CCL2 Levels Research Articles

Regulatory role and translational potential of CCL11 in liver fibrosis.

Myofibroblasts are considered the major effector cell type of liver fibrosis and primarily derived from hepatic stellate cells (HSCs). In the present study, we investigated the contribution of C-C motif chemokine (CCL11) to HSC-myofibroblast trans -differentiation and its implication in liver fibrosis. We report that CCL11 levels were elevated in HSCs, but not in hepatocytes or Kupffer cells, isolated from mice with liver fibrosis compared with the control mice. CCL11 levels were also up-regulated by 2 pro-fibrogenic growth factors TGF-β and platelet derived growth factor in cultured HSCs. Mechanistically, zinc finger factor 281 bound to the CCL11 promoter and mediated CCL11 trans -activation in HSCs. Depletion of CCL11 attenuated whereas treatment with recombinant CCL11 promoted HSC activation. Further, global CCL11 deletion ( CCL11-/- ) or HSC/myofibroblast-specific CCL11 knockdown mitigated fibrogenesis in mice. RNA-sequencing revealed that CCL11 might regulate HSC activation by stimulating the transcription of Jagged 1. Reconstitution of Jagged 1 restored the fibrogenic response in CCL11-/- mice. Finally, several targeting strategies that aimed at blockading CCL11 signaling, either by administration of an antagonist to its receptor C-C motif chemokine receptor 3 or neutralizing antibodies against CCL11/C-C motif chemokine receptor 3, ameliorated liver fibrosis in mice. Our data unveil a previously unrecognized role for CCL11 in liver fibrosis and provide proof-of-concept evidence that targeting CCL11 can be considered as an effective therapeutic approach.

Effect of 12-Week Aerobic Exercise Training on Chemokine Ligands and Their Relative Receptors in Balb/C Mice with Breast Cancer

Background: Some chemokines like C C motif chemokine ligand (CCL) 2 and 5 and their receptors (CCR) 2 and 5 are mediators of chronic inflammation and cancer development. Moreover, physical exercise can increase the activity of antioxidant enzymes. However, its effect on cancer cells has not been reported at present. Objectives: Therefore, the present study aimed to ascertain the effect of 12-week aerobic exercise training (AET) on CCL2, CCR2, CCL5, and CCR5 in mice with breast cancer. Methods: Sixteen Balb/c mice aged 4 - 5 weeks (n = 16; approximate weight: 18 ± 2 g) were divided into two groups: AET group (AETG) and control group (CG) (n = 8 per group). The AETG performed 12-week treadmill running at 18 m/min for 40 min and five times a week. Plasma levels of CCL2 and CCL5 were measured by ELISA, and the CCR2 and CCR5 were evaluated by Western blotting. Two independent sample t-test was applied to compare the differences between AETG and CG. Results: The analysis displayed after 12 weeks showed a significant reduction in AETG compared to CG in CCL2 (3.94 ± 1.12 vs. 15.40 ± 3.29 pg/mL; P = 0.001), CCR2 (0.56 ± 0.19 vs. 1.00 ± 0.001; P = 0.002), CCL5 (138.59 ± 15.72 vs. 267.57 ± 49.06 ng/mL; P = 0.001) and CCR5 (0.36 ± 0.12 vs. 1.00 ± 0.001; P = 0.001), respectively. Conclusions: We concluded that one of the main mechanisms of a positive effect of exercise on breast cancer is reducing the inflammation via CCL2 and CCL5 and their related receptors CCR2 and CCR5, respectively. Since these molecules can be triggered off oxidative stress and tumorigenesis, these results can pave the way for further studies in this field.

IFN-λ3 and CCL17 as predictors of disease progression in patients with mild to moderate COVID-19: A cohort study in a real-world setting

Coronavirus disease 2019 (COVID-19) has overwhelmed hospitals worldwide. In Japan, serum interferon lambda 3 (IFN-λ3) and C–C motif ligand (CCL) 17 levels have been used as predictive markers for disease progression to severe COVID-19. However, the relationship between these predictive markers and the disease progression of COVID-19 has not been well evaluated. We retrospectively evaluated the patient characteristics, serum IFN-λ3 and CCL17 levels, and comorbidities of 92 patients with mild (n = 20) and moderate (n = 72) COVID-19 who were hospitalized in our institution. The results of the multivariable analysis showed that the positive rates of IFN-λ3, CCL17, and the combination of these markers were significantly elevated in patients with progressed COVID-19. Furthermore, patients who were negative for both markers did not experience disease progression. This study illustrates the importance of measuring these markers to predict disease severity and progression in patients with COVID-19.

Plasma levels of CCL21, but not CCL19, independently predict future coronary events in a prospective population-based cohort

Background and aimsThe homeostatic chemokines CCL21 and CCL19 have been explored as biomarkers in cardiovascular disease prediction in patients with established cardiovascular disease, but associations between these chemokines and first-time coronary event incidence have not been investigated before. Here, we explored associations between CCL21 or CCL19 and first-time incident coronary events in the general population-based Malmö Diet and Cancer cohort with two decades of follow-up. MethodsCCL21 and CCL19 levels in plasma were analysed with ELISA and proximity extension assay and associations with disease incidence were explored with conditional logistic regression in a nested case-control cohort (CCL21; n = 676) and with Cox regression in a population-based cohort (CCL19; n = 4636). ResultsHigh CCL21 levels in plasma were associated with incident first-time coronary events independently of traditional risk factors (odds ratio of 2.64 with 95% confidence interval 1.62–4.31, p < 0.001, comparing the highest versus the lowest tertile of CCL21), whereas CCL19 was not. CCL19 was, however, associated with incident heart failure, as well as increased all-cause, cardiovascular and cancer mortality independently of age and sex. ConclusionsEven though CCL21 and CCL19 both signal through CCR7, these chemokines may not be interchangeable as disease predictors and CCL21 could be used for prediction of future coronary events in individuals without any previous coronary heart disease history.

Diagnosing Acute Cellular Rejection after Paediatric Liver Transplantation-Is There Room for Interleukin Profiles?

The current gold standard to diagnose T-cell-mediated acute rejection (TCMR) requires liver histology. Using data from the ChilSFree study on immune response after paediatric liver transplantation (pLT), we aimed to assess whether soluble cytokines can serve as an alternative diagnostic tool in children suspected to have TCMR. A total of n = 53 blood samples obtained on the day of or up to 3 days before liver biopsy performed for suspected TCMR at median 18 days (range 7-427) after pLT in n = 50 children (38% female, age at pLT 1.8 (0.5-17.5) years) were analysed for circulating cytokine levels using Luminex-based Multiplex technology. Diagnostic accuracy of cytokine concentrations was assessed using a multivariable model based on elastic net regression and gradient boosting machine analysis. TCMR was present in 68% of biopsies. There was strong evidence that patients with TCMR had increased levels of soluble CXCL8, CXCL9, CXCL10, IL-16, IL-18, HGF, CCL4, MIF, SCGF-β, and HGF before biopsy. There was some evidence for increased levels of sCD25, ICAM-1, IL-6, IL-3, and CCL11. Diagnostic value of both single cytokine levels and a combination of cytokines and clinical markers was poor, with AUROCs not exceeding 0.7. Patients with TCMR showed raised levels of cytokines and chemokines reflective of T-cell activation and chemotaxis. Despite giving insight into the mechanisms of TCMR, the diagnostic value of soluble cytokines for the confirmation of TCMR in a clinical scenario of suspected TCMR is poor.

Glioma-derived CCL2 and CCL7 mediate migration of immune suppressive CCR2+/CX3CR1+ M-MDSCs into the tumor microenvironment in a redundant manner.

Glioblastoma (GBM) is the most common and malignant primary brain tumor, resulting in poor survival despite aggressive therapies. GBM is characterized in part by a highly heterogeneous and immunosuppressive tumor microenvironment (TME) made up predominantly of infiltrating peripheral immune cells. One significant immune cell type that contributes to glioma immune evasion is a population of immunosuppressive, hematopoietic cells, termed myeloid-derived suppressor cells (MDSCs). Previous studies suggest that a potent subset of myeloid cells, expressing monocytic (M)-MDSC markers, distinguished by dual expression of chemokine receptors CCR2 and CX3CR1, utilize CCR2 to infiltrate into the TME. This study evaluated the T cell suppressive function and migratory properties of CCR2+/CX3CR1+ MDSCs. Bone marrow-derived CCR2+/CX3CR1+ cells adopt an immune suppressive cell phenotype when cultured with glioma-derived factors. Recombinant and glioma-derived CCL2 and CCL7 induce the migration of CCR2+/CX3CR1+ MDSCs with similar efficacy. KR158B-CCL2 and -CCL7 knockdown murine gliomas contain equivalent percentages of CCR2+/CX3CR1+ MDSCs compared to KR158B gliomas. Combined neutralization of CCL2 and CCL7 completely blocks CCR2-expressing cell migration to KR158B cell conditioned media. CCR2+/CX3CR1+ cells are also reduced within KR158B gliomas upon combination targeting of CCL2 and CCL7. High levels of CCL2 and CCL7 are also associated with negative prognostic outcomes in GBM patients. These data provide a more comprehensive understanding of the function of CCR2+/CX3CR1+ MDSCs and the role of CCL2 and CCL7 in the recruitment of these immune suppressive cells and further support the significance of targeting this chemokine axis in GBM.

The Effects of 4-Week Aerobic Exercise on the Levels of CCl2, CCl5, and their Respective Receptors in Female BALB/C Mice Suffering from Breast Cancer.

The studies reported that chemokines Chemokine (C-C motif) ligand 2 (CCL2) and Chemokine (C-C motif) ligand 5 (CCL5) have tumor-promoting roles in breast cancer (BC). The aim of the present study was to evaluate the effect of 4 weeks of continuous aerobic exercise (AE) on chemokines CCL2 and CCL5 and their relative receptors in animal model of human BC. BALB/c mice were divided randomly into four groups included cancer control (CC) and three other groups. The total duration of the experiment was 14 weeks, including 2 weeks of familiarization of mice with treadmills and three of 4-week periods of experiment. Tumor inoculation and formation were performed in the second 4-week period. Group 1 received AE in the first 4-week, Group 2 received AE in the second 4-week and Group 3 in the third 4-week. The CCL2 was reduced significantly in Groups 1, 2, and 3 compared to control (F3,12= 4705, P = 0.0001). In terms of CCL5, a significant decrease was seen only between Group 3 and control. Western blot results showed a significant reduction in C-C chemokine receptor Type 2 (CCR2) between Group 1 versus CC and Group 2 versus CC (F3,20= 1.812, P = 0.004). In terms of C-C chemokine receptor Type 5 (CCR5) a significant decrease was observed between Group 2 versus control and Group 3 versus control (F3,20= 273.3, P = 0.042), (P = 0.004). It can be concluded that 4-week AE significantly reduces the chemokines CCL2 and CCL5 and their respective receptors levels CCR5 and CCR2 in different stages, and it may have an inhibitory effect on tumor growth.

Alteration in IFN-γ and CCL2 serum levels at first trimester of pregnancy contribute to development of preeclampsia and fetal growth restriction

ObjectivePregnancy is a unique challenge for the immune system. Any disturbance in the immune system in the first trimester could result in further pregnancy complications. In this regard, the current study aimed to investigate the association between serum levels of a group of cytokines in the first trimester of pregnancy with the onset of preeclampsia (PE) and fetal growth restriction (FGR). Materials and methodsSerum samples were collected from 550 pregnant women at their 11th - 13th weeks of pregnancy and followed up to delivery. Out of all cases, 15 women complicated with preeclampsia and 15 ones diagnosed with FGR were included in the study. The serum levels of IFN-γ, CCL2, IL-10, IL-35 and IL-27 were checked in the collected sera of mentioned patients and compared to 60 women with normal pregnancy outcomes. ResultsIn the preeclampsia group, the mean level of IFN-γ was significantly higher (p < 0.001) while the CCL2 serum level was significantly lower (p < 0.003) as compared to control group. There was no significant difference between the preeclampsia group and controls regarding other cytokines. In the FGR group, the mean serum level of IFN-γ was significantly higher compared to the healthy pregnancy group (p < 0.001) but other cytokines showed no significant differences. In the FGR group, a significant positive correlation was found between IL-10 level and neonates' weight (p < 0.05). ConclusionBased on the results of the present study, an elevated level of IFN-γ and a reduced level of CCL2 at the first trimester of pregnancy could lead to complications such as PE and/or FGR.

Promising Modulatory Effects of Cenicriviroc on the Progression of Mouse Colorectal Cancer through Inhibition of CCR2_CCL2 Signaling Pathway.

The study was designed to assay the efficacy of cenicriviroc (CVC) on the progression of mouse colorectal cancer by downregulation of CCR2_CCL2. In this study, CVC was used to inhibit the CCR2 receptor. Next, an MTT assay was performed to evaluate the cytotoxic effects of CVC on the CT26 cell line. CT26 cells were implanted subcutaneously in BALB/c mice. After tumor implantation, one group of animals received 20 mg/kg of CVC several times. The mRNA levels of CCR2, CCL2, VEGF, NF-κB, c-Myc, vimentin, and IL33 were determined in the CT26 cell line and then tumor tissues (after 21 days), by qRT-PCR. Protein levels of the above-mentioned targets were determined by western blot and ELISA. Flow cytometry was performed to assess the changes in apoptosis. Tumor growth inhibition was measured on the 1st, 7th, and 21st days after the first treatment. In both cell line and tumor cells treated with CVC, expression levels of the markers of our interest in mRNA and protein levels were significantly reduced compared to controls. A significantly higher apoptotic index was observed in CVC-treated groups. The rates of tumor growth were significantly decreased on the 7th and 21st days after the first injection. To our knowledge, this was the first time that we demonstrated the promising effect of CVC on the development of CRC through inhibition of the CCR2_CCL2 signaling and its downstream biomarkers.

PD-1 Deficiency in Regulatory T Cells May be Involved in the Pathogenesis of Takayasu's Arteritis.

This study aims to investigate whether PD-1 expressions are abnormal in patients with TAK. PD-1 expression was analyzed by flow cytometry. Serum cytokines IL-10, IL-7, IL-2, IL-15, CCL2, CCL3, and CXCL10 were detected using a cytokine cytometric bead array. Immunohistochemistry staining analysis was used to test PD-1 and programmed death-ligand 1 (PD-L1) expression in the aorta of three patients with TAK and three patients with atherosclerosis as controls. The mean fluorescence intensity of PD-1 in CD4+PD-1+ cells was decreased in patients with TAK and the frequency of CD4+Foxp3-PD-1+ cells among CD4+T cells was also decreased in peripheral blood relative to healthy controls (P < .05). The percentage of CD4+CD25+Foxp3+PD-1+ cells in the CD4+CD25+T cell population was lower in patients with TAK than in healthy control and was lower in active TAK group (P < .05). Comparing PD-1 and PDL-1 expression in aorta tissue showed that patients with TAK tended to have lower levels than patients with atherosclerosis, but the difference was not significant (P > .05). Patients with TAK had higher serum levels of IL-10, IL-7, CCL2, and CCL3 (P < .05). Abnormal expression of PD-1 in serum and aorta tissue of patients with TAK may contribute to TAK pathogenesis. PD-1 expression in both peripheral blood and aorta tissue of TAK patients decreased relative to healthy controls, indicating that PD-1 might be involved in TAK pathogenesis.

PS-BPB09-7: ENDOTHELIAL CNP-GC-B SYSTEM PLAYS A PROTECTIVE ROLE IN THE DEVELOPMENT OF PULMONARY HYPERTENSION

Background: Pulmonary hypertension (PH) is a disease with a poor prognosis despite the development of various treatments, and a further therapeutic agent is required. C-type natriuretic peptide (CNP), one of the natriuretic peptide family, affects vasorelaxation and inhibition of vascular remodeling through its receptor guanylyl cyclase-B (GC-B). However, the beneficial effect of CNP on PH is still controversial. In this study, we examined the role of the CNP-GC-B pathway in the pathogenesis of PH. Methods and Results: To clarify the effect of the endogenous CNP-GC-B system on PH, we evaluated two types of PH models (monocrotaline pyrrole-induced and hypoxia-induced PH models) by using endothelial cell-specific CNP knockout mice (ecCNP-cKO), endothelial cell-specific GC-B knockout mice (ecGC-B-cKO), and smooth muscle cell-specific CG-B knockout mice (smGC-B-cKO). In both PH models, ecGC-B-cKO and ecCNP-cKO mice exacerbated PH compared to control cre-mice. Besides, mRNA levels of Edn1, IL6 and Ccl2 of the lung were significantly increased in the PH models of these mice. However, PH models of smGC-B-cKO mice showed no significant difference compared to those of control cre-mice. In cultured pulmonary arterial endothelial cells, synthesised CNP significantly attenuated PDGF- or hypoxia-induced increase in mRNA expression of Edn1, IL-6, and Ccl2. Moreover, continuous subcutaneous administration of synthesised CNP by osmotic mini-pump significantly ameliorated PH in PH model mice. Conclusion: CNP plays a protective role in the development of PH via endothelial GC-B through inhibiting endothelin-1 and inflammatory signals involvement. These data suggest CNP could be a novel therapeutic agent for PH.

Chronic Oral Administration of Aluminum Hydroxide Stimulates Systemic Inflammation and Redox Imbalance in BALB/c Mice.

The present study is aimed at investigating the long-term effects of the aluminum hydroxide administration in the small intestine, lung, liver, and kidney of male BALB/c mice. The mice received via orogastric gavage phosphate buffered or 10 mg/kg aluminum hydroxide 3 times a week for 6 months. Administration of aluminum hydroxide decreased hemoglobin, hematocrit, and erythrocyte. In the blood, kidney and liver function markers were evaluated, and long-term administration of aluminum hydroxide led to an increase in AST levels and a decrease in urea levels. The animals exposed to aluminum showed higher lipid and protein oxidation in all the organs analyzed. In relation to the enzymes involved in antioxidant defense, the lungs showed lower superoxide dismutase (SOD) and catalase activity and a lower reduced and oxidized glutathione (GSH/GSSG) ratio. In the liver, aluminum administration led to a decrease in catalase activity and the GSH/GSSG ratio. Lower catalase activity was observed in the small intestine, as well as in the lungs and liver. In addition to alterations in antioxidant defense, increased levels of the chemokine CCL-2 were observed in the lungs, lower levels of IL-10 in the liver and small intestine, and decreased levels of IL-6 in the intestine of the animals that received aluminum hydroxide for 6 months. Long-term exposure to aluminum promoted steatosis in the liver. In the kidneys, mice treated with aluminum presented a decreased glomerular density than in the naive control group. In the small intestine, exposure caused villi shortening. Our results indicate that long-term oral administration of aluminum hydroxide provokes systemic histological damage, inflammation, and redox imbalance.

Ketogenic diet attenuates neuroinflammation and induces conversion of M1 microglia to M2 in an EAE model of multiple sclerosis by regulating the NF-κB/NLRP3 pathway and inhibiting HDAC3 and P2X7R activation.

Multiple sclerosis (MS) is an autoimmune disorder characterized by demyelination and neurodegeneration in the central nervous system (CNS); severe symptoms lead MS patients to use complementary treatments. Ketogenic diet (KD) shows wide neuroprotective effects, but the precise mechanisms underlying the therapeutic activity of KD in MS are unclear. The present study established a continuous 24 days experimental autoimmune encephalomyelitis (EAE) mouse model with or without KD. The changes in motor function, pathological hallmarks of EAE, the status of microglia, neuroinflammatory response and intracellular signaling pathways in mice were detected by the rotarod test, histological analysis, real-time PCR (RT-PCR) and western blotting. Our results showed that KD could prevent motor deficiency, reduce clinical scores, inhibit demyelination, improve pathological lesions and suppress microglial activation in the spinal cord of EAE mice. Meanwhile, KD shifted microglial polarization toward the protective M2 phenotype and modified the inflammatory milieu by downregulating the production of pro-inflammatory cytokines, including TNF-α, IL-1β and IL-6, as well as upregulating the release of anti-inflammatory cytokines such as TGF-β. Furthermore, KD decreased the expression levels of CCL2, CCR2, CCL3, CCR1, CCR5, CXCL10 and CXCR3 in the spinal cord and spleen with reduced monocyte/macrophage infiltration in the CNS. In addition, KD inhibits NLRP3 activation in the microglia, as revealed by the significantly decreased co-expression of NLRP3+ and Iba-1+ in the KD + EAE group. Further studies demonstrated that KD suppresses inflammatory response and M1 microglial polarization by inhibiting the TLR4/MyD88/NF-κB/NLRP3 pathway, the JAK1/STAT1 pathway, HDAC3 and P2X7R activation, as well as up-regulation of JAK3/STAT6.

Immunobiochemical profile of clear cell renal cell carcinoma (ccRCC): A preliminary study.

Clear cell renal cell carcinoma (ccRCC) is the most common variant of RCC. It is an aggressive disease with an unfavorable prognosis. The rich immune infiltrates present in the tumor microenvironment (TME) of ccRCC produce various signaling molecules, especially cytokines, which primarily activate the Jak/STAT pathway and significantly influence tumor pathogenesis. STAT3 has a well-defined oncogenic character. Using multiplex assays and ELISA, we have measured the concentrations of 27 cytokines and STAT3 in tumor and healthy renal tissue from 16 patients with histologically verified ccRCC. We have detected significantly higher levels of G-CSF, IL-6, CXCL10, CCL3, and CCL4 in tumor tissue than in their healthy counterparts. There were significant differences in the levels of IL-1β and PDGF-BB between tumors of different nuclear grades (NG). Intratumoral IL-12p70 and IL-15 showed a significant positive correlation with intratumoral STAT3. The concentration of STAT3 in tumors was significantly lower than in the kidney. An increase in tumor STAT3 levels was associated with an increase in the pathological stage of the disease (TNM), but not with NG. The results of our study confirm the significant role of various cytokines and STAT3 in the pathogenesis of ccRCC and indicate their clinical relevance.

Vascular smooth muscle cell phenotype is modulated by ligands of the lymphotoxin β receptor and the tumor necrosis factor receptor

ObjectiveVascular smooth muscle cells (VSMCs) undergo a phenotypic-switching process during the generation of unstable atheroma plaques. In this investigation, the potential implication of the tumor necrosis factor superfamily (TNFSF) ligands, in the gene expression signature associated with VSMC plasticity was studied. Material and methodsHuman aortic (ha)VSMCs were obtained commercially and treated with the cytokine TNFSF14, also called LIGHT, the lymphotoxin alpha (LTα), the heterotrimer LTα1β2 or with vehicle for 72h. The effect of the different treatments on gene expression was analyzed by quantitative PCR and included the study of genes associated with myofibroblast-like cell function, osteochondrogenesis, pluripotency, lymphorganogenesis and macrophage-like cell function. ResultsHaVSMCs displayed a change in myofibroblast-like cell genes which consisted in reduced COL1A1 and TGFB1 mRNA levels when treated with LTα or LIGHT and with augmented MMP9 expression levels when treated with LTα. LTα and LIGHT treatments also diminished the expression of genes associated with osteochondrogenesis and pluripotency SOX9, CKIT, and KLF4. By contrary, all the above genes were no affected by the treatment with the trimer LTα1β2. In addition, haVSMC treatment with LTα, LTα1β2 and LIGHT altered lymphorganogenic cytokine gene expression which consisted of augmented CCL20 and CCL21 mRNA levels by LTα and a reduction in the gene expression of CCL21 and CXCL13 by LIGHT and LTα1β2 respectively. Neither, LTα or LIGHT or LTα1β2 treatments affected the expression of macrophage-like cell markers in haVSMC. ConclusionsAltogether, indicates that the TNFSF ligands through their interconnected network of signaling, are important in the preservation of VSMC identity against the acquisition of a genetic expression signature compatible with functional cellular plasticity.

MRNA expression levels of CCL4, IL6, and CXCL2 in multiwalled carbon nanotube induced lung tumors in rats

mRNA expression levels of CCL4, IL6, and CXCL2 in multiwalled carbon nanotube induced lung tumors in rats

Blood Content of Pro-Inflammatory Chemokines in Patients with First Episode of Schizophrenia before Therapy

The role of chemokines involved in the processes of neuroinflammation is not well understood in schizophrenia, especially in patients with the first episode of the disease. The aim of the study: to study the content of pro-inflammatory chemokines in the blood of patients with the first episode of paranoid schizophrenia. We examined 18 patients with a diagnosis of F20.09, the control group – 35 people. Determination of the content of 13 chemokines in blood serum was carried out by flow fluorometry. Blood sampling was carried out before the start of therapy. In patients with the first episode of schizophrenia before the appointment of therapy, an increase in the blood level of CCL4 (MIP-1β) by 1.1 times, CXCL9 (MIG) – by 1.4 times, CCL11 (Eotaxin), CXCL5 (ENA-78), CXCL10 (IP-10) – 1.5 times, CXCL1 (GRO-α) – 1.6 times, СCL20 (MIP-3α) – 2.1 times, CXCL8 (IL-8) – 21.0 times. The results obtained indicate the importance of neuroimmune inflammation in the manifestation of schizophrenia with the involvement of chemokines in this process.

Bidirectional Mendelian Randomisation Analysis Provides Evidence for the Causal Involvement of Dysregulation of CXCL9, CCL11 and CASP8 in the Pathogenesis of Ulcerative Colitis.

Systemic inflammation is well recognised to be associated with ulcerative colitis [UC], but whether these effects are causal or consequential remains unclear. We aimed to define potential causal relationship of cytokine dysregulation with different tiers of evidence. We first synthesised serum proteomic profiling data from two multicentred observational studies, in which a panel of systemic inflammatory proteins was analysed to examine their associations with UC risk. To further dissect observed associations, we then performed a bidirectional two-sample Mendelian randomisation [TSMR] analysis from both forward and reverse directions using five genome-wide association study [GWAS] summary level data for serum proteomic profiles and the largest GWAS of 28 738 European-ancestry individuals for UC risk. Pooled analysis of serum proteomic data identified 14 proteins to be associated with the risk of UC. Forward MR analysis using only cis-acting protein quantitative trait loci [cis-pQTLs] or trans-pQTLs further validated causal associations of two chemokines and the increased risk of UC: C-X-C motif chemokine ligand 9 [CXCL9] [OR 1.45, 95% CI 1.08, 1.95, p = 0.012] and C-C motif chemokine ligand 11 [CCL11] [OR 1.14, 95% CI 1.09, 1.18, p = 3.89 × 10-10]. Using both cis- and trans-acting pQTLs, an association of caspase-8 [CASP8] [OR 1.04, 95% CI 1.03, 1.05, p = 7.63 × 10-19] was additionally identified. Reverse MR did not find any influence of genetic predisposition to UC on any of these three inflammation proteins. Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.

Association between the expression of toll-like receptors, cytokines, and homeostatic chemokines in SARS-CoV-2 infection and COVID-19 severity

The recent identification of the involvement of the immune system response in the severity and mortality of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection highlights the importance of cytokines and chemokines as important factors in the clinical outcomes of COVID-19. However, the impact and roles of the BAFF/APRIL cytokine system, homeostatic chemokines (CXCL12, CXCL13, CCL19, and CCL21), as well as Toll-like receptor (TLR)-3/4 in COVID-19, have not been investigated. We sought to assess the expression levels and roles of TLR3/4, BAFF, APRIL, IFN-β, homeostatic chemokines (CXCL12, CXCL13, CCL19, and CCL21), SARS-CoV-2 IgG and IgM antibodies in patients with critical (ICU) and non-ICU (mild) COVID-19 and their association with mortality and disease severity. Significant high levels of TLR-4 mRNA, IFN-β, APRIL, CXCL13, and IgM and IgG antibodies were observed in ICU patients with severe COVID-19 compared to non-ICU COVID-19 patients and healthy controls. On the other hand, BAFF and CCL21 expression were significantly upregulated in non-ICU patients with COVID-19 compared with that in critical COVID-19 patients. The two groups did not differ in TLR-3, CXCL12, and CCL19 levels. Our findings show high expression levels of some inflammatory chemokines in ICU patients with COVID-19. These findings highlight the potential utility of chemokine antagonists as an immune-based treatment for the severe form of COVID-19. We also believe that selective targeting of TLR/spike protein interactions might lead to the development of a new COVID-19 therapy.

Peripheral Inflammatory Markers TNF-α and CCL2 Revisited: Association with Parkinson’s Disease Severity

One of the major mediators of neuroinflammation in PD is tumour necrosis factor alpha (TNF-α), which, similar to other cytokines, is produced by activated microglia and astrocytes. Although TNF-α can be neuroprotective in the brain, long-term neuroinflammation and TNF release can be harmful, having a neurotoxic role that leads to death of oligodendrocytes, astrocytes, and neurons and, therefore, is associated with neurodegeneration. Apart from cytokines, a wide family of molecules with homologous structures, namely chemokines, play a key role in neuro-inflammation by drawing cytotoxic T-lymphocytes and activating microglia. The objective of the current study was to examine the levels of the serum TNF-α and CCL2 (Chemokine (C-C motif) ligand 2), also known as MCP-1 (Monocyte Chemoattractant Protein-1), in PD patients compared with healthy controls. We also investigated the associations between the serum levels of these two inflammatory mediators and a number of clinical symptoms, in particular, disease severity and cognition. Such an assessment may point to their prognostic value and provide some treatment hints. PD patients with advanced stage on the Hoehn-Yahr scale showed an increase in TNF-α levels compared with PD patients with stages 1 and 2 (p = 0.01). Additionally, the UPDRS score was significantly associated with TNF-α levels. CCL2 levels, however, showed no significant associations.