). Other parental anxiety disorders (OR=2.9, 95%CI:1.4–6.1), depression (OR=2.6, 95%CI:1.2–5.4), and alcohol use disorders (OR=2.8, 95%CI:1.3–6.1) were also associated with offspring SP. Parental rearing styles of overprotection, rejection, and lack of emotional warmth were associated with offspring SP. Family functioning measures were not associated with offspring SP. Analyses of interaction of parental psychopathology and parental rearing indicated combined effects on the risk for offspring SP. Conclusions: Parental psychopathology and rearing were associated with offspring SP, independently as well as in their interaction. Further delineation of these associations is warranted as malleable components of these risk factors may provide potential targets for prevention programs. In addition, parent‐to‐offspring transmission of other internalizing disorders should be considered to examine the degree of diagnostic specificity. Depression and Anxiety, 2009. © 2008 Wiley‐Liss, Inc.     

A population-based study of IL4 polymorphisms in multiple sclerosis

Previous studies have suggested a role for interleukin-4 gene (IL4) in susceptibility to multiple sclerosis (MS) as well as other autoimmune diseases. We screened the promoter region, exons 1-4 and their splice sites for polymorphisms and tested the association between novel polymorphisms E1(33)*C-->T and I3(2580)*C-->A, and the established 5'(-523)*C-->T and I3(709)*VNTR polymorphisms with susceptibility to, age of onset in, and course and severity of MS in sporadic cases. I3(709)*VNTR was associated with susceptibility to MS (p=0.004) due to a dearth of heterozygotes in patients (29/122; 23.8%) compared to controls (91/244; 37.3%). Homozygotes for the uncommon I3(709)*allele-2 may have increased susceptibility (p=0.044; OR=5.17, 95% CI: 0.83-54.95) as might carriers for the extended haplotypes 5'(-523)*T/E1(33)*T/I3(709)*allele-2/I3(2580)*C (p=0.003; OR: 3.75, 95% CI: 1.18-11.93) or 5'(-523)*C/E1(33)*C/I3(709)*allele-1/I3(2580)*A (p=0.004; OR: 4.22, 95% CI: 1.22-14.54). We could not confirm the previously reported association between carriage of I3(709)*allele-2 and older age of onset. However, we found a trend for association between the homozygous state for this allele and older age of onset.     

Alzheimer risk associated with a copy number variation in the complement receptor 1 increasing C3b/C4b binding sites

Two multicentre genome-wide association (GWA) studies provided substantial evidence, implicating the complement receptor 1 gene (CR1) in Alzheimer disease (AD) genetic etiology. CR1 encodes a large transmembrane receptor with a crucial role in the immune complement cascade. We performed a genetic follow-up of the GWA CR1 association in a Flanders-Belgian cohort (n=1883), and investigated the effect of single-nucleotide polymorphisms (SNPs) located in the CR1 locus on AD risk and cerebrospinal fluid (CSF) biomarker levels. We obtained significant association (P(adj)<0.03; odds ratio (OR)=1.24 (95% confidence interval (CI): 1.02-1.51)) for one CR1 risk haplotype, and haplotype association was strongest in individuals carrying apolipoprotein E (APOE) ?4 alleles (P(adj)<0.006; OR=1.50 (95% CI: 1.08-2.09)). Also, four SNPs correlated with increased CSF amyloid Aβ???? levels, suggesting a role for the CR1 protein in Aβ metabolism. Moreover, we quantified a low-copy repeat (LCR)-associated copy number variation (CNV) in CR1, producing different CR1 isoforms, CR1-F and CR1-S, and obtained significant association in carriers of CR1-S. We replicated the CR1 CNV association finding in a French cohort (n=2003) and calculated in the combined cohorts, an OR of 1.32; 95% CI: 1.10-1.59 (P=0.0025). Our data showed that the common AD risk association may well be explained by the presence of CR1-S increasing the number of C3b/C4b and cofactor activity sites and AD risk with 30% in CR1-S carriers. How precisely the different functional role of CR1-S in the immune complement cascade contributes to AD pathogenesis will need additional functional studies.     

Microglial phagocytosis and activation underlying photoreceptor degeneration is regulated by CX3CL1‐CX3CR1 signaling in a mouse model of retinitis pigmentosa

Retinitis pigmentosa (RP), a disease characterized by the progressive degeneration of mutation‐bearing photoreceptors, is a significant cause of incurable blindness in the young worldwide. Recent studies have found that activated retinal microglia contribute to photoreceptor demise via phagocytosis and proinflammatory factor production, however mechanisms regulating these contributions are not well‐defined. In this study, we investigate the role of CX3CR1, a microglia‐specific receptor, in regulating microglia‐mediated degeneration using the well‐established rd10 mouse model of RP. We found that in CX3CR1‐deficient (CX3CR1^GFP/GFP) rd10 mice microglial infiltration into the photoreceptor layer was significantly augmented and associated with accelerated photoreceptor apoptosis and atrophy compared with CX3CR1‐sufficient (CX3CR1^GFP/+) rd10 littermates. CX3CR1‐deficient microglia demonstrated increased phagocytosis as evidenced by (1) having increased numbers of phagosomes in vivo, (2) an increased rate of phagocytosis of fluorescent beads and photoreceptor cellular debris in vitro, and (3) increased photoreceptor phagocytosis dynamics on live cell imaging in retinal explants, indicating that CX3CR1 signaling in microglia regulates the phagocytic clearance of at‐risk photoreceptors. We also found that CX3CR1 deficiency in retinal microglia was associated with increased expression of inflammatory cytokines and microglial activation markers. Significantly, increasing CX3CL1‐CX3CR1 signaling in the rd10 retina via exogenous intravitreal delivery of recombinant CX3CL1 was effective in (1) decreasing microglial infiltration, phagocytosis and activation, and (2) improving structural and functional features of photoreceptor degeneration. These results indicate that CX3CL1‐CX3CR1 signaling is a molecular mechanism capable of modulating microglial‐mediated degeneration and represents a potential molecular target in therapeutic approaches to RP. GLIA 2016;64:1479–1491     

Childhood infections as risk factors for multiple sclerosis: Belgrade case-control study

The aim of this case-control study was to analyze the role of childhood infections and vaccinations in patients with MS in the Belgrade population. The study group comprised 110 cases with definite MS according to Poser's criteria, in whom onset symptoms occurred up to 2 years prior to the interview. An equal number of controls, individually matched by sex, age and area of residence, was recruited from patients with various nonautoimmune neurological disorders. Measles (OR = 2.6, 95%CI 1.4-5.0), chickenpox (OR = 3.0, 95%CI 1.5-6.0), rubella (OR = 2.4, 95%CI 1.2-4.7), whooping cough (OR = 1.9, 95%CI 0.8-4.4), and mumps (OR = 1.8, 95%CI 0.8-4.5), at age < or = 7 years, were more frequently reported by MS cases. The total number of childhood viral infections (including measles, rubella, chickenpox, and mumps) at age < or = 7 years was significantly higher in MS cases than in controls (OR = 1.8, 95%CI 1.4-2.5). Concerning vaccinations, no statistically significant differences were found between groups. According to multivariate analysis, rubella (OR = 2.5, 95%CI 1.4-4.4, p = 0.001) and measles (OR = 2.4, 95%CI 1.3-4.3, p = 0.003) at age < or = 7 years were significantly related to MS.     

CX3CR1 deficiency leads to impairment of hippocampal cognitive function and synaptic plasticity

The protective/neurotoxic role of fractalkine (CX3CL1) and its receptor CX3C chemokine receptor 1 (CX3CR1) signaling in neurodegenerative disease is an intricate and highly debated research topic and it is becoming even more complicated as new studies reveal discordant results. It appears that the CX3CL1/CX3CR1 axis plays a direct role in neurodegeneration and/or neuroprotection depending on the CNS insult. However, all the above studies focused on the role of CX3CL1/CX3CR1 signaling in pathological conditions, ignoring the relevance of CX3CL1/CX3CR1 signaling under physiological conditions. No approach to date has been taken to decipher the significance of defects in CX3CL1/CX3CR1 signaling in physiological condition. In the present study we used CX3CR1?/?, CX3CR1?/?, and wild-type mice to investigate the physiological role of CX3CR1 receptor in cognition and synaptic plasticity. Our results demonstrate for the first time that mice lacking the CX3CR1 receptor show contextual fear conditioning and Morris water maze deficits. CX3CR1 deficiency also affects motor learning. Importantly, mice lacking the receptor have a significant impairment in long-term potentiation (LTP). Infusion with IL-1β receptor antagonist significantly reversed the deficit in cognitive function and impairment in LTP. Our results reveal that under physiological conditions, disruption in CX3CL1 signaling will lead to impairment in cognitive function and synaptic plasticity via increased action of IL-1β.     

Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS

In this study, we investigate the expression of fractalkine (CX3CL1) and the fractalkine receptor (CX3CR1) in the naive rat and mouse central nervous system (CNS). We determine if the expression of this chemokine and its receptor are altered during chronic or acute inflammation in the CNS. In addition, we determine if CX3CL1, which has been reported to be chemoattractant to leukocytes in vitro, is capable of acting as a chemoattractant in the CNS in vivo. Immunohistochemistry was performed using primary antibodies recognizing soluble and membrane-bound CX3CL1 and the N-terminus of the CX3CR1. We found that neurons in the naive rodent brain are immunoreactive for CX3CL1 and CX3CR1, both showing a perinuclear staining pattern. Resident microglia associated with the parenchyma and macrophages in the meninges and choroid plexus constituitively express CX3CR1. In a prion model of chronic neurodegeneration and inflammation, CX3CL1 immunoreactivity is upregulated in astrocytes and CX3CR1 expression is elevated on microglia. In surviving neurons, expression of CX3CL1 appears unaltered relative to normal neurons. There is a decrease in neuronal CX3CR1 expression. Acute inflammatory responses in the CNS, induced by stereotaxic injections of lipopolysaccharide or kainic acid, results in activation of microglia and astrocytes but no detectable changes in the glial expression of CX3CL1 or CX3CR1. The expression of CX3CL1 and CX3CR1 by glial cells during inflammation in the CNS may be influenced by the surrounding cytokine milieu, which has been shown to differ in acute and chronic neuroinflammation.     

血浆CX3CL1水平与急性脑梗死病情严重程度及预后的相关性

目的 探讨血浆CX3CL1水平与急性脑梗死患者病情严重程度及预后的关系.方法 收集139例急性脑梗死患者(病例组)及82名健康对照者(对照组)的临床资料及血浆,采用ELISA法测定其血浆CX3CL1水平.病例组患者于入院后24 h内行NIHSS评分,并于发病3个月后随访行mRS评分.将病例组患者根据NIHSS评分及mRS评分分别进行分组,比较各亚组间血浆CX3CL1水平有无差异.结果 病例组血浆CX3CL1水平明显低于对照组(P=0.009),经Logistic回归分析显示血浆CX3CL1水平与急性脑梗死发病密切相关(OR=0.387,P=0.020),且血浆CX3CL1水平与CRP呈负相关(r=-0.232,P=0.003).急性脑梗死患者血浆CX3CL1水平与其入院后24 h内NIHSS评分呈负相关(r=-0.179,P=0.034).预后不良组(mRS>2分)血浆CX3CL1水平显著低于预后良好组(mRS≤2分),白细胞计数及CRP显著高于预后良好组(均P<0.05),血浆CX3CL1水平与急性脑梗死后3个月mRS评分呈负相关(r=-0.263,P=0.002).Logistic回归分析提示血浆CX3CL1水平与急性脑梗死预后密切相关(OR=0.087,P=0.004).结论 急性脑梗死患者的血浆CX3CL1水平较低,且血浆CX3CL1水平与急性脑梗死患者的病情严重程度及预后密切相关.     

CX3CL1/CX3CR1-mediated microglia activation plays a detrimental role in ischemic mice brain via p38MAPK/PKC pathway

The exact roles of activated microglia and fractalkine (CX3CL1)/fractalkine receptor (CX3CR1) signaling are not fully understood in brain ischemic injury and the findings reported are controversial. Here, we investigated the effects of CX3CR1 siRNA on the expression of CX3CR1, p38 mitogen-activated protein kinase (p38MAPK), Protein Kinase C (PKC) and inflammatory cytokines, microglia activation, white matter lesions, and cognitive function in mice treated with bilateral common carotid artery stenosis (BCAS) in vivo as well as effects of exogenous CX3CL1, CX3CR1 siRNA, and SB2035080 on expression of inflammatory cytokines in BV2 microglia treated with oxygen–glucose deprivation (OGD) in vitro. We showed that CX3CR1 siRNA significantly inhibited the increased expression of CX3CR1, p38MAPK, PKC as well as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, and also attenuated microglia activation, white matter lesions, and cognitive deficits induced by BCAS in mice brain. We also showed that exogenous CX3CL1 could induce a further enhancement in TNF-α and IL-1β expression, which could be suppressed by CX3CR1 siRNA or by the p38MAPK inhibitor in OGD-treated BV2 microglial cells in vitro. Our findings indicated that CX3CL1/CX3CR1-mediated microglial activation plays a detrimental role in ischemic brain via p38MAPK/PKC signaling and also suggested that CX3CL1/CX3CR1 axis might be a putative therapeutic target to disrupt the cascade of deleterious events that lead to brain ischemic injury.