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1.
Respir Res ; 25(1): 119, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38459541

RESUMO

BACKGROUND: The pattern recognition receptor Dectin-1 was initially discovered to play a pivotal role in mediating pulmonary antifungal immunity and promoting neutrophil-driven inflammation. Recent studies have revealed that Dectin-1 is overexpressed in asthma, but the specific mechanism remains elusive. Additionally, Dectin-1 has been implicated in promoting pyroptosis, a hallmark of severe asthma airway inflammation. Nevertheless, the involvement of the non-classical pyroptosis signal caspase-11/4 and its upstream regulatory mechanisms in asthma has not been completely explored. METHODS: House dust mite (HDM)-induced mice was treated with Dectin-1 agonist Curdlan, Dectin-1 inhibitor Laminarin, and caspase-11 inhibitor wedelolactone separately. Subsequently, inflammatory cells in bronchoalveolar lavage fluid (BALF) were analyzed. Western blotting was performed to measure the protein expression of caspase-11 and gasdermin D (GSDMD). Cell pyroptosis and the expression of chemokine were detected in vitro. The correlation between Dectin-1 expression, pyroptosis factors and neutrophils in the induced sputum of asthma patients was analyzed. RESULTS: Curdlan appeared to exacerbate neutrophil airway inflammation in asthmatic mice, whereas wedelolactone effectively alleviated airway inflammation aggravated by Curdlan. Moreover, Curdlan enhanced the release of caspase-11 activation fragments and N-terminal fragments of gasdermin D (GSDMD-N) stimulated by HDM both in vivo or in vitro. In mouse alveolar macrophages (MH-S cells), Curdlan/HDM stimulation resulted in vacuolar degeneration and elevated lactate dehydrogenase (LDH) release. In addition, there was an upregulation of neutrophil chemokines CXCL1, CXCL3, CXCL5 and their receptor CXCR2, which was suppressed by wedelolactone. In asthma patients, a positive correlation was observed between the expression of Dectin-1 on macrophages and caspase-4 (the human homology of caspase-11), and the proportion of neutrophils in induced sputum. CONCLUSION: Dectin-1 activation in asthma induced caspase-11/4 mediated macrophage pyroptosis, which subsequently stimulated the secretion of chemokines, leading to the exacerbation of airway neutrophil inflammation.


Assuntos
Asma , Lectinas Tipo C , Neutrófilos , Animais , Humanos , Camundongos , Asma/metabolismo , Caspases/metabolismo , Quimiocinas/metabolismo , Gasderminas , Inflamação/metabolismo , Pulmão/metabolismo , Macrófagos/metabolismo , Neutrófilos/metabolismo , Pyroglyphidae , Piroptose
2.
Front Cell Infect Microbiol ; 14: 1308362, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38476167

RESUMO

Infectious peritonitis is a leading cause of peritoneal functional impairment and a primary factor for therapy discontinuation in peritoneal dialysis (PD) patients. Although bacterial infections are a common cause of peritonitis episodes, emerging evidence suggests a role for viral pathogens. Toll-like receptors (TLRs) specifically recognize conserved pathogen-associated molecular patterns (PAMPs) from bacteria, viruses, and fungi, thereby orchestrating the ensuing inflammatory/immune responses. Among TLRs, TLR3 recognizes viral dsRNA and triggers antiviral response cascades upon activation. Epigenetic regulation, mediated by histone deacetylase (HDAC), has been demonstrated to control several cellular functions in response to various extracellular stimuli. Employing epigenetic target modulators, such as epidrugs, is a current therapeutic option in several cancers and holds promise in treating viral diseases. This study aims to elucidate the impact of TLR3 stimulation on the plasticity of human mesothelial cells (MCs) in PD patients and to investigate the effects of HDAC1-3 inhibition. Treatment of MCs from PD patients with the TLR3 agonist polyinosinic:polycytidylic acid (Poly(I:C)), led to the acquisition of a bona fide mesothelial-to-mesenchymal transition (MMT) characterized by the upregulation of mesenchymal genes and loss of epithelial-like features. Moreover, Poly(I:C) modulated the expression of several inflammatory cytokines and chemokines. A quantitative proteomic analysis of MCs treated with MS-275, an HDAC1-3 inhibitor, unveiled altered expression of several proteins, including inflammatory cytokines/chemokines and interferon-stimulated genes (ISGs). Treatment with MS-275 facilitated MMT reversal and inhibited the interferon signature, which was associated with reduced STAT1 phosphorylation. However, the modulation of inflammatory cytokine/chemokine production was not univocal, as IL-6 and CXCL8 were augmented while TNF-α and CXCL10 were decreased. Collectively, our findings underline the significance of viral infections in acquiring a mesenchymal-like phenotype by MCs and the potential consequences of virus-associated peritonitis episodes for PD patients. The observed promotion of MMT reversal and interferon response inhibition by an HDAC1-3 inhibitor, albeit without a general impact on inflammatory cytokine production, has translational implications deserving further analysis.


Assuntos
Benzamidas , Interferon Tipo I , Peritonite , Piridinas , Viroses , Humanos , Interferon Tipo I/metabolismo , Receptor 3 Toll-Like/metabolismo , Epigênese Genética , Proteômica , Citocinas/metabolismo , Quimiocinas/metabolismo , Poli I-C/farmacologia , Receptores Toll-Like/metabolismo , Viroses/genética , Fenótipo , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo
3.
Exp Biol Med (Maywood) ; 249: 10120, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38463392

RESUMO

Neuroinflammation is considered a balanced inflammatory response important in the intrinsic repair process after injury or infection. Under chronic states of disease, injury, or infection, persistent neuroinflammation results in a heightened presence of cytokines, chemokines, and reactive oxygen species that result in tissue damage. In the CNS, the surrounding microglia normally contain macrophages and other innate immune cells that perform active immune surveillance. The resulting cytokines produced by these macrophages affect the growth, development, and responsiveness of the microglia present in both white and gray matter regions of the CNS. Controlling the levels of these cytokines ultimately improves neurocognitive function and results in the repair of lesions associated with neurologic disease. MicroRNAs (miRNAs) are master regulators of the genome and subsequently control the activity of inflammatory responses crucial in sustaining a robust and acute immunological response towards an acute infection while dampening pathways that result in heightened levels of cytokines and chemokines associated with chronic neuroinflammation. Numerous reports have directly implicated miRNAs in controlling the abundance and activity of interleukins, TGF-B, NF-kB, and toll-like receptor-signaling intrinsically linked with the development of neurological disorders such as Parkinson's, ALS, epilepsy, Alzheimer's, and neuromuscular degeneration. This review is focused on discussing the role miRNAs play in regulating or initiating these chronic neurological states, many of which maintain the level and/or activity of neuron-specific secondary messengers. Dysregulated miRNAs present in the microglia, astrocytes, oligodendrocytes, and epididymal cells, contribute to an overall glial-specific inflammatory niche that impacts the activity of neuronal conductivity, signaling action potentials, neurotransmitter robustness, neuron-neuron specific communication, and neuron-muscular connections. Understanding which miRNAs regulate microglial activation is a crucial step forward in developing non-coding RNA-based therapeutics to treat and potentially correct the behavioral and cognitive deficits typically found in patients suffering from chronic neuroinflammation.


Assuntos
MicroRNAs , Doenças do Sistema Nervoso , Humanos , Doenças Neuroinflamatórias , Doenças do Sistema Nervoso/genética , Microglia/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Citocinas/metabolismo , Quimiocinas/metabolismo
4.
J Clin Immunol ; 44(3): 77, 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38451335

RESUMO

PURPOSE: To assess the role of the interleukin (IL)-17 A/IL-17 receptor A (IL-17RA) in Kawasaki disease (KD)-related coronary arteritis (CA). METHODS: In human study, the plasma levels of IL-17 A and coronary arteries were concurrently examined in acute KD patients. In vitro responses of human coronary endothelial cells to plasma stimulation were investigated with and without IL-17RA neutralization. A murine model of Lactobacillus casei cell-wall extract (LCWE)-induced CA using wild-type Balb/c and Il17ra-deficient mice were also inspected. RESULTS: The plasma levels of IL-17 A were significantly higher in KD patients before intravenous immunoglobulin therapy, especially in those with coronary artery lesion. The pre-IVIG IL-17 A levels positively correlated with maximal z scores of coronary diameters and plasma-induced endothelial mRNA levels of chemokine (C-X-C motif) ligand-1, IL-8, and IL-17RA. IL-17RA blockade significantly reduced such endothelial upregulations of aforementioned three genes and inducible nitric oxide synthase, and neutrophil transmigration. IL-17RA expression was enhanced on peripheral blood mononuclear cells in pre-IVIG KD patients, and in the aortic rings and spleens of the LCWE-stimulated mice. LCWE-induced CA composed of dual-positive Ly6G- and IL-17 A-stained infiltrates. Il17ra-deficient mice showed reduced CA severity with the fewer number of neutrophils and lower early inducible nitric oxide synthase and chemokine (C-X-C motif) ligand-1 mRNA expressions than Il17ra+/+ littermates, and absent IL-17RA upregulation at aortic roots. CONCLUSION: IL-17 A/IL-17RA axis may play a role in mediating aortic neutrophil chemoattraction, thus contributory to the severity of CA in both humans and mice. These findings may help to develop a new therapeutic strategy toward ameliorating KD-related CA.


Assuntos
Arterite , Síndrome de Linfonodos Mucocutâneos , Humanos , Animais , Camundongos , Infiltração de Neutrófilos , Óxido Nítrico Sintase Tipo II , Receptores de Interleucina-17/genética , Células Endoteliais , Imunoglobulinas Intravenosas , Interleucina-17 , Leucócitos Mononucleares , Ligantes , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Quimiocinas , RNA Mensageiro
5.
Medicine (Baltimore) ; 103(11): e37484, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38489730

RESUMO

Colorectal cancer (CRC) is one of the most prevalent types of malignant tumors. It's vital to explore new biomarkers and potential therapeutic targets in CRC lung metastasis through adopting integrated bioinformatics tools. Multiple cohort datasets and databases were integrated to clarify and verify potential key candidate biomarkers and signal transduction pathways in CRC lung metastasis. DAVID, STRING, UALCAN, GEPIA, TIMER, cBioPortal, THE HUMAN PROTEIN ATLAS, GSEA 4.3.2, FUNRICH 3.1.3, and R 4.2.3 were utilized in this study. The enriched biological processes and pathways modulated by the differentially expressed genes (DEGs) were determined with Gene Ontology, Kyoto Encyclopedia of Genes and Genomes. The search tool Retrieval of Interacting Genes and Cytoscape were used to construct a protein-protein interaction network among DEGs. Four hundred fifty-nine colorectal primary cancer and lung metastatic gene expression profiles were screened from 3 gene expression profiles (GSE41258, GSE68468, and GSE41568). Forty-one upregulated genes and 8 downregulated genes were identified from these 3 gene expression profiles and verified by the transcriptional levels of hub genes in other GEO datasets and The Cancer Genome Atlas database. Two pathways (immune responses and chemokine receptors bind chemokines), 13 key DEGs, 6 hub genes (MMP3, SFTPD, ABCA3, CLU, APOE, and SPP1), and 2 biomarkers (APOE, SPP1) with significantly prognostic values were screened. Forty-nine DEGs were identified as potential candidate diagnostic biomarkers for patients with CRC lung metastasis in present study. Enrichment analysis indicated that immune responses and chemokine receptors bind chemokines may play a leading role in lung metastasis of CRC, and further studies are needed to validate these findings.


Assuntos
Neoplasias Colorretais , Neoplasias Pulmonares , Humanos , Prognóstico , Perfilação da Expressão Gênica , Biomarcadores , Neoplasias Pulmonares/genética , Neoplasias Colorretais/genética , Receptores de Quimiocinas/genética , Receptores de Quimiocinas/metabolismo , Quimiocinas/metabolismo , Apolipoproteínas E/genética , Biologia Computacional , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica
6.
Inhal Toxicol ; 36(2): 106-123, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38477125

RESUMO

OBJECTIVE: Occupational exposure to respirable crystalline silica (cSiO2) has been linked to lupus development. Previous studies in young lupus-prone mice revealed that intranasal cSiO2 exposure triggered autoimmunity, preventable with docosahexaenoic acid (DHA). This study explores cSiO2 and DHA effects in mature lupus-prone adult mice, more representative of cSiO2-exposed worker age. METHODS: Female NZBWF1 mice (14-week old) were fed control (CON) or DHA-supplemented diets. After two weeks, mice were intranasally instilled saline (VEH) or 1 mg cSiO2 weekly for four weeks. Cohorts were then analyzed 1- and 5-weeks postinstillation for lung inflammation, cell counts, chemokines, histopathology, B- and T-cell infiltration, autoantibodies, and gene signatures, with results correlated to autoimmune glomerulonephritis onset. RESULTS: VEH/CON mice showed no pathology. cSiO2/CON mice displayed significant ectopic lymphoid tissue formation in lungs at 1 week, increasing by 5 weeks. cSiO2/CON lungs exhibited elevated cellularity, chemokines, CD3+ T-cells, CD45R + B-cells, IgG + plasma cells, gene expression, IgG autoantibodies, and glomerular hypertrophy. DHA supplementation mitigated all these effects. DISCUSSION: The mature adult NZBWF1 mouse used here represents a life-stage coincident with immunological tolerance breach and one that more appropriately represents the age (20-30 yr) of cSiO2-exposed workers. cSiO2-induced robust pulmonary inflammation, autoantibody responses, and glomerulonephritis in mature adult mice, surpassing effects observed previously in young adults. DHA at a human-equivalent dosage effectively countered cSiO2-induced inflammation/autoimmunity in mature mice, mirroring protective effects in young mice. CONCLUSION: These results highlight life-stage significance in this preclinical lupus model and underscore omega-3 fatty acids' therapeutic potential against toxicant-triggered autoimmune responses.


Assuntos
Ácidos Graxos Ômega-3 , Glomerulonefrite , Pneumonia , Feminino , Camundongos , Humanos , Animais , Ácidos Graxos Ômega-3/toxicidade , Autoimunidade , Dióxido de Silício/toxicidade , Pneumonia/induzido quimicamente , Glomerulonefrite/induzido quimicamente , Glomerulonefrite/metabolismo , Glomerulonefrite/patologia , Ácidos Docosa-Hexaenoicos/toxicidade , Quimiocinas/toxicidade , Autoanticorpos , Imunoglobulina G
7.
Sci Adv ; 10(11): eadh9547, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38489372

RESUMO

Solid tumors, especially those with aberrant MYCN activation, often harbor an immunosuppressive microenvironment to fuel malignant growth and trigger treatment resistance. Despite this knowledge, there are no effective strategies to tackle this problem. We found that chemokine-like factor (CKLF) is highly expressed by various solid tumor cells and transcriptionally up-regulated by MYCN. Using the MYCN-driven high-risk neuroblastoma as a model system, we demonstrated that as early as the premalignant stage, tumor cells secrete CKLF to attract CCR4-expressing CD4+ cells, inducing immunosuppression and tumor aggression. Genetic depletion of CD4+ T regulatory cells abolishes the immunorestrictive and protumorigenic effects of CKLF. Our work supports that disrupting CKLF-mediated cross-talk between tumor and CD4+ suppressor cells represents a promising immunotherapeutic approach to battling MYCN-driven tumors.


Assuntos
Quimiocinas , Proteínas com Domínio MARVEL , Proteína Proto-Oncogênica N-Myc , Neuroblastoma , Humanos , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas com Domínio MARVEL/metabolismo , Proteína Proto-Oncogênica N-Myc/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/patologia , Neuroblastoma/terapia , Microambiente Tumoral
8.
Cell Commun Signal ; 22(1): 177, 2024 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-38475811

RESUMO

BACKGROUND: The incidence of multiple myeloma (MM), a type of blood cancer affecting monoclonal plasma cells, is rising. Although new drugs and therapies have improved patient outcomes, MM remains incurable. Recent studies have highlighted the crucial role of the chemokine network in MM's pathological mechanism. Gaining a better understanding of this network and creating an overview of chemokines in MM could aid in identifying potential biomarkers and developing new therapeutic strategies and targets. PURPOSE: To summarize the complicated role of chemokines in MM, discuss their potential as biomarkers, and introduce several treatments based on chemokines. METHODS: Pubmed, Web of Science, ICTRP, and Clinical Trials were searched for articles and research related to chemokines. Publications published within the last 5 years are selected. RESULTS: Malignant cells can utilize chemokines, including CCL2, CCL3, CCL5, CXCL7, CXCL8, CXCL12, and CXCL13 to evade apoptosis triggered by immune cells or medication, escape from bone marrow and escalate bone lesions. Other chemokines, including CXCL4, CCL19, and CXCL10, may aid in recruiting immune cells, increasing their cytotoxicity against cancer cells, and inducing apoptosis of malignant cells. CONCLUSION: Utilizing anti-tumor chemokines or blocking pro-tumor chemokines may provide new therapeutic strategies for managing MM. Inspired by developed CXCR4 antagonists, including plerixafor, ulocuplumab, and motixafortide, more small molecular antagonists or antibodies for pro-tumor chemokine ligands and their receptors can be developed and used in clinical practice. Along with inhibiting pro-tumor chemokines, studies suggest combining chemokines with chimeric antigen receptor (CAR)-T therapy is promising and efficient.


Assuntos
Compostos Heterocíclicos , Mieloma Múltiplo , Humanos , Mobilização de Células-Tronco Hematopoéticas , Quimiocinas , Transdução de Sinais , Biomarcadores
9.
Psychiatry Res ; 334: 115812, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38442479

RESUMO

This research assessed the effects of adverse childhood experiences (ACEs) and negative life events (NLEs) on forty-eight cytokines/chemokines/growth factors, in 71 FE-MDMD patients and forty heathy controls. ACEs are highly significantly associated with the classical M1 macrophage, T helper (Th)-1, Th-1 polarization, IRS, and neurotoxicity immune profiles, and not with the alternative M2, and Th-2 immune profiles. There are highly significant correlations between ACEs and NLEs and different cytokines/chemokines/growth factors, especially with interleukin (IL)-16, CCL27, stem cell growth factor, and platelet-derived growth factor. Partial Least Squares analysis showed that 62.3 % of the variance in the depression phenome (based on severity of depression, anxiety and suicidal behaviors) was explained by the regression on IL-4 (p = 0.001, inversely), the sum of ACEs + NLEs (p < 0.0001), and a vector extracted from 10 cytokines/chemokines/growth factors (p < 0.0001; both positively associated). The latter partially mediated (p < 0.0001) the effects of ACE + NLEs on the depression phenome. In conclusion, part of the effects of ACEs and NLEs on the depression phenome is mediated via activation of immune and growth factor networks. These pathways have a stronger impact in subjects with lowered activities of the compensatory immune-regulatory system.


Assuntos
Experiências Adversas da Infância , Transtorno Depressivo Maior , Humanos , Depressão , Ideação Suicida , Transtorno Depressivo Maior/genética , Citocinas , Quimiocinas
10.
PLoS One ; 19(3): e0300461, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38512862

RESUMO

Polycystic ovary syndrome (PCOS), a common endocrine and metabolic disorder affecting women in their reproductive years. Emerging evidence suggests that the maternal-fetal immune system is crucial for proper pregnancy. However, whether immune function is altered at the end of pregnancy in PCOS women and the underlying molecular mechanisms is currently unexplored. Herein, the basic maternal immune system was investigated (n = 136 in the control group; n = 103 in the PCOS group), and whole-transcriptome sequencing was carried out to quantify the mRNAs, miRNAs, and lncRNAs expression levels in fetal side placental tissue of women with PCOS. GO, KEGG, and GSEA analysis were employed for functional enrichment analysis. The process of identifying hub genes was conducted utilizing the protein-protein interaction network. CIBERSORT and Connectivity Map were deployed to determine immune cell infiltration and predict potential drugs, respectively. A network of mRNA-miRNA-lncRNA was constructed and then validated by qRT-PCR. First, red blood cell count, neutrophil count, lymphocyte count, hypersensitive C-reactive protein, and procalcitonin were significantly elevated, while placental growth factor was hindered in PCOS women. We identified 308 DEmRNAs, 77 DEmiRNAs, and 332 DElncRNAs in PCOS samples. Functional enrichment analysis revealed that there were significant changes observed in terms of the immune system, especially the chemokine pathway. Eight genes, including FOS, JUN, EGR1, CXCL10, CXCR1, CXCR2, CXCL11, and CXCL8, were considered as hub genes. Furthermore, the degree of infiltration of neutrophils was dramatically decreased in PCOS tissues. In total, 57 ceRNA events were finally obtained, and immune-related ceRNA networks were validated. Some potential drug candidates, such as enalapril and RS-100329, could have a function in PCOS therapy. This study represents the inaugural attempt to evaluate the immune system at the end of pregnancy and placental ceRNA networks in PCOS, indicating alterations in the chemokine pathway, which may impact fetal and placental growth, and provides new therapy targets.


Assuntos
MicroRNAs , Síndrome do Ovário Policístico , RNA Longo não Codificante , Humanos , Feminino , Gravidez , Síndrome do Ovário Policístico/genética , Síndrome do Ovário Policístico/metabolismo , Placenta/metabolismo , Fator de Crescimento Placentário/genética , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Quimiocinas/genética , RNA Longo não Codificante/genética , Redes Reguladoras de Genes
11.
BMC Immunol ; 25(1): 20, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38515019

RESUMO

BACKGROUND: The human interleukin-17 (IL-17) family comprises IL-17A to IL-17 F; their receptors are IL-17RA to IL-17RE. Evidence revealed that these cytokines can have a tumor-supportive or anti-tumor impact on human malignancies. The purpose of this study was to assess the expression of CXCR2, IL-17RA, and IL-17RC genes at the mRNA level as well as tissue and serum levels of IL-17A, vascular endothelial growth factor (VEGF), and transforming growth factor ß (TGF-ß) in patients with bladder cancer (BC) compared to control. RESULTS: This study showed that gene expression of IL-17RA, IL-17RC, and CXCR2 in the tumoral tissue of BC patients was significantly upregulated compared with normal tissue. The findings disclosed a significant difference in the serum and tissue concentrations of IL-17A, VEGF, and TGF-ß between the patient and the control groups, as well as tumor and normal tissues. CONCLUSION: This study reveals notable dysregulation of CXCR2, IL-17RA, and IL-17RC genes, alongside changes in IL-17A, VEGF, and TGF-ß levels in patients with BC than in controls. These findings indicate their possible involvement in BC development and their potential as diagnostic and therapeutic targets.


Assuntos
Interleucina-17 , Neoplasias da Bexiga Urinária , Humanos , Interleucina-17/genética , Interleucina-17/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismo , Quimiocinas , Neoplasias da Bexiga Urinária/genética , Fator de Crescimento Transformador beta
12.
J Cell Mol Med ; 28(7): e18193, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38506205

RESUMO

Colorectal cancer (CRC) liver metastasis, albeit a stage-IV disease, is completely curable by surgical resection in selected patients. In addressing the molecular basics of this phenomenon, differentially expressed genes at primary and liver metastatic sites were screened by RNA sequencing with the use of paraffin-embedded surgical specimens. Chemokine C-C motif ligand 1 (CCL1), a chemotactic factor for a ligand of the chemokine C-C motif receptor 8 (CCR8), was isolated as one of the differentially expressed genes. Histological analysis revealed that the number of CCL1-positive cells, mainly tumour associated macrophages (TAMs) located in the stroma of CRC, decreased significantly at liver metastatic sites, while the expression level of CCR8 on CRC remained unchanged. To explore the biological significance of the CCL1-CCR8 axis in CRC, CCR8-positive CRC cell line Colo320DM was used to assess the effect of the CCL1-CCR8 axis on major signalling pathways, epithelial mesenchymal transition induction and cell motility. Upon stimulation of recombinant CCL1 (rCCL1), phosphorylation of AKT was observed in Colo320DM cells; on the other hand, the corresponding significant increase in MMP-2 levels demonstrated by RT-qPCR was nullified by siRNA (siCCR8). In the scratch test, rCCL1 treatment significantly increased the motility of Colo320DM cells, which was similarly nullified by siCCR8. Thus, the activation of the CCL1-CCR8 axis is a positive regulator of CRC tumour progression. Reduced CCL1 expression of TAMs at liver metastatic sites may partly explain the unique slow tumour progression of CRC, thus providing for a grace period for radical resection of metastatic lesions.


Assuntos
Neoplasias Colorretais , Fígado , Humanos , Quimiocina CCL1 , Ligantes , Fígado/metabolismo , Quimiocinas , Receptores de Quimiocinas/metabolismo , Neoplasias Colorretais/genética
13.
World J Urol ; 42(1): 173, 2024 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-38507059

RESUMO

PURPOSE: To identify predictive factors for satisfactory treatment outcome of the patients with IC/BPS using urine biomarkers and machine-learning models. METHODS: The IC/BPS patients were prospectively enrolled and provide urine samples. The targeted analytes included inflammatory cytokines, neurotrophins, and oxidative stress biomarkers. The patients with overall subjective symptom improvement of ≥ 50% were considered to have satisfactory results. Binary logistic regression, receiver-operating characteristic (ROC) curve, machine-learning decision tree, and random forest models were used to analyze urinary biomarkers to predict satisfactory results. RESULTS: Altogether, 57.4% of the 291 IC/BPS patients obtained satisfactory results. The patients with satisfactory results had lower levels of baseline urinary inflammatory cytokines and oxidative biomarkers than patients without satisfying results, including interleukin-6, monocyte chemoattractant protein-1 (MCP-1), C-X-C motif chemokine 10 (CXCL10), oxidative stress biomarkers 8-hydroxy-2'-deoxyguanosine (8-OHDG), 8-isoprostane, and total antioxidant capacity (TAC). Logistic regression and multivariable analysis revealed that lower levels of urinary CXCL10, MCP-1, 8-OHDG, and 8-isoprostane were independent factors. The ROC curve revealed that MCP-1 level had best area under curve (AUC: 0.797). In machine-learning decision tree model, combination of urinary C-C motif chemokine 5, 8-isoprostane, TAC, MCP-1, and 8-OHDG could predict satisfactory results (accuracy: 0.81). The random forest model revealed that urinary 8-isoprostance, MCP-1, and 8-OHDG levels had the most important influence on accuracy. CONCLUSION: Machine learning decision tree model provided a higher accuracy for predicting treatment outcome of patients with IC/BPS than logistic regression, and levels of 8-isoprostance, MCP-1, and 8-OHDG had the most important influence on accuracy.


Assuntos
Cistite Intersticial , Humanos , Cistite Intersticial/diagnóstico , Biomarcadores/urina , Quimiocinas , Citocinas , Resultado do Tratamento , Antioxidantes
14.
Front Immunol ; 15: 1359555, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38510248

RESUMO

Background: Latent tuberculosis (TB) infection can progress to active TB, which perpetuates community transmission that undermines global TB control efforts. Clinically, interferon-γ release assays (IGRAs) are commonly used for active TB case detection. However, low IGRA sensitivity rates lead to false-negative results for a high proportion of active TB cases, thus highlighting IGRA ineffectiveness in differentiating MTB-infected individuals from healthy individuals. Methods: Participants enrolled at Beijing Chest Hospital from May 2020-April 2022 were assigned to healthy control (HC), LTBI, IGRA-positive TB, and IGRA-negative TB groups. Screening cohort MTB antigen-specific blood plasma chemokine concentrations were measured using Luminex xMAP assays then were verified via testing of validation cohort samples. Results: A total of 302 individuals meeting study inclusion criteria were assigned to screening and validation cohorts. Testing revealed significant differences in blood plasma levels of CXCL9, CXCL10, CXCL16, CXCL21, CCL1, CCL19, CCL27, TNF-α, and IL-4 between IGRA-negative TB and HC groups. Levels of CXCL9, CXCL10, IL-2, and CCL8 biomarkers were predictive for active TB, as reflected by AUC values of ≥0.9. CXCL9-based enzyme-linked immunosorbent assay sensitivity and specificity rates were 95.9% (95%CI: 91.7-98.3) and 100.0% (92.7-100.0), respectively. Statistically similar AUC values were obtained for CXCL9 and CXCL9-CXCL10 assays, thus demonstrating that combined analysis of CXCL10 and CXCL9 levels did not improve active TB diagnostic performance. Conclusion: The MTB antigen stimulation-based CXCL9 assay may compensate for low IGRA diagnostic accuracy when used to diagnose IGRA-negative active TB cases and thus is an accurate and sensitive alternative to IGRAs for detecting MTB infection.


Assuntos
Tuberculose Latente , Mycobacterium tuberculosis , Tuberculose , Humanos , Interferon gama , Antígenos , Quimiocinas , Biomarcadores
15.
Front Immunol ; 15: 1331322, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38487542

RESUMO

Vγ9Vδ2 T cells represent a promising cancer therapy platform because the implementation of allogenic, off-the-shelf product candidates is possible. However, intravenous administration of human Vγ9Vδ2 T cells manufactured under good manufacturing practice (GMP)-compliant, serum-free conditions are not tested easily in most mouse models, mainly because they lack the ability to migrate from the blood to tissues or tumors. We demonstrate that these T cells do not migrate from the circulation to the mouse bone marrow (BM), the site of many malignancies. Thus, there is a need to better characterize human γδ T-cell migration in vivo and develop strategies to direct these cells to in vivo sites of therapeutic interest. To better understand the migration of these cells and possibly influence their migration, NSG mice were conditioned with agents to clear BM cellular compartments, i.e., busulfan or total body irradiation (TBI), or promote T-cell migration to inflamed BM, i.e., incomplete Freund's adjuvant (IFA), prior to administering γδ T cells. Conditioning with TBI, unlike busulfan or IFA, increases the percentage and number of γδ T cells accumulating in the mouse BM, and cells in the peripheral blood (PB) and BM display identical surface protein profiles. To better understand the mechanism by which cells migrate to the BM, mice were conditioned with TBI and administered γδ T cells or tracker-stained red blood cells. The mechanism by which γδ T cells enter the BM after radiation is passive migration from the circulation, not homing. We tested if these ex vivo-expanded cells can migrate based on chemokine expression patterns and showed that it is possible to initiate homing by utilizing highly expressed chemokine receptors on the expanded γδ T cells. γδ T cells highly express CCR2, which provides chemokine attraction to C-C motif chemokine ligand 2 (CCL2)-expressing cells. IFNγ-primed mesenchymal stromal cells (MSCs) (γMSCs) express CCL2, and we developed in vitro and in vivo models to test γδ T-cell homing to CCL2-expressing cells. Using an established neuroblastoma NSG mouse model, we show that intratumorally-injected γMSCs increase the homing of γδ T cells to this tumor. These studies provide insight into the migration of serum-free, ex vivo-expanded Vγ9Vδ2 T cells in NSG mice, which is critical to understanding the fundamental properties of these cells.


Assuntos
Neuroblastoma , Receptores de Antígenos de Linfócitos T gama-delta , Humanos , Camundongos , Animais , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Bussulfano , Quimiocinas , Receptores de Quimiocinas
16.
Sci Signal ; 17(828): eabl3758, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38502733

RESUMO

CXCL17 is a chemokine principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, and its expression is increased during viral infections of the lung. However, the exact role of CXCL17 in health and disease requires further investigation, and there is a need for confirmed molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET)-based assays, here we demonstrated that CXCL17 inhibited CXCR4-mediated signaling and ligand binding. Moreover, CXCL17 interacted with neuropillin-1, a VEGFR2 coreceptor. In addition, we found that CXCL17 only inhibited CXCR4 ligand binding in intact cells and demonstrated that this effect was mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. Disruption of putative GAG binding domains in CXCL17 prevented CXCR4 binding. This indicated that CXCL17 inhibited CXCR4 by a mechanism of action that potentially required the presence of a glycosaminoglycan-containing accessory protein. Together, our results revealed that CXCL17 is an endogenous inhibitor of CXCR4 and represents the next step in our understanding of the function of CXCL17 and regulation of CXCR4 signaling.


Assuntos
Quimiocinas CXC , Glicosaminoglicanos , Quimiocinas CXC/metabolismo , Glicosaminoglicanos/farmacologia , Ligantes , Quimiocinas/metabolismo , Transdução de Sinais , Receptores CXCR4/genética , Quimiocina CXCL12
17.
Cytokine ; 177: 156565, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38442443

RESUMO

BACKGROUND: Perinatal hypoxia triggers the release of cytokines and chemokines by neurons, astrocytes and microglia. In response to hypoxia-ischemia resting/ramified microglia proliferate and undergo activation, producing proinflammatory molecules. The brain damage extension seems to be related to both the severity of hypoxia and the balance between pro and anti-inflammatory response and can be explored with neuroimaging. AIMS: The aim of this preliminary study was to explore possible relationships between plasma levels of inflammatory cytokines/chemokines and the severe brain damage detectable by Magnetic Resonance Imaging (MRI), performed during the hospitalization. METHODS: In 10 full terms neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH), divided into cases and controls, according to MRI results, we measured and compared the plasma levels of CCL2/MCP-1, CXCL8, GFAP, IFN y, IL-10, IL-18, IL-6, CCL3, ENOLASE2, GM-CSF, IL-1b, IL-12p70, IL-33, TNFα, collected at four different time points during TH (24, 25-48, 49-72 h of life, and 7-10 days from birth). Five of enrolled babies had pathological brain MRI (cases) and 5 had a normal MRI examination (controls). Cytokines were measured by Magnetic Luminex Assay. MRI images were classified according to Barkovich's score. RESULTS: Mean levels of all cytokines and molecules at time T1 were not significantly different in the two groups. Comparing samples paired by day of collection, the greatest differences between cases and controls were found at times T2 and T3, during TH. At T4, levels tended to get closer again (except for IL-6, IL10 and IL18). Infants with worse MRI showed higher plasmatic GFAP levels than those with normal MRI, while their IL-18 was lower. The mean levels of CCL3MIP1alpha, GMCSF, IL1BETA overlapped throughout the observation period in both groups. CONCLUSION: In a small number of infants with worse brain MRI, we found higher levels of GFAP and of IL-10 at T4 and a trend toward low IL-18 levels than in infants with normal MRI, considered early biomarker of brain damage and a predictor of adverse outcome, respectively. The greatest, although not significant, difference between the levels of molecules was found in cases and controls at time points T2 and T3, during TH.


Assuntos
Lesões Encefálicas , Hipóxia-Isquemia Encefálica , Recém-Nascido , Lactente , Feminino , Gravidez , Humanos , Hipóxia-Isquemia Encefálica/diagnóstico por imagem , Citocinas/metabolismo , Interleucina-10/metabolismo , Interleucina-18/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Interleucina-6/metabolismo , Encéfalo/metabolismo , Imageamento por Ressonância Magnética/métodos , Quimiocinas/metabolismo , Neuroimagem
18.
Cancer Med ; 13(4): e6940, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38457216

RESUMO

BACKGROUND: Tumor metastasis is responsible for the high mortality rate of patients with oral squamous cell carcinoma (OSCC). Although many hypotheses have been proposed to elucidate the mechanism of tumor metastasis, the origin of the metastatic tumor cells remains unclear. In this study, we explored the role of cell fusion in the formation of OSCC metastatic tumor cells. METHODS: Murine OSCC tumor cells and macrophages were fused in vitro, and the cell proliferation, migration, and phagocytosis abilities of hybrid cells and parental cells were compared. Subsequently, we compared the transcriptome differences between hybrid and parental cells. RESULTS: Murine OSCC tumor cells and macrophages were successfully fused in vitro. The cytological and molecular experimental results revealed that OSCC tumor cells obtained a migration-related phenotype after fusion with macrophages, and the migration ability of hybrid cells was related to the activation of the "chemokine signal pathway". CONCLUSION: After fusion with macrophages, the chemokine signaling pathway in OSCC tumor cells was activated, leading to metastasis.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Humanos , Animais , Camundongos , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Neoplasias Bucais/patologia , Fusão Celular , Linhagem Celular Tumoral , Movimento Celular/genética , Transdução de Sinais/genética , Macrófagos/metabolismo , Quimiocinas/metabolismo , Neoplasias de Cabeça e Pescoço/patologia
19.
Viruses ; 16(2)2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38400076

RESUMO

There is great enthusiasm toward the development of novel immunotherapies for the treatment of cancer, and given their roles in immune system regulation, chemokines stand out as promising candidates for use in new cancer therapies. Many previous studies have shown how chemokine signaling pathways could be targeted to halt cancer progression. We and others have revealed that the chemokine CXCL14 promotes antitumor immune responses, suggesting that CXCL14 may be effective for cancer immunotherapy. However, it is still unknown what mechanism governs CXCL14-mediated antitumor activity, how to deliver CXCL14, what dose to apply, and what combinations with existing therapy may boost antitumor immune responses in cancer patients. Here, we provide updates on the role of CXCL14 in cancer progression and discuss the potential development and application of CXCL14 as an immunotherapeutic agent.


Assuntos
Quimiocinas , Neoplasias , Humanos , Quimiocinas CXC , Imunoterapia , Neoplasias/terapia , Neoplasias/patologia
20.
Immun Inflamm Dis ; 12(2): e1167, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38415923

RESUMO

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), a causative pathogen of the COVID-19 pandemic, affects all age groups. However, various studies have shown that COVID-19 presentation and severity vary considerably with age. We, therefore, wanted to examine the differences between the immune responses of children with COVID-19 and elderly COVID-19 individuals. METHODS: We analyzed cytokines, chemokines, growth factors, and acute phase proteins in acute and convalescent COVID-19 children and the elderly with acute and convalescent COVID-19. RESULTS: We show that most of the pro-inflammatory cytokines (interferon [IFN]γ, interleukin [IL]-2, tumor necrosis factor-α [TNFα], IL-1α, IFNα, IFNß, IL-6, IL-12, IL-3, IL-7, IL-1Ra, IL-13, and IL-10), chemokines (CCL4, CCL11, CCL19, CXCL1, CXCL2, CXCL8, and CXL10), growth factors (vascular endothelial growth factor and CD40L) and acute phase proteins (C-reactive protein, serum amyloid P, and haptoglobin) were decreased in children with acute COVID 19 as compared with elderly individuals. In contrast, children with acute COVID-19 exhibited elevated levels of cytokines- IL-1ß, IL-33, IL-4, IL-5, and IL-25, growth factors-fibroblast growth factor-2, platelet- derived growth factors-BB, and transforming growth factorα as compared with elderly individuals. Similar, differences were manifest in children and elderly with convalescent COVID-19. CONCLUSION: Thus, COVID-19 children are characterized by distinct cytokine/chemokine/growth factor/acute phase protein markers that are markedly different from elderly COVID-19 individuals.


Assuntos
COVID-19 , Criança , Idoso , Humanos , COVID-19/terapia , Pandemias , SARS-CoV-2 , Fator A de Crescimento do Endotélio Vascular , Citocinas , Proteínas de Fase Aguda , Quimiocinas
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