Downregulation Of CX3CR1 Research Articles

Single-cell Transcriptome Analysis Confirms that Down-regulation of CX3CR1 in Monocytes of MDS Patients Alters Cell Communication and Immune Microenvironment Patterns

Single-cell Transcriptome Analysis Confirms that Down-regulation of CX3CR1 in Monocytes of MDS Patients Alters Cell Communication and Immune Microenvironment Patterns

Neuroinflammation and microglial expression in brains of social-isolation rearing model of schizophrenia

Schizophrenia is a psychiatric disorder with a global prevalence of approximately 0.45%. It is considered a mental illness, with negative symptoms, positive symptoms, and cognitive dysfunction. The outcomes of studies on the role of microglia and neuroinflammation have been conflicting. In addition, there is a poor understanding of the sex differences in microglial expression and neuroinflammation markers in the prefrontal cortex, hippocampus, and nucleus accumbens. Understanding the exact roles of neuroinflammation may guide the development of efficient therapeutic drugs that can address the negative, positive, and cognitive symptoms of the disease. We examined the effect of social isolation rearing on schizophrenia-related behaviours in male and female BALB/c mice. The social-isolation rearing protocol started on post-natal day (PND) 21, lasting for 35 days. Animals were assigned to four cohorts, consisting of five animals per group. On PND 56, animals were assessed for behavioural changes. We used enzyme-linked immunosorbent assays to investigate the expression of nuclear factor kappa B (NF-κB), tumour necrosis factor-α (TNF-α), and Interleukin-1β (IL-1β) in the hippocampus, nucleus accumbens, and prefrontal cortex. Immunohistochemistry was used to assess the expression of microglia in the three brain regions. Our study showed that isolation rearing led to increasing locomotion, heightened anxiety, depression, and a reduced percentage of prepulse inhibition. There was a significant increase (p < 0.05) in anxiety in the female isolation mice compared to male isolation mice. Furthermore, isolation rearing significantly increased microglia count (p < 0.05) in the hippocampus, nucleus accumbens, and prefrontal cortex, only in the male group. There was microglial hyper-activation as evident in the downregulation of CX3CR1 in both male and female social-isolation groups. Male social-isolation mice showed a significant increase (p < 0.05) in neuroinflammation markers only in the nucleus accumbens while the female social-isolation mice showed a significant increase (p < 0.05) in neuroinflammation markers in both the nucleus accumbens and hippocampus. The study showed that therapeutic interventions aimed at modulating CX3CR1 activity and reducing inflammation may be beneficial for patients with schizophrenia.

Ovariectomy in mice primes hippocampal microglia to exacerbate behavioral sickness responses

Estrogens are a group of steroid hormones that promote the development and maintenance of the female reproductive system and secondary sex characteristics. Estrogens also modulate immune responses; estrogen loss at menopause increases the risk of inflammatory disorders. Elevated inflammatory responses in the brain can lead to affective behavioral changes, which are characteristic of menopause. Thus, here we examined whether loss of estrogens sensitizes microglia, the primary innate immune cell of the brain, leading to changes in affective behaviors. To test this question, adult C57BL/6 mice underwent an ovariectomy to remove endogenous estrogens and then received estradiol hormone replacement or vehicle. After a one-month recovery, mice received an immune challenge with lipopolysaccharide (LPS) or vehicle control treatment and underwent behavioral testing. Ovariectomized, saline-treated mice exhibited reduced social investigation compared to sham-operated mice. Furthermore, ovariectomized mice that received LPS exhibited an exacerbated decrease in sucrose preference, which was ameliorated by estradiol replacement. These results indicate that ovariectomy modulates affective behaviors at baseline and in response to an inflammatory challenge. Ovariectomy-related behavioral changes were associated with downregulation of Cx3cr1, a microglial receptor that limits activation, suggesting that estrogen loss can disinhibit microglia to immune stimuli. Indeed, estradiol treatment reduced ovariectomy-induced increases in Il1b and Il6 expression after an immune challenge. Changes in microglial reactivity following ovariectomy are likely subtle, as overt changes in microglial morphology (e.g., soma size and branching) were limited. Collectively, these results suggest that a lack of estrogens may allow microglia to confer exaggerated neuroimmune responses, thereby raising vulnerability to adverse affective- and sickness-related behavioral changes.

Airway allergy causes alveolar macrophage death, profound alveolar disorganization and surfactant dysfunction.

Respiratory disorders caused by allergy have been associated to bronchiolar inflammation leading to life-threatening airway narrowing. However, whether airway allergy causes alveolar dysfunction contributing to the pathology of allergic asthma remains unaddressed. To explore whether airway allergy causes alveolar dysfunction that might contribute to the pathology of allergic asthma, alveolar structural and functional alterations were analyzed during house dust mite (HDM)-induced airway allergy in mice, by flow cytometry, light and electron microscopy, monocyte transfer experiments, assessment of intra-alveolarly-located cells, analysis of alveolar macrophage regeneration in Cx3cr1 cre:R26-yfp chimeras, analysis of surfactant-associated proteins, and study of lung surfactant biophysical properties by captive bubble surfactometry. Our results demonstrate that HDM-induced airway allergic reactions caused severe alveolar dysfunction, leading to alveolar macrophage death, pneumocyte hypertrophy and surfactant dysfunction. SP-B/C proteins were reduced in allergic lung surfactant, that displayed a reduced efficiency to form surface-active films, increasing the risk of atelectasis. Original alveolar macrophages were replaced by monocyte-derived alveolar macrophages, that persisted at least two months after the resolution of allergy. Monocyte to alveolar macrophage transition occurred through an intermediate stage of pre-alveolar macrophage and was paralleled with translocation into the alveolar space, Siglec-F upregulation, and downregulation of CX3CR1. These data support that the severe respiratory disorders caused by asthmatic reactions not only result from bronchiolar inflammation, but additionally from alveolar dysfunction compromising an efficient gas exchange.

Regulation of DNA damage repair and lipid uptake by CX3CR1 in epithelial ovarian carcinoma

Failure of currently used cytotoxic chemotherapy is one of the main reasons behind high mortality from metastatic high grade serous ovarian carcinoma. We found that high expression of a receptor for fractalkine (CX3CR1) significantly correlated with shorter survival of patients with serous ovarian carcinoma treated with cytotoxic DNA damage chemotherapies, and reduction of CX3CR1 expression resulted in sensitization to several DNA damaging modalities, including x-ray radiation and cisplatin. Here, we show that CX3CR1 plays a role in double-strand DNA break response and repair by regulating expression of RAD50 by a MYC-dependent mechanism. We demonstrate that downregulation of CX3CR1 alone and in a combination with irradiation affects peritoneal metastasis in an organ-specific manner; we show that CX3CR1 regulates lipid uptake which could control omental metastasis. This study identifies CX3CR1 as a novel potential target for sensitization of ovarian carcinoma to DNA damage therapies and reduction of peritoneal carcinomatosis.

Determinants of long term treatment response following intra-articular steroid therapy in knee OA

Determinants of long term treatment response following intra-articular steroid therapy in knee OA

CX3CL1/CX3CR1 and CCL2/CCR2 chemokine/chemokine receptor complex in patients with AMD.

PurposeThe chemokine receptors CX3CR1 and CCR2 have been implicated in the development of age-related macular degeneration (AMD). The evidence is mainly derived from experimental cell studies and murine models of AMD. The purpose of this study was to investigate the association between expression of CX3CR1 and CCR2 on different leukocyte subsets and AMD. Furthermore we measured the plasma levels of ligands CX3CL1 and CCL2.MethodsPatients attending our department were asked to participate in the study. The diagnosis of AMD was based on clinical examination and multimodal imaging techniques. Chemokine plasma level and chemokine receptor expression were measured by flow-cytometry.ResultsA total of 150 participants were included. We found a significantly lower expression of CX3CR1 on CD8+ T cells in the neovascular AMD group compared to the control group (p = 0.04). We found a significant positive correlation between CCR2 and CX3CR1 expression on CD8+ cells (r = 0.727, p = 0.0001). We found no difference in plasma levels of CX3CL1 and CCL2 among the groups.ConclusionsOur results show a down regulation of CX3CR1 on CD8+ cells; this correlated to a low expression of CCR2 on CD8+ cells. Further studies are needed to elucidate the possible role of this cell type in AMD development.

Abstract A32: Fractalkine receptor, CX3CR1, Can regulate the response of ovarian carcinoma cells to radiation therapy

Abstract Ovarian carcinoma is a leading cause of death from gynecologic malignancies. The current treatment, a combination of chemotherapy and radiation, fails to keep patients in remission. Therefore, mechanistical understanding of the disease and modifications of the therapy could offer benefits to overcome current problems and combat the disease. Fractalkine receptor (CX3CR1) belongs to a chemokine family of G protein-coupled receptors, the most frequently and successfully drug-targeted group of proteins. Previous publications show that interaction of chemokines with their receptors plays an important role in homing distant metastasis, as well as promoting migration, adhesion, and proliferation in many types of cancer. X-Ray radiotherapy is a well-developed method of anti-cancer treatment, however, it is seldom used against ovarian carcinoma due to multiple reasons, including dose-related effects. Hence, strategies for reducing the dose of radiation while keeping its efficiency at a therapeutically effective level could provide rational for developing approaches for a more wide-spread use of this method. Our data indicate that transient downregulation of CX3CR1 in p53-null cells and p53-mutant cells but not in p53 wild-type ovarian carcinoma cell lines can lead to approximately 50% sensitization to x-ray radiation, as determined by the clonogenic assay. Importantly, our in vivo studies demonstrated that a transient downregulation of CX3CR1 in combination with x-ray radiation led to approximately 50% reduction of tumor weights compared to either downregulation of CX3CR1 or x-ray radiation alone. We are currently characterizing the detailed mechanisms behind the CX3CR1-dependent radiosensitization, including those related to changes in cell cycle progression, involvement of cellular reactive oxygen species accumulation and regulation of DNA single and double strand break repair. Taken together, our date indicate that disruption of the CX3CR1 signaling could sensitize ovarian carcinoma to radiation therapy. Citation Format: Jia Xie, Hilal Gurler, Maria Barbolina. Fractalkine receptor, CX3CR1, Can regulate the response of ovarian carcinoma cells to radiation therapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A32.

Abstract 5323: Fractalkine receptor CX3CR1 regulates peritoneal dissemination of ovarian carcinoma

Abstract Epithelial ovarian carcinoma (EOC) is the deadliest gynecologic malignancy largely due to the metastatic disease. EOC metastases spread by shedding the malignant cells off of the ovarian surface and seeding tissues and organs of the peritoneal cavity. Currently used therapies, a combination of chemotherapy and surgery, fail to keep most patients in the remission. Mechanistic understanding of the biology of EOC metastasis will facilitate development of new therapeutic approaches. Our previous data demonstrated that fractalkine receptor (CX3CR1) is expressed by EOC cells and can support cell migration and proliferation. Moreover, our previous data suggested that CX3CR1-positive EOC cells can adhere to the CX3CL1-postive peritoneal mesothelial cells in in vitro assay. Thus, we hypothesized that CX3CL1/CX3CR1 axis could be important for peritoneal dissemination of metastatic EOC. To test this hypothesis, we performed short-term ex vivo and in vivo adhesion assay, as well as long-term metastasis formation assay. Expression of CX3CR1 in EOC cells was downregulated in SKOV-3 using shRNA. Both CX3CR1 shRNA-expressing and scrambled shRNA-expressing EOC cells were seeded atop of mouse peritoneum and omentum tissues in the ex vivo assay and allowed to adhere for up to 24 h. CX3CR1 shRNA-expressing and scrambled shRNA-expressing EOC cells were intraperitoneally injected into abdomens of athymic nude mice for 4 h following sacrifice of the animals and examination of the peritoneal organs and tissues for green fluorescence. Data analysis has demonstrated that downregulation of CX3CR1 in EOC cells led to a significant decrease of adhesion in these assays. Furthermore, parental SKOV-3 as well as CX3CR1 shRNA-, scrambled shRNA-, and vector shRNA-expressing cells were intraperitoneally injected into athymic nude mice and allowed to form metastasis for 10 weeks. As a result, we observed very small omental metastatic lesions in three out of six animals injected with CX3CR1 shRNA-expressing cells. In opposite, all of the control groups developed gross intraperitoneal metastasis in many organs and tissues. Our data suggest that CX3CR1 may be one of the key factors that determine peritoneal dissemination of EOC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5323. doi:1538-7445.AM2012-5323

Abstract 3452: The role of CX3CR1 in resistance of ovarian carcinoma cells to radiation therapy

Abstract Ovarian carcinoma is a leading cause of death from gynecologic malignancies. The current standard of care, a combination of chemotherapy and radiation, fails to keep patients in remission. Thus, modifications of the therapy and the combinations with the new molecular biological technologies are crucial for the development of the modernized approaches to combat this disease. Previous attempts to use radiotherapy as an additional treatment was not successful mainly due to the dose-related side effects, as well as radioresistance. Therefore, mechanistical understanding of the biology of ovarian carcinoma could offer ways to overcome current problems. Fractalkine receptor (CX3CR1) belongs to a chemokine family of G protein-coupled receptors, the most frequently and successfully drug-targeted group of proteins. Interaction of chemokines with their receptors plays a pivotal role in homing distant metastasis, as well as promoting migration, adhesion, and proliferation in many types of cancer. This project is aimed at understanding the role of CX3CR1 in sensitization of epithelial ovarian cancer cells to radiotherapy. Our data indicate that downregulation of CX3CR1 in ovarian carcinoma cells leads to approximately 50% sensitization to x-ray radiation, as determined by the clonogenic ability assay. Our Western blotting and immunofluorescence analysis data also show that downregulation of CX3CR1 results in accumulation of DNA damage at lower doses. Thus, our data indicate that disruption of the CX3CR1 signaling could sensitize ovarian carcinoma to radiation therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3452. doi:1538-7445.AM2012-3452

Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge

Protracted downregulation of CX3CR1 on microglia of aged mice after lipopolysaccharide challenge