Safety and effectiveness of mogamulizumab in relapsed or refractory CC chemokine receptor 4-positive peripheral T-cell lymphoma and relapsed or refractory cutaneous T-cell lymphoma: A post-marketing surveillance in Japan.

Mogamulizumab is a humanized antibody targeting CC chemokine receptor 4 (CCR4). This post-marketing surveillance was conducted in Japan as a regulatory requirement from 2014 to 2020 to ensure the safety and effectiveness of mogamulizumab in patients with relapsed or refractory (r/r) CCR4-positive peripheral T-cell lymphoma (PTCL) or r/r cutaneous T-cell lymphoma (CTCL). Safety and effectiveness data were collected for up to 31 weeks after treatment initiation. A total of 142 patients were registered; safety was evaluated in 136 patients. The median number of doses was 8.0 (range, 1-18). The main reasons for treatment termination were insufficient response (22.1%) and adverse events (13.2%). The frequency of any grade adverse drug reaction was 57.4%, including skin disorders (26.5%), infections and immune system disorders (16.2%), and infusion-related reactions (13.2%). Graft-versus-host disease, grade 2, developed in one of two patients who underwent allogeneic-hematopoietic stem cell transplantation after receiving mogamulizumab. Effectiveness was evaluated in 131 patients (103 with PTCL; 28 with CTCL). The best overall response rate was 45.8% (PTCL, 47.6%; CTCL, 39.3%). At week 31, the survival rate was 69.0% (95% confidence interval, 59.8%-76.5%) [PTCL, 64.4% (54.0%-73.0%); CTCL, 90.5% (67.0%-97.5%)]. Safety and effectiveness were comparable between patients <70 and ≥ 70 years old and between those with relapsed and refractory disease. The safety and effectiveness of mogamulizumab for PTCL and CTCL in the real world were comparable with the data reported in previous clinical trials. Clinical Trial Registration.

Targeting CCR3 with antagonist SB 328437 sensitizes 5­fluorouracil­resistant gastric cancer cells: Experimental evidence and computational insights.

Gastric cancer (GC) ranks fifth globally in cancer diagnoses and third for cancer-related deaths. Chemotherapy with 5-fluorouracil (5-FU), a primary treatment, faces challenges due to the development of chemoresistance. Tumor microenvironment factors, including C-C motif chemokine receptor 3 (CCR3), can contribute to chemoresistance. The present study evaluated the effect of CCR3 receptor inhibition using the antagonist SB 328437 and the molecular dynamics of this interaction on resistance to 5-FU in gastric cancer cells. The 5-FU-resistant AGS cell line (AGS R-5FU) demonstrated notable tolerance to higher concentrations of 5-FU, with a 2.6-fold increase compared with the parental AGS cell line. Furthermore, the mRNA expression levels of thymidylate synthase (TS), a molecular marker for 5-FU resistance, were significantly elevated in AGS R-5FU cells. CCR3 was shown to be expressed at significantly higher levels in these resistant cells. Combining SB 328437 with 5-FU resulted in a significant decrease in cell viability, particularly at higher concentrations of 5-FU. Furthermore, when SB 328437 was combined with 5-FU at a high concentration, the relative mRNA expression levels of CCR3 and TS decreased significantly. Computational analysis of CCR3 demonstrated dynamic conformational changes, especially in extracellular loop 2 region, which indicated potential alterations in ligand recognition. Docking simulations demonstrated that SB 328437 bound to the allosteric site of CCR3, inducing a conformational change in ECL2 and hindering ligand recognition. The present study provides comprehensive information on the molecular and structural aspects of 5-FU resistance and CCR3 modulation, highlighting the potential for therapeutic application of SB 328437 in GC treatment.

CB-0821, a novel CC chemokine receptor 5 (CCR5) inhibitor with improved binding efficacy proposed as anti-HIV candidate: Computational and in vitro approach.

The CC chemokine receptor 5 (CCR5) serves a pivotal role in human immunodeficiency virus 1 (HIV-1) infection by acting as a co-receptor and facilitating the binding of the viral envelope glycoprotein (env). Maraviroc (MVC), a Food and Drug Administration-approved monocarboxylic acid amide, is one of the CCR5 inhibitors employed in HIV treatment. Despite the existence of approved drugs, the emergence of drug resistance underscores the necessity for novel compounds to combat resistance and enhance therapeutic efficacy. In this study, CB-0821, identified from the ChemBridge library, emerged as a promising CCR5 inhibitor. Molecular dynamics simulations indicate comparable dynamic properties for CB-0821 and MVC. In silico comparisons with other CCR5 inhibitors emphasize CB-0821's superior binding affinity, positioning it as a potential lead compound. Evaluations of the dissociation constant (Ki) and absorption, distribution, metabolism, and excretion predictions suggest CB-0821 as a well-tolerated drug. Furthermore, the dose-dependent inhibition of CCR5 by CB-0821 in Peripheral blood mononuclear cells (PBMCs) (ranging from 10 to 200 nM) demonstrates efficacy, coupled with nontoxicity to Vero cells at concentrations up to 500 nM. These results underscore the potential of CB-0821 in HIV antiviral therapy, calling for additional preclinical validations before advancing to clinical considerations.

Association of CCR6 functional polymorphisms with Primary Biliary Cholangitis.

The biliary epithelial cells release CC chemokine receptor 6 (CCR6) ligand 20 (CCL20), leading to recruitment of CCR6+ T cells and subsequent infiltration into the biliary epithelium in primary biliary cholangitis patients. Previous genome-wide multi-national meta-analysis, including our Han Chinese cohort, showed significant association of CCR6 and CCL20 single nucleotide polymorphisms (SNP) with PBC. We report here that significantly associated SNPs, identified in the CCR6 locus based on our Han Chinese genome-wide association study, can be separated into "protective" and "risk" groups, but only "risk" SNPs were confirmed using a separate Han Chinese PBC cohort. Only weak association of CCL20 SNPs was observed in Han Chinese PBC cohorts. Fine-mapping and logistical analysis identified a previously defined functional variant that, leads to increased CCR6 expression, which contributed to increased genetic susceptibility to PBC in Han Chinese cohort.

Astragaloside IV targeting autophagy of T cells improves inflammation of asthma.

Astragaloside IV (AST) has been confirmed to have antiasthmatic effects. However, the underline mechanism is unclear. The study aimed to explore the treatment mechanism of AST based on autophagy of memory T cells. AST treatment significantly decreased the number of T effector cells in asthma mice blood and the nude mice that received AST-treated TCMs had relieved inflammation compared with the untreated group; meanwhile, we found that AST significantly decreased the autophagy level and inhibited OX40/OX40L signal pathway of lymphocytes. The results highlighted that AST regulated autophagy to inhibit differentiation of effector T-cell phenotype.

Profiling CCR3 target pathways for discovering novel antagonists from natural products using label-free cell phenotypic assays.

CC chemokine receptor 3 (CCR3) plays important roles in atopic dermatitis (AD) and other related allergic diseases. Activation of CCR3 receptor signaling pathways regulates the recruitment of eosinophils to related tissues, releasing inflammatory mediators and causing inflammatory responses. However, none of the known CCR3 antagonists exhibit promising efficacy in clinical trials. In this work, we sought new natural CCR3 antagonists for drug development. To construct a high-throughput screening model, we established a stably transfected CHO-K1-Gα15-CCR3 cell line, and receptor expression was demonstrated by real-time quantitative PCR, confocal detection and flow cytometry analysis. Then, we applied a label-free cell phenotyping technique to profile and deconvolute CCR3 target pathways in CHO-K1-Gα15-CCR3 cells and found that activation of CCR3 triggered the Gq-PLC-Ca2+ and MAPK-P38-ERK pathways. By in vitro and in silico experiments, we discovered a novel CCR3 antagonist emodin, with an IC50 value of 27.28 ± 1.71 µM out of 266 compounds that were identified in 15 traditional Chinese medicines used in the clinical treatment of skin diseases. Molecular docking graphically presented the binding mode of emodin on CCR3. This work reports a new approach for CCR3 antagonist screening and pathway detection and identifies a new antagonist that would benefit future drug development.

Studying allosteric regulation of chemokines and antagonists using a nanoscale hCCR3 receptor sensor.

CC chemokine receptor-3 (hCCR3), a G protein-coupled receptor (GPCR) expressed predominantly on eosinophils, is an important drug target. However, it was unclear how chemokine ligands, activators and antagonists recognize hCCR3, and quantitative measurements of hCCR3 inhibition or activation were rare. This study constructed a nanogold receptor sensor using hCCR3 as the molecular recognition element and horseradish peroxidase as the signal amplifier. We quantified the kinetic antagonism between chemokines and hCCR3 before and after adding hCCR3 antagonists. A molecular docking study was carried out to investigate how hCCR3 and its ligands work. The study results indicate chemokines interact with hCCR3 at low concentrations, and reversible hCCR3 inhibitors solely inhibit hCCR3, not CCLs. Moreover, a quantitative evaluation of hCCR3 chemokine activators and their antagonists was carried out using a directed weighted network. This offers a novel approach to quantitatively evaluate chemokine-receptor activation and antagonism together. This research could potentially offer new insights into the mechanisms of action of chemokines and drug screening.

CC chemokines and receptors in osteoarthritis: new insights and potential targets.

Osteoarthritis (OA) is a prevalent degenerative disease accompanied by the activation of innate and adaptive immune systems-associated inflammatory responses. Due to the local inflammation, the expression of various cytokines was altered in affected joints, including CC motif chemokine ligands (CCLs) and their receptors (CCRs). As essential members of chemokines, CCLs and CCRs played an important role in the pathogenesis and treatment of OA. The bindings between CCLs and CCRs on the chondrocyte membrane promoted chondrocyte apoptosis and the release of multiple matrix-degrading enzymes, which resulted in cartilage degradation. In addition, CCLs and CCRs had chemoattractant functions to attract various immune cells to osteoarthritic joints, further leading to the aggravation of local inflammation. Furthermore, in the nerve endings of joints, CCLs and CCRs, along with several cellular factors, contributed to pain hypersensitivity by releasing neurotransmitters in the spinal cord. Given this family's diverse and complex functions, targeting the functional network of CCLs and CCRs is a promising strategy for the prognosis and treatment of OA in the future.

CKLF1 interference alleviates IL­1ß­induced inflammation, apoptosis and degradation of the extracellular matrix in chondrocytes via CCR5.

Osteoarthritis (OA) is a type of joint disease with a rising prevalence and incidence among the elderly across the global population. Chemokine-like factor 1 (CKLF1) is a human cytokine, which has been demonstrated to be involved in the progression of multiple human diseases. However, little attention has been paid to the impact of CKLF1 on OA. The present study was designed to identify the role of CKLF1 in OA and to clarify the regulatory mechanism. The expression levels of CKLF1 and its receptor CC chemokine receptor 5 (CCR5) were examined by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. A Cell Counting Kit-8 assay was used to estimate cell viability. The levels and expression of inflammatory factors were determined by ELISA and RT-qPCR, respectively. Apoptosis was investigated by TUNEL assays and the protein levels of apoptosis-related factors were analyzed by western blotting. RT-qPCR and western blotting were used to examine the expression of extracellular matrix (ECM) degradation-associated proteins and ECM components. Dimethylmethylene blue analysis was used to analyze the production of soluble glycosamine sulfate additive. A co-immunoprecipitation assay was used to confirm the protein interaction between CKLF1 and CCR5. The results revealed that CKLF1 expression was increased in IL-1ß-exposed murine chondrogenic ATDC5 cells. Furthermore, CKLF1 silencing enhanced the viability of IL-1ß-induced ATDC5 cells, while inflammation, apoptosis and degradation of the ECM were reduced. Additionally, CKLF1 knockdown led to decreased CCR5 expression in IL-1ß-challenged ATDC5 cells, and CKLF1 bound with CCR5. The enhanced viability, as well as the suppressed inflammation, apoptosis and degradation of the ECM, following CKLF1 knockdown in the IL-1ß-induced ATDC5 cells were all restored after CCR5 was overexpressed. In conclusion, CKLF1 might serve a detrimental role in the development of OA by targeting its receptor CCR5.

M2 Macrophage-Derived sEV Regulate Pro-Inflammatory CCR2+ Macrophage Subpopulations to Favor Post-AMI Cardiac Repair.

Tissue-resident cardiac macrophage subsets mediate cardiac tissue inflammation and repair after acute myocardial infarction (AMI). CC chemokine receptor 2 (CCR2)-expressing macrophages have phenotypical similarities to M1-polarized macrophages, are pro-inflammatory, and recruit CCR2+ circulating monocytes to infarcted myocardium. Small extracellular vesicles (sEV) from CCR2̶ macrophages, which phenotypically resemble M2-polarized macrophages, promote anti-inflammatory activity and cardiac repair. Here, the authors harvested M2 macrophage-derived sEV (M2EV ) from M2-polarized bone-marrow-derived macrophages for intramyocardial injection and recapitulation of sEV-mediated anti-inflammatory activity in ischemic-reperfusion (I/R) injured hearts. Rats and pigs received sham surgery; I/R without treatment; or I/R with autologous M2EV treatment. M2EV rescued cardiac function and attenuated injury markers, infarct size, and scar size. M2EV inhibited CCR2+ macrophage numbers, reduced monocyte-derived CCR2+ macrophage recruitment to infarct sites, induced M1-to-M2 macrophage switching and promoted neovascularization. Analysis of M2EV microRNA content revealed abundant miR-181b-5p, which regulated macrophage glucose uptake, glycolysis, and mitigated mitochondrial reactive oxygen species generation. Functional blockade of miR-181b-5p is detrimental to beneficial M2EV actions and resulted in failure to inhibit CCR2+ macrophage numbers and infarct size. Taken together, this investigation showed that M2EV rescued myocardial function, improved myocardial repair, and regulated CCR2+ macrophages via miR-181b-5p-dependent mechanisms, indicating an option for cell-free therapy for AMI.

Scale down and optimized automated production of [68Ga]68Ga-DOTA-ECL1i PET tracer targeting CCR2 expression.

BACKGROUND: Recently it has been identified a short peptide that showed allosteric antagonism against C-C motif chemokine receptor 2 (CCR2) expressed on inflammatory monocyte and macrophages. A 7-D-amino acid peptidic CCR2 inhibitor called extracellular loop 1 inverso (ECL1i), d(LGTFLKC) has been identified and labeled to obtain a new probe for positron emission tomography in pulmonary fibrosis, heart injury, abdominal aortic aneurysm inflammation, atherosclerosis, head and neck cancer. Our goal was to develop, optimize and validate an automated synthesis method for [68Ga]68Ga-DOTA-ECL1i to make it available for a broader community. The synthesis of [68Ga]68Ga-DOTA-ECL1i was done using the Scintomics GRP® module with the already estabilished synthesis template for [68Ga]68Ga-DOTATOC/[68Ga]68Ga-PSMA. The radiopharmaceutical production was optimized scaling down the amount of DOTA-ECL1i (from 50 to 10 µg), evaluating synthesis efficiency and relevant quality control parameters in accordance with the European Pharmacopeia. RESULTS: Best results were yielded with 20 µg DOTA-ECL1i and then the process validation was carried out by producing three different batches on three different days obtaining an optimal radiochemical yield (66.69%) as well as radiochemical purity (100%) and molar activity (45.41 GBq/µmol). CONCLUSIONS: [68Ga]68Ga-DOTA-ECL1i was successfully synthesized and it is, thus, available for multi-dose application in clinical settings.

Impact of cancer-associated mutations in CC chemokine receptor 2 on receptor function and antagonism.

CC chemokine receptor 2 (CCR2), a G protein-coupled receptor, plays a role in many cancer-related processes such as metastasis formation and immunosuppression. Since âˆ¼ 20 % of human cancers contain mutations in G protein-coupled receptors, ten cancer-associated CCR2 mutants obtained from the Genome Data Commons were investigated for their effect on receptor functionality and antagonist binding. Mutations were selected based on either their vicinity to CCR2's orthosteric or allosteric binding sites or their presence in conserved amino acid motifs. One of the mutant receptors, namely S101P2.63 with a mutation near the orthosteric binding site, did not express on the cell surface. All other studied mutants showed a decrease in or a lack of G protein activation in response to the main endogenous CCR2 ligand CCL2, but no change in potency was observed. Furthermore, INCB3344 and LUF7482 were chosen as representative orthosteric and allosteric antagonists, respectively. No change in potency was observed in a functional assay, but mutations located at F1163.28 impacted orthosteric antagonist binding significantly, while allosteric antagonist binding was abolished for L134Q3.46 and D137N3.49 mutants. As CC chemokine receptor 2 is an attractive drug target in cancer, the negative effect of these mutations on receptor functionality and drugability should be considered in the drug discovery process.

CCR2 Imaging in Human ST-Segment Elevation Myocardial Infarction.

Among the diverse populations of myeloid cells that reside within the healthy and diseased heart, C-C chemokine receptor 2 (CCR2) is specifically expressed on inflammatory populations of monocytes and macrophages that contribute to the development and progression of heart failure1-4. Here, we evaluated a peptide-based imaging probe (64Cu-DOTA-ECL1i) that specifically recognizes CCR2+ monocytes and macrophages for human cardiac imaging. Compared to healthy controls, 64Cu-DOTA-ECL1i heart uptake was increased in subjects following acute myocardial infarction, predominately localized within the infarct area, and was associated with impaired myocardial wall motion. These findings establish the feasibility of molecular imaging of CCR2 expression to visualize inflammatory monocytes and macrophages in the injured human heart.

Impacts of isorhynchophylline on airway inflammation in asthmatic mice / 中国药房

OBJECTIVE To investigate the impacts of isorhynchophylline （IRN） on airway inflammation in asthmatic mice by regulating the monocyte chemotactic protein-1 （MCP-1）/CC chemokine receptor 2 （CCR2） signaling pathway. METHODS The asthmatic mice model was established by injecting and inhaling ovalbumin. The successfully modeled mice were randomly grouped into asthma group， IRN low-dose group （IRN-L， intragastric administration of 10 mg/kg IRN）， IRN high-dose group （IRN-H， intragastric administration of 20 mg/kg IRN）， IRN-H+CCL2 group [intragastric administration of 20 mg/kg IRN+intraperitoneal injection of 7.5 ng CC chemokine ligand 2 （CCL2）] and positive control group （intraperitoneal injection of 2 mg/kg dexamethasone）. The mice injected and inhaled with sterile phosphate-buffered solution were included in the blank control group， with 10 mice in each group. The mice in administration groups were given relevant medicine once a day， for consecutive 2 weeks. The levels of airway hyperreactivity indexes such as enhanced （Penh） value， tumor necrosis factor-α （TNF-α），interleukin-13 （IL-13） and IL-4 in serum， the number of eosinophil （EOS）， lymphocyte （LYM） and neutrophils （NEU） in alveolar lavage fluid and the protein expressions of MCP-1 and CCR2 in lung tissue were observed in each group； the pulmonary histopathological changes were observed， and inflammatory cell infiltration score was evaluated. RESULTS Compared with the blank control group， the infiltration of inflammatory cells in the lung tissue of mice was more significant in the asthma group， and there was swelling and shedding of cells； inflammatory infiltration score， Penh value， the levels of IL-4， IL-13 and TNF-α， the number of EOS， NEU and LYM， the protein expressions of MCP-1 and CCR2 were increased significantly （P＜0.05）. Compared with the asthma group， the pathological injuries of the IRN-L group， IRN-H group and positive control group were improved， and the above quantitative indexes were decreased significantly （P＜0.05）. Compared with the IRN-L group， the above quantitative indexes of the IRN-H group and positive control group were decreased significantly （P＜0.05）. There was no statistical significance in the above quantitative indexes between the IRN-H group and the positive control group （P＞0.05）. Compared with the IRN-H group， the above quantitative indexes of the IRN-H+CCL2 group were increased significantly （P＜0.05）. CCL2 reversed the protective effect of high-dose IRN on asthmatic mice. CONCLUSIONS IRN may reduce the release of airway inflammatory factors in asthmatic mice by inhibiting the activation of the MCP-1/CCR2 signaling pathway， so as to achieve the purpose of improving asthma.

Development of a human antibody that exhibits antagonistic activity toward CC chemokine receptor 7.

Background: CC chemokine receptor 7 (CCR7) is a member of G-protein-coupled receptor family and mediates chemotactic migration of immune cells and different cancer cells induced via chemokine (C-C motif) ligand 19 (CCL19) or chemokine (C-C motif) ligand 21 (CCL21). Hence, the identification of blockade antibodies against CCR7 could lead to the development of therapeutics targeting metastatic cancer. Methods: CCR7 was purified and stabilized in its active conformation, and antibodies specific to purified CCR7 were screened from the synthetic M13 phage library displaying humanized scFvs. The in vitro characterization of selected scFvs identified two scFvs that exhibited CCL19-competitive binding to CCR7. IgG4's harboring selected scFv sequences were characterized for binding activity in CCR7+ cells, inhibitory activity toward CCR7-dependent cAMP attenuation, and the CCL19 or CCL21-dependent migration of CCR7+ cells. Results: Antibodies specifically binding to purified CCR7 and CCR7+ cells were isolated and characterized. Two antibodies, IgG4(6RG11) and IgG4(72C7), showed ligand-dependent competitive binding to CCR7 with KD values of 40 nM and 50 nM, respectively. Particularly, IgG4(6RG11) showed antagonistic activity against CCR7, whereas both antibodies significantly blocked the ligand-induced migration and invasion activity of CCR7+ cancer cells. Conclusions: Two antibody clones were successfully identified from a synthetic scFv-displaying phage library using purified recombinant CCR7 as an antigen. Antibodies specifically bound to the surface of CCR7+ cells and blocked CCR7+ cell migration. Particularly, 6RG11 showed antagonist activity against CCR7-dependent cAMP attenuation.

The Multi-Functional Roles of CCR7 in Human Immunology and as a Promising Therapeutic Target for Cancer Therapeutics.

An important hallmark of the human immune system is to provide adaptive immunity against pathogens but tolerance toward self-antigens. The CC-chemokine receptor 7 (CCR7) provides a significant contribution in guiding cells to and within lymphoid organs and is important for acquiring immunity and tolerance. The CCR7 holds great importance in establishing thymic architecture and function and naïve and regulatory T-cell homing in the lymph nodes. Similarly, the receptor is a key regulator in cancer cell migration and the movement of dendritic cells. This makes the CCR7 an important receptor as a drug and prognostic marker. In this review, we discussed several biological roles of the CCR7 and its importance as a drug and prognostic marker.

Characterization and distribution of HIV-infected cells in semen.

Semen is a known vector for both human immunodeficiency virus (HIV) infection and transmission. However, the distribution and characteristics of HIV-infected cells in semen remain unclear. Investigating the possibility of transmission through the spermatozoon in semen is of great clinical significance to improve the strategies for exposure prevention and assisted reproduction for HIV-infected partners. Twenty-six HIV-infected patients, including twelve treatment-naïve (TN) patients and fourteen antiretroviral treated (ART) patients, were enrolled in this study. HIV p24 protein in spermatozoa was detected using imaging flow cytometry and immunohistochemistry, and HIV RNA was identified using next-generation RNAscope in situ hybridization. Additionally, we described the rates of HIV-positive spermatozoon and CD4+ T lymphocytes in semen, and found that p24+ spermatozoon were mainly CD4 negative regardless of whether the patients received ART. Of note, p24-positive cells in semen are predominantly spermatozoa, and we confirmed that motile spermatozoa carried HIV into peripheral blood mononuclear cells of healthy men in vitro. Our findings provide evidence regarding the risk of HIV-infected spermatozoa.

Role of CC Chemokine Ligand 17 in Mouse Models of Chronic Obstructive Pulmonary Disease.

Lung function deterioration is significantly associated with poor prognosis in patients with chronic obstructive pulmonary disease (COPD). We previously reported that CC chemokine ligand 17/thymus and activation-regulated chemokine (CCL17/TARC) could be a predictive factor of lung function decline in patients with COPD. However, the role of CCL17 in the pathogenesis of COPD is unclear. Here we examined the role of CCL17 in lung inflammation using mouse COPD models. Exposure to cigarette smoking induced CCL17 production in bronchial epithelial cells and accumulation of alveolar macrophages in the lungs. Intranasal administration of recombinant CCL17 further enhanced cigarette smoke-induced macrophage accumulation and also aggravated elastase-induced pulmonary emphysema. We confirmed that cigarette smoke (CS) extract as well as hydrogen peroxide upregulated CCL17 in BAES-2B cells. Of note, macrophages of both M1 and M2 surface markers were accumulated by cigarette smoke. Both alveolar macrophage accumulation via exposure to cigarette smoking and emphysematous changes induced by elastase administration were significantly reduced in CCL17-deficient mice. We further demonstrated that CCL17 strongly induced the expression of CC chemokine ligand 2 (CCL2), a chemoattractant for macrophages, in RAW264.7 cells, and its production was inhibited by knockdown of CCR4, the receptor of CCL17. Collectively, the present results demonstrate that CCL17 is produced by lung epithelial cells upon CS exposure. Furthermore, CCL17 is involved in CS-induced accumulation of alveolar macrophages and development of elastase-induced pulmonary emphysema, possibly through CCL17-induced production of CCL2 by macrophages. Our findings may provide a new insight into the pathogenesis of COPD.

MicroRNAs based regulation of cytokine regulating immune expressed genes and their transcription factors in COVID-19.

BACKGROUND: Coronavirus disease 2019 is characterized by the elevation of a broad spectrum of inflammatory mediators associated with poor disease outcomes. We aimed at an in-silico analysis of regulatory microRNA and their transcription factors (TF) for these inflammatory genes that may help to devise potential therapeutic strategies in the future. METHODS: The cytokine regulating immune-expressed genes (CRIEG) were sorted from literature and the GEO microarray dataset. Their co-differentially expressed miRNA and transcription factors were predicted from publicly available databases. Enrichment analysis was done through mienturnet, MiEAA, Gene Ontology, and pathways predicted by KEGG and Reactome pathways. Finally, the functional and regulatory features were analyzed and visualized through Cytoscape. RESULTS: Sixteen CRIEG were observed to have a significant protein-protein interaction network. The ontological analysis revealed significantly enriched pathways for biological processes, molecular functions, and cellular components. The search performed in the miRNA database yielded ten miRNAs that are significantly involved in regulating these genes and their transcription factors. CONCLUSION: An in-silico representation of a network involving miRNAs, CRIEGs, and TF, which take part in the inflammatory response in COVID-19, has been elucidated. Thus, these regulatory factors may have potentially critical roles in the inflammatory response in COVID-19 and may be explored further to develop targeted therapeutic strategies and mechanistic validation.