-
Journal of Crohn's & Colitis May 2023Systemic inflammation is well recognised to be associated with ulcerative colitis [UC], but whether these effects are causal or consequential remains unclear. We aimed...
Bidirectional Mendelian Randomisation Analysis Provides Evidence for the Causal Involvement of Dysregulation of CXCL9, CCL11 and CASP8 in the Pathogenesis of Ulcerative Colitis.
BACKGROUND AND AIMS
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.
METHODS
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.
RESULTS
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.
CONCLUSION
Pre-existing elevated levels of CXCL9, CCL11 and CASP8 may play a role in the pathogenesis of UC.
Topics: Humans; Colitis, Ulcerative; Genome-Wide Association Study; Caspase 8; Ligands; Proteomics; Chemokines; Inflammation; Polymorphism, Single Nucleotide; Chemokine CXCL9; Chemokine CCL11
PubMed: 36576886
DOI: 10.1093/ecco-jcc/jjac191 -
Biomolecules Feb 2023Idiopathic pulmonary fibrosis (IPF), characterized by progressive worsening of dyspnea and irreversible decline in lung function, is a chronic and progressive... (Review)
Review
Idiopathic pulmonary fibrosis (IPF), characterized by progressive worsening of dyspnea and irreversible decline in lung function, is a chronic and progressive respiratory disease with a poor prognosis. Chronic or repeated lung injury results in inflammation and an excessive injury-repairing response that drives the development of IPF. A number of studies have shown that the development and progression of IPF are associated with dysregulated expression of several chemokines and chemokine receptors, several of which have been used as predictors of IPF outcome. Chemokines of the CC family play significant roles in exacerbating IPF progression by immune cell attraction or fibroblast activation. Modulating levels of detrimental CC chemokines and interrupting the corresponding transduction axis by neutralizing antibodies or antagonists are potential treatment options for IPF. Here, we review the roles of different CC chemokines in the pathogenesis of IPF, and their potential use as biomarkers or therapeutic targets.
Topics: Humans; Chemokines, CC; Idiopathic Pulmonary Fibrosis; Lung; Chemokines; Inflammation; Fibroblasts
PubMed: 36830702
DOI: 10.3390/biom13020333 -
JCI Insight Jun 2023ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and...
ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2-knockout (Mdr2-/-) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis.
Topics: Animals; Humans; Mice; Chemokine CCL24; Cholangitis, Sclerosing; Cholestasis; Fibrosis; Inflammation; Liver
PubMed: 37345655
DOI: 10.1172/jci.insight.162270 -
PLoS Biology May 2023Atypical chemokine receptors (ACKRs) scavenge chemokines and can contribute to gradient formation by binding, internalizing, and delivering chemokines for lysosomal...
Atypical chemokine receptors (ACKRs) scavenge chemokines and can contribute to gradient formation by binding, internalizing, and delivering chemokines for lysosomal degradation. ACKRs do not couple to G-proteins and fail to induce typical signaling induced by chemokine receptors. ACKR3, which binds and scavenges CXCL12 and CXCL11, is known to be expressed in vascular endothelium, where it has immediate access to circulating chemokines. ACKR4, which binds and scavenges CCL19, CCL20, CCL21, CCL22, and CCL25, has also been detected in lymphatic and blood vessels of secondary lymphoid organs, where it clears chemokines to facilitate cell migration. Recently, GPR182, a novel ACKR-like scavenger receptor, has been identified and partially deorphanized. Multiple studies point towards the potential coexpression of these 3 ACKRs, which all interact with homeostatic chemokines, in defined cellular microenvironments of several organs. However, an extensive map of ACKR3, ACKR4, and GPR182 expression in mice has been missing. In order to reliably detect ACKR expression and coexpression, in the absence of specific anti-ACKR antibodies, we generated fluorescent reporter mice, ACKR3GFP/+, ACKR4GFP/+, GPR182mCherry/+, and engineered fluorescently labeled ACKR-selective chimeric chemokines for in vivo uptake. Our study on young healthy mice revealed unique and common expression patterns of ACKRs in primary and secondary lymphoid organs, small intestine, colon, liver, and kidney. Furthermore, using chimeric chemokines, we were able to detect distinct zonal expression and activity of ACKR4 and GPR182 in the liver, which suggests their cooperative relationship. This study provides a broad comparative view and a solid stepping stone for future functional explorations of ACKRs based on the microanatomical localization and distinct and cooperative roles of these powerful chemokine scavengers.
Topics: Animals; Mice; Chemokine CCL19; Signal Transduction; Cell Movement
PubMed: 37159457
DOI: 10.1371/journal.pbio.3002111 -
Virology Journal Jun 2021It has been reported that polyomaviruses are the microbes which can be a cause of several human pathological conditions including cancers, nephropathy, progressive... (Review)
Review
It has been reported that polyomaviruses are the microbes which can be a cause of several human pathological conditions including cancers, nephropathy, progressive multifocal leukoencephalopathy and gynaecological disease. Although investigators proposed some mechanisms used by the viruses to induce the disorders, the roles played by chemokines in the pathogenesis of polyomaviruses infections are yet to be clarified. This review article investigated recent studies regarding the roles played by chemokines in the pathogenesis of the polyomaviruses infections. The research in the literature revealed that CXC chemokines, including CXCL1, CXCL5, CXCL8, CXCL9, CXCL10, CXCL11, CXCL12 and CXCL16, significantly participate in the pathogenesis of polyomaviruses. CC chemokines, such as CCL2, CCL5 and CCL20 also participate in the induction of the pathological conditions. Therefore, it appears that CXC chemokines may be considered as the strategic factors involved in the pathogenesis of polyomaviruses.
Topics: Chemokines, CC; Chemokines, CXC; Humans; Polyomavirus; Polyomavirus Infections
PubMed: 34082771
DOI: 10.1186/s12985-021-01582-4 -
CCL17 and CCL22 chemokines are upregulated in human obesity and play a role in vascular dysfunction.Frontiers in Endocrinology 2023Chemokines are known to play critical roles mediating inflammation in many pathophysiological processes. The aim of this study was to investigate the role of chemokine...
BACKGROUND/AIMS
Chemokines are known to play critical roles mediating inflammation in many pathophysiological processes. The aim of this study was to investigate the role of chemokine receptor CCR4 and its ligands CCL17 and CCL22 in human morbid obesity.
METHODS
Circulating levels of CCL17 and CCL22 were measured in 60 morbidly obese patients (mean age, 45 ± 1 years; body mass index/BMI, 44 ± 1 kg/m) who had undergone bariatric bypass surgery, and 20 control subjects. Paired subcutaneous (SCAT) and visceral adipose tissue (VCAT) from patients were analysed to measure expression of CCR4 and its ligands by RT-PCR, western blot and immunohistochemical analysis. The effects of CCR4 neutralization on leukocyte-endothelial cells were also evaluated.
RESULTS
Compared with controls, morbidly obese patients presented higher circulating levels of CCL17 (p=0.029) and CCL22 (p<0.001) and this increase was positively correlated with BMI (p=0.013 and p=0.0016), and HOMA-IR Index (p=0.042 and p< 0.001). Upregulation of CCR4, CCL17 and CCL22 expression was detected in VCAT in comparison with SCAT (p<0.05). Using the parallel-plate flow chamber model, blockade of endothelial CCR4 function with the neutralizing antibody anti-CCR4 in morbidly obese patients significantly reduced leucocyte adhesiveness to dysfunctional endothelium, a key event in atherogenesis. Additionally, CCL17 and CCL22 increased activation of the ERK1/2 mitogen-activated protein kinase signalling pathway in human aortic endothelial cells, which was significantly reduced by CCR4 inhibition (p=0.016 and p<0.05).
CONCLUSION
Based on these findings, pharmacological modulation of the CCR4 axis could represent a new therapeutic approach to prevent adipose tissue dysfunction in obesity.
Topics: Humans; Adult; Middle Aged; Endothelial Cells; Obesity, Morbid; Chemokine CCL17; Chemokines; Signal Transduction; Receptors, Chemokine; Chemokine CCL22
PubMed: 37124725
DOI: 10.3389/fendo.2023.1154158 -
Journal of Leukocyte Biology Aug 2022Increased levels of the anti-inflammatory peptide Catestatin (CST), a cleavage product of the pro-hormone chromogranin A, correlate with less severe outcomes in...
Increased levels of the anti-inflammatory peptide Catestatin (CST), a cleavage product of the pro-hormone chromogranin A, correlate with less severe outcomes in hypertension, colitis, and diabetes. However, it is unknown how CST reduces the infiltration of monocytes and macrophages (Mϕs) in inflamed tissues. Here, it is reported that CST blocks leukocyte migration toward inflammatory chemokines. By in vitro and in vivo migration assays, it is shown that although CST itself is chemotactic, it blocks migration of monocytes and neutrophils to inflammatory attracting factor CC-chemokine ligand 2 (CCL2) and C-X-C motif chemokine ligand 2 (CXCL2). Moreover, it directs CX CR1 Mϕs away from pancreatic islets. These findings suggest that the anti-inflammatory actions of CST are partly caused by its regulation of chemotaxis.
Topics: Anti-Inflammatory Agents; Chemokine CCL2; Chemokines; Chemotaxis; Chemotaxis, Leukocyte; Chromogranin A; Ligands; Neutrophils; Peptide Fragments; Peptides
PubMed: 34939227
DOI: 10.1002/JLB.3CRA1220-790RR -
Cells Feb 2022C-C chemokine receptor 7 (CCR7) was one of the first two chemokine receptors that were found to be upregulated in breast cancers. Chemokine receptors promote chemotaxis... (Review)
Review
C-C chemokine receptor 7 (CCR7) was one of the first two chemokine receptors that were found to be upregulated in breast cancers. Chemokine receptors promote chemotaxis of cells and tissue organization. Since under homeostatic conditions, CCR7 promotes migration of immune cells to lymph nodes, questions immediately arose regarding the ability of CCR7 to direct migration of cancer cells to lymph nodes. The literature since 2000 was examined to determine to what extent the expression of CCR7 in malignant tumors promoted migration to the lymph nodes. The data indicated that in different cancers, CCR7 plays distinct roles in directing cells to lymph nodes, the skin or to the central nervous system. In certain tumors, it may even serve a protective role. Future studies should focus on defining mechanisms that differentially regulate the unfavorable or beneficial role that CCR7 plays in cancer pathophysiology, to be able to improve outcomes in patients who harbor CCR7-positive cancers.
Topics: Breast Neoplasms; Chemokines, CC; Chemotaxis; Female; Humans; Lymph Nodes; Receptors, CCR7
PubMed: 35203305
DOI: 10.3390/cells11040656 -
Cell Proliferation Jul 2023Appropriate responses to inflammation are conducive to pathogen elimination and tissue repair, while uncontrolled inflammatory reactions are likely to result in the... (Review)
Review
Appropriate responses to inflammation are conducive to pathogen elimination and tissue repair, while uncontrolled inflammatory reactions are likely to result in the damage of tissues. Chemokine (CC-motif) Ligand 2 (CCL2) is the main chemokine and activator of monocytes, macrophages, and neutrophils. CCL2 played a key role in amplifying and accelerating the inflammatory cascade and is closely related to chronic non-controllable inflammation (cirrhosis, neuropathic pain, insulin resistance, atherosclerosis, deforming arthritis, ischemic injury, cancer, etc.). The crucial regulatory roles of CCL2 may provide potential targets for the treatment of inflammatory diseases. Therefore, we presented a review of the regulatory mechanisms of CCL2. Gene expression is largely affected by the state of chromatin. Different epigenetic modifications, including DNA methylation, post-translational modification of histones, histone variants, ATP-dependent chromatin remodelling, and non-coding RNA, could affect the 'open' or 'closed' state of DNA, and then significantly affect the expression of target genes. Since most epigenetic modifications are proven to be reversible, targeting the epigenetic mechanisms of CCL2 is expected to be a promising therapeutic strategy for inflammatory diseases. This review focuses on the epigenetic regulation of CCL2 in inflammatory diseases.
Topics: Humans; Chemokine CCL2; Epigenesis, Genetic; Ligands; Chemokines; Inflammation
PubMed: 36872292
DOI: 10.1111/cpr.13428 -
Malaria Journal Nov 2022Eotaxin-1 concentrations in plasma have been inversely associated with malaria exposure, malaria infection and pregnancy, but the effect of these conditions on the...
BACKGROUND
Eotaxin-1 concentrations in plasma have been inversely associated with malaria exposure, malaria infection and pregnancy, but the effect of these conditions on the levels of the related chemokines eotaxin-2 and eotaxin-3 remains unknown.
METHODS
Eotaxin-2 and -3 concentrations were measured in 310 peripheral or placental plasma samples from pregnant and non-pregnant individuals from Papua New Guinea (malaria-endemic country) and Spain (malaria-naïve individuals) with previous data on eotaxin-1 concentrations. Correlations between eotaxin concentrations were examined with the Spearman's test. Differences in eotaxin concentrations among groups were evaluated with the Kruskal-Wallis or Mann Whitney tests. The pairwise Wilcoxon test was performed to compare eotaxin-2 concentration between peripheral and placental matched plasmas. Univariable and multivariable linear regression models were estimated to assess the association between eotaxins and Plasmodium infection or gestational age.
RESULTS
Eotaxin-2 concentrations in plasma showed a weak positive correlation with eotaxin-3 (rho = 0.35, p < 0.05) concentrations. Eotaxin-2 concentrations in the malaria-exposed non-pregnant group were significantly lower than the in the malaria-naive non-pregnant and the malaria-exposed pregnant groups. Eotaxin-3 plasma concentrations were lower in malaria-exposed than in non-exposed groups (p < 0.05), but no differences were found associated to pregnancy. Eotaxin-2 and eotaxin-3 plasma concentrations were negatively correlated with anti-Plasmodium IgG levels: PfDBL5ε-IgG (rho = - 0.35, p = 0.005; rho =- 0.37, p = 0.011), and eotaxin-3 was negatively correlated with PfDBL3x-IgG levels (rho =- 0.36; p = 0.011). Negative correlations of eotaxin-2 and 3 in plasma were also observed with atypical memory B cells (rho = - 0.37, p < 0.001; rho - 0.28, p = 0.006), a B cell subset expanded in malaria-exposed individuals. In addition, a borderline negative association was observed between eotaxin-3 concentrations and Plasmodium infection (adjusted effect estimate, β = - 0.279, 95% CI - 0.605; 0.047, p = 0.091). Moreover, eotaxin-2 placental concentrations were significantly increased compared to peripheral concentrations in the malaria-exposed pregnant group whereas the contrary was observed in the non-exposed pregnant group (p < 0.005).
CONCLUSION
Although a clear epidemiological negative association is observed between eotaxins concentrations and malaria exposure and/or infection, pregnancy may alter this association for eotaxin-2. Further research is required to understand the role of these chemokines in this disease and in combination with pregnancy.
Topics: Female; Humans; Pregnancy; Chemokine CCL11; Chemokine CCL24; Chemokine CCL26; Immunoglobulin G; Malaria; Malaria, Falciparum; Placenta; Plasmodium falciparum; Pregnancy Complications, Infectious; Pregnancy Complications, Parasitic
PubMed: 36380370
DOI: 10.1186/s12936-022-04372-7