RESUMEN
Primary sclerosing cholangitis (PSC) is a rare, progressive disease, characterized by inflammation and fibrosis of the bile ducts, lacking reliable prognostic biomarkers for disease activity. Machine learning applied to broad proteomic profiling of sera allowed for the discovery of markers of disease presence, severity, and cirrhosis and the exploration of the involvement of CCL24, a chemokine with fibro-inflammatory activity. Sera from 30 healthy controls and 45 PSC patients were profiled with proximity extension assay, quantifying the expression of 2870 proteins, and used to train an elastic net model. Proteins that contributed most to the model were tested for correlation to enhanced liver fibrosis (ELF) score and used to perform pathway analysis. Statistical modeling for the presence of cirrhosis was performed with principal component analysis (PCA), and receiver operating characteristics (ROC) curves were used to assess the useability of potential biomarkers. The model successfully predicted the presence of PSC, where the top-ranked proteins were associated with cell adhesion, immune response, and inflammation, and each had an area under receiver operator characteristic (AUROC) curve greater than 0.9 for disease presence and greater than 0.8 for ELF score. Pathway analysis showed enrichment for functions associated with PSC, overlapping with pathways enriched in patients with high levels of CCL24. Patients with cirrhosis showed higher levels of CCL24. This data-driven approach to characterize PSC and its severity highlights potential serum protein biomarkers and the importance of CCL24 in the disease, implying its therapeutic potential in PSC.
Asunto(s)
Biomarcadores , Quimiocina CCL24 , Colangitis Esclerosante , Cirrosis Hepática , Aprendizaje Automático , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores/sangre , Estudios de Casos y Controles , Quimiocina CCL24/metabolismo , Quimiocina CCL24/sangre , Colangitis Esclerosante/sangre , Colangitis Esclerosante/metabolismo , Progresión de la Enfermedad , Cirrosis Hepática/sangre , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Proteómica/métodos , Curva ROCRESUMEN
INTRODUCTION: Eotaxin-2 and -3 of the C-C chemokine subfamily function as potent chemoattractant factors for eosinophil recruitment and various immune responses in allergic and inflammatory airway diseases. Mucin 5AC (MUC5AC), a major gel-forming secretory mucin, is overexpressed in airway inflammation. However, the association between mucin secretion and eotaxin-2/3 expression in the upper and lower airway epithelial cells has not been fully elucidated. Therefore, in this study, we investigated the effects of eotaxin-2/3 on MUC5AC expression and its potential signaling mediators. METHODS: We analyzed the effects of eotaxin-2 and -3 on NCI-H292 human airway epithelial cells and primary human nasal epithelial cells (HNEpCs) via reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and western blotting. Along with immunoblot analyses with specific inhibitors and small interfering RNA (siRNA), we explored the signaling pathway involved in MUC5AC expression following eotaxin-2/3 treatment. RESULTS: In HCI-H292 cells, eotaxin-2/3 activated the mRNA expression and protein production of MUC5AC. A specific inhibitor of C-C motif chemokine receptor 3 (CCR3), SB328437, suppressed eotaxin-2/3-induced MUC5AC expression at both the mRNA and protein levels. Eotaxin-2/3 induced the phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 and p38, whereas pretreatment with a CCR3 inhibitor significantly attenuated this effect. Induction of MUC5AC expression with eotaxin-2/3 was decreased by U0126 and SB203580, specific inhibitors of ERK1/2 and p38 mitogen-activated protein kinase (MAPK), respectively. In addition, cell transfection with ERK1/2 and p38 siRNAs inhibited eotaxin-2/3-induced MUC5AC expression. Moreover, specific inhibitors (SB328437, U0126, and SB203580) attenuated eotaxin-2/3-induced MUC5AC expression in HNEpCs. CONCLUSION: Our results imply that CCR3-mediated ERK1/2 and p38 MAPK are involved in the signal transduction of eotaxin-2/3-induced MUC5AC overexpression.
Asunto(s)
Mucina 5AC , Proteínas Quinasas p38 Activadas por Mitógenos , Humanos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Línea Celular , Mucina 5AC/genética , Mucina 5AC/metabolismo , Quimiocina CCL24/metabolismo , Quimiocina CCL24/farmacología , Quimiocina CCL26/metabolismo , Transducción de Señal , Células Epiteliales/metabolismo , Receptores de Quimiocina/metabolismo , ARN Mensajero/metabolismoRESUMEN
AIMS: We aimed to investigate the effect and mechanism of pleiotropic chemokine CCL24 in heart failure. METHODS AND RESULTS: Compared with normal donators, the expression of CCL24 and number of cardiac M2 macrophages in heart were higher in heart failure patients, the same as plasma CCL24. Treatment with CCL24 antibody hindered Ang II (1500 ng/kg/min)-induced cardiac adverse remodeling through preventing cardiac hypertrophy and fibrosis. RNA-seq showed that CCL24/CCR3 axis was involved in immune and inflammatory responses. Single-cell analysis of cytometry by time of flight (CyTOF) revealed that CCL24 antibody decreased the M2 macrophage and monocyte polarization during Ang II stimulation. Immunofluorescence co-localization analysis confirmed the expression of CCR3 in macrophage and fibroblasts. Then, in vitro experiments confirmed that CCL24/CCR3 axis was also involved in cardiac primary fibroblast activation through its G protein-coupled receptor function. CONCLUSION: CCL24/CCR3 axis plays a crucial part in cardiac remodeling by stimulating M2 macrophage polarization and cardiac fibroblast activation. Cardiac M2 macrophages, CCL24 and circulation CCL24 increased in heart failure patients. Treatment with CCL24 Ab hindered Ang II induced cardiac structural dysfunction and electrical remodeling. In CCL24 Ab group RNA-seq found that it was related to immune responses and hypertrophic cardiomyopathy, CytoF revealed M2 macrophages and monocytes decreased obviously. In vitro,CCL24 promoted activation and migration of cardiac fibroblast.
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Angiotensina II , Insuficiencia Cardíaca , Humanos , Animales , Ratones , Quimiocina CCL24/metabolismo , Angiotensina II/farmacología , Angiotensina II/metabolismo , Macrófagos/metabolismo , Insuficiencia Cardíaca/metabolismo , Fibroblastos , Ratones Endogámicos C57BL , Receptores CCR3/metabolismoRESUMEN
OBJECTIVE: Oligoarticular JIA disease progression and outcomes are variable. Our objective is to detect protein markers that would allow for earlier intervention to potentially halt disease progression. In this retrospective study of serial SF samples, elevated expression of CCL24, CXCL9 and CXCL10 was linked to the eventual need for advanced medications. METHODS: Serial SF samples were selected from patients with persistent and extended oligoarticular JIA. The samples were separated into two groups: those who did and did not receive advanced medications throughout their disease course. Protein antibody arrays and Luminex assays were performed to determine changes in protein expression. RESULTS: CCL24, CXCL9 and CXCL10 expression levels were significantly higher in patients who eventually required advanced treatment than in those who did not. The expression levels of CCL24 and CXCL9 were consistently elevated in paired samples of those who later received advanced medications. In the persistent oligoarticular JIA group, CXCL10 levels remained elevated over time in those who required advanced treatment. Conversely, CCL24 levels decreased in patients who did not require advanced treatment. In the extended samples, the levels of CCL24 and CXCL10 expression increased significantly over time in the patients who ultimately required advanced treatment. CONCLUSION: In patients with oligoarticular JIA, regardless of disease onset and progression, the consistent elevation of any or all three markers, the CCL24, CXCL9 and CXCL10 in SFs was associated with the future use of advanced therapy, which could be reflective of disease severity.
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Artritis Juvenil , Líquido Sinovial , Humanos , Líquido Sinovial/metabolismo , Artritis Juvenil/diagnóstico , Estudios Retrospectivos , Progresión de la Enfermedad , Quimiocina CXCL9/metabolismo , Quimiocina CXCL10/metabolismo , Quimiocina CCL24/metabolismoRESUMEN
The majority of lung diseases occur with a sex bias in terms of prevalence and/or severity. Previous studies demonstrated that, compared with males, female mice develop greater eosinophilic inflammation in the airways after multiwalled carbon nanotube (MWCNT) exposure. However, the mechanism by which this sex bias occurs is unknown. Two immune cells that could account for the sex bias are type II innate lymphoid cells (ILC2s) and alveolar macrophages (AMs). In order to determine which immune cell type was responsible for MWCNT-induced airway eosinophil recruitment and subsequent sex differences in inflammation and disease, male and female C57BL/6 mice were exposed to MWCNTs (2 mg/kg) via oropharyngeal aspiration, and the respiratory immune response was assessed 7 d later. Greater eosinophilia and eotaxin 2 levels were observed in MWCNT-treated females and corresponded with greater changes in airway hyperresponsiveness than those in MWCNT-treated males. In MWCNT-treated females, there was a significant increase in the frequency of ILC2s within the lungs compared with control animals. However, depletion of ILC2s via α-CD90.2 administration did not decrease eosinophil recruitment 24 h and 7 d after MWCNT exposure. AMs isolated from control and MWCNT-treated animals demonstrated that M2a macrophage phenotype gene expression, ex vivo cytokine production, and activation of (p)STAT6 were upregulated to a significantly greater degree in MWCNT-treated females than in males. Our findings suggest that sex differences in AM phenotype development, not ILC2 signaling, are responsible for the observed female bias in eosinophilic inflammation after MWCNT inhalation.
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Eosinófilos/inmunología , Inflamación/inmunología , Pulmón/inmunología , Linfocitos/inmunología , Macrófagos Alveolares/inmunología , Caracteres Sexuales , Animales , Diferenciación Celular , Quimiocina CCL24/metabolismo , Citocinas/metabolismo , Exposición a Riesgos Ambientales/efectos adversos , Femenino , Inmunidad Innata , Activación de Macrófagos , Masculino , Ratones , Ratones Endogámicos C57BL , Nanotubos de Carbono/efectos adversos , Transducción de Señal , Células Th2/inmunologíaRESUMEN
BACKGROUND: Histiocytic sarcoma (HS) is a rare neoplasm showing morphological and immunophenotypic features of mature tissue histiocytes. We report a patient with nodal HS exhibiting prominent reactive eosinophilic infiltration. CASE PRESENTATION: A 68-year-old man presented with intermittent left lower abdominal pain and weight loss over 3 months. A computed tomography scan revealed multiple abdominal nodules. Open biopsy of the mesenteric tumors was performed for definitive diagnosis. Histologically, the tumor was comprised of a diffuse noncohesive proliferation of pleomorphic large cells, including multinucleated cells. Neoplastic cells were positive for histiocytic markers (CD68, CD163, and LIGHT) and PD-L1 but lacked markers of Langerhans cells, follicular dendritic cells, and epithelial cells. Frequent reactive inflammatory cells were intermingled in the background. Interestingly, prominent eosinophilic infiltration was also noted. Spindle neoplastic cells were prone to be present around areas with little to no eosinophilic infiltration and exhibiting fibrosis and lymphatic vessel proliferation. Conversely, polygonal neoplastic cells were prone to be present around areas with relatively large amounts of eosinophilic infiltration without fibrosis or lymphatic vessel proliferation. Immunohistochemically, the tumor cells and reactive eosinophils expressed eotaxin-2 and eotaxin-3, respectively. CONCLUSION: We revealed that eotaxins induced the selective migration of eosinophils into tissues in this case. These eosinophils may affect the tumor remodeling and tumor biology characteristics of HS, such as fibrosis and lymphatic vessel proliferation.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Quimiocina CCL24/metabolismo , Sarcoma Histiocítico/diagnóstico por imagen , Anciano , Biopsia , Eosinófilos/patología , Histiocitos/metabolismo , Sarcoma Histiocítico/patología , Humanos , Inmunohistoquímica , Inmunofenotipificación , Masculino , Tomografía Computarizada por Rayos XRESUMEN
Sarcoidosis is a genetically complex systemic inflammatory disease that affects multiple organs. We present a GWAS of a Japanese cohort (700 sarcoidosis cases and 886 controls) with replication in independent samples from Japan (931 cases and 1,042 controls) and the Czech Republic (265 cases and 264 controls). We identified three loci outside the HLA complex, CCL24, STYXL1-SRRM3, and C1orf141-IL23R, which showed genome-wide significant associations (P < 5.0 × 10-8) with sarcoidosis; CCL24 and STYXL1-SRRM3 were novel. The disease-risk alleles in CCL24 and IL23R were associated with reduced CCL24 and IL23R expression, respectively. The disease-risk allele in STYXL1-SRRM3 was associated with elevated POR expression. These results suggest that genetic control of CCL24, POR, and IL23R expression contribute to the pathogenesis of sarcoidosis. We speculate that the CCL24 risk allele might be involved in a polarized Th1 response in sarcoidosis, and that POR and IL23R risk alleles may lead to diminished host defense against sarcoidosis pathogens.
Asunto(s)
Quimiocina CCL24/genética , Sistema Enzimático del Citocromo P-450/genética , Predisposición Genética a la Enfermedad , Receptores de Interleucina/genética , Sarcoidosis/etiología , Alelos , Quimiocina CCL24/metabolismo , Sistema Enzimático del Citocromo P-450/metabolismo , Femenino , Estudios de Asociación Genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Japón , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Receptores de Interleucina/metabolismo , Sarcoidosis/diagnóstico , Sarcoidosis/metabolismoRESUMEN
BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. Inflammatory mediators have been implicated in the pathogenesis of DN, thus considered an inflammatory disease. However, further studies are required to assess the renal damage caused by the action of these molecules. Therefore, the objective of this study was to analyze the expression of cytokines and chemokines in renal biopsies from patients with DN and to correlate it with interstitial inflammation and decreased renal function. METHODS: Forty-four native renal biopsies from patients with DN and 23 control cases were selected. In situ expression of eotaxin, MIP-1α (macrophage inflammatory protein-1α), IL-8 (interleukin-8), IL-4, IL-10, TNF-α (tumor necrosis factor-α), TNFR1 (tumor necrosis factor receptor-1), IL-1ß, and IL-6 were evaluated by immunohistochemistry. RESULTS: The DN group showed a significant increase in IL-6 (p < 0.0001), IL-1ß (p < 0.0001), IL-4 (p < 0.0001) and eotaxin (p = 0.0012) expression, and a decrease in TNFR1 (p = 0.0107) and IL-8 (p = 0.0262) expression compared to the control group. However, there were no significant differences in IL-10 (p = 0.4951), TNF-α (p = 0.7534), and MIP-1α (p = 0.3816) expression among groups. Regarding interstitial inflammation, there was a significant increase in IL-6 in scores 0 and 1 compared to score 2 (p = 0.0035), in IL-10 in score 2 compared to score 0 (p = 0.0479), and in eotaxin in score 2 compared to scores 0 and 1 (p < 0.0001), whereas IL-8 (p = 0.0513) and MIP-1α (p = 0.1801) showed no significant differences. There was a tendency for negative correlation between eotaxin and estimated glomerular filtration rate (eGFR) (p = 0.0566). CONCLUSIONS: Our results indicated an increased in situ production of cytokines and chemokines in DN, including IL-6, IL-1ß, IL-4, and eotaxin. It was observed that, possibly, eotaxin may have an important role in the progression of interstitial inflammation in DN and in eGFR decrease of these patients.
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Citocinas/metabolismo , Nefropatías Diabéticas/metabolismo , Riñón/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Quimiocina CCL11/metabolismo , Quimiocina CCL24/metabolismo , Quimiocina CCL26/metabolismo , Quimiocina CCL3/metabolismo , Quimiocinas/metabolismo , Nefropatías Diabéticas/patología , Femenino , Humanos , Inmunohistoquímica , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Interleucina-4/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Riñón/patología , Masculino , Persona de Mediana Edad , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adulto JovenRESUMEN
Helminth infection represents a major health problem causing approximately 5 million disability-adjusted life years worldwide. Concerns that repeated anti-helminthic treatment may lead to drug resistance render it important that vaccines are developed but will require increased understanding of the immune-mediated cellular and antibody responses to helminth infection. IL-4 or antibody-activated murine macrophages are known to immobilize parasitic nematode larvae, but few studies have addressed whether this is translatable to human macrophages. In the current study, we investigated the capacity of human macrophages to recognize and attack larval stages of Ascaris suum, a natural porcine parasite that is genetically similar to the human helminth Ascaris lumbricoides. Human macrophages were able to adhere to and trap A suum larvae in the presence of either human or pig serum containing Ascaris-specific antibodies and other factors. Gene expression analysis of serum-activated macrophages revealed that CCL24, a potent eosinophil attractant, was the most upregulated gene following culture with A suum larvae in vitro, and human eosinophils displayed even greater ability to adhere to, and trap, A suum larvae. These data suggest that immune serum-activated macrophages can recruit eosinophils to the site of infection, where they act in concert to immobilize tissue-migrating Ascaris larvae.
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Ascariasis/inmunología , Ascaris suum/inmunología , Quimiocina CCL24/metabolismo , Eosinófilos/inmunología , Macrófagos/inmunología , Animales , Anticuerpos Antihelmínticos/sangre , Formación de Anticuerpos , Ascaris lumbricoides/inmunología , Humanos , Sueros Inmunes/farmacología , Larva/inmunología , Recuento de Leucocitos , Ratones , Porcinos , Enfermedades de los Porcinos/inmunología , Vacunas/inmunologíaRESUMEN
The poor prognosis of clear-cell renal cell carcinoma (ccRCC) patients is due to progression and targeted drug resistance, but the underlying molecular mechanisms need further elucidation. This study examined the biological function and related mechanisms of gankyrin in ccRCC based on the results of our previous study. To this end, in vitro functional experiments; in vivo models of subcutaneous tumor formation, lung metastasis, and orthotopic ccRCC; and antibody chip detection, co-IP, ChIP assays were performed to examine the biological role and molecular mechanisms of gankyrin in ccRCC. Two hundred fifty-six ccRCC patients were randomly divided into training and validation cohorts to examine the prognostic value of gankyrin and other markers through IHC and statistical analyses. We observed that the gankyrin-overexpressing ccRCC cell lines 786-O and 769-P exhibited increased proliferation, invasion, migration, tumorigenicity, and pazopanib resistance and decreased apoptosis, while gankyrin knockdown achieved the opposite results. Mechanistically, gankyrin recruited STAT3 via direct binding, and STAT3 binding to the CCL24 promoter promoted its expression. Reciprocally, an increase in autocrine CCL24 enhanced the expression of gankyrin and STAT3 activation via CCR3 in ccRCC, forming a positive autocrine-regulatory loop. Furthermore, in vivo experimental results revealed that blocking the positive loop through gankyrin knockdown or treatment with the CCR3 inhibitor SB328437 reversed the resistance to pazopanib and inhibited lung metastasis in ccRCC. Moreover, a positive correlation between gankyrin and STAT3 or CCL24 expression in ccRCC specimens was observed, and improved accuracy for ccRCC patient prognosis was achieved by combining gankyrin and STAT3 or CCL24 expression with existing clinical prognostic indicators, including the TNM stage and SSIGN score. In summary, targeting the gankyrin/STAT3/CCL24/CCR3 autocrine-regulatory loop may serve as a remedy for patients with advanced ccRCC, and combining gankyrin and STAT3 or CCL24 expression with the current clinical indicators better predicts ccRCC patient prognosis.
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Antineoplásicos/farmacología , Comunicación Autocrina/efectos de los fármacos , Carcinoma de Células Renales/tratamiento farmacológico , Quimiocina CCL24/metabolismo , Resistencia a Antineoplásicos , Neoplasias Renales/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Pirimidinas/farmacología , Receptores CCR3/metabolismo , Factor de Transcripción STAT3/metabolismo , Sulfonamidas/farmacología , Animales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/metabolismo , Carcinoma de Células Renales/secundario , Línea Celular Tumoral , Quimiocina CCL24/genética , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Indazoles , Neoplasias Renales/genética , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Masculino , Ratones Endogámicos NOD , Ratones SCID , Complejo de la Endopetidasa Proteasomal/genética , Proteínas Proto-Oncogénicas/genética , Receptores CCR3/genética , Factor de Transcripción STAT3/genética , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The inflammatory functions of the cytokine tumor necrosis factor (TNF) rely on its ability to induce cytokine production and to induce cell death. Caspase-dependent and caspase-independent pathways-apoptosis and necroptosis, respectively-regulate immunogenicity by the release of distinct sets of cellular proteins. To obtain an unbiased, systems-level understanding of this important process, we here applied mass spectrometry-based proteomics to dissect protein release during apoptosis and necroptosis. We report hundreds of proteins released from human myeloid cells in time course experiments. Both cell death types induce receptor shedding, but only apoptotic cells released nucleosome components. Conversely, necroptotic cells release lysosomal components by activating lysosomal exocytosis at early stages of necroptosis-induced membrane permeabilization and show reduced release of conventionally secreted cytokines.
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Apoptosis , Caspasa 8/metabolismo , Citocinas/metabolismo , Necroptosis , Ácidos Pentanoicos/farmacología , Proteoma/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Apoptosis/efectos de los fármacos , Inhibidores de Caspasas/farmacología , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Quimiocina CCL2/metabolismo , Quimiocina CCL24/metabolismo , Dipéptidos/farmacología , Exocitosis/efectos de los fármacos , Vesículas Extracelulares/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Células HEK293 , Histonas/metabolismo , Humanos , Indoles/farmacología , Interleucina-8/metabolismo , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Espectrometría de Masas , Necroptosis/efectos de los fármacosRESUMEN
BACKGROUND: Partial burn injury in older patients is associated with higher rates of morbidity, mortality, and conversion to full thickness burn (Finnerty et al., 2009; Pham et al., 2009). Both human and mouse models demonstrate an altered systemic immune response in older subjects, however less is known about the localized response (Jeschke et al., 2016; Farinas et al., 2018; Mohs et al., 2017). We hypothesized that a mouse model could demonstrate differences in the localized inflammatory response of the old. METHODS: Six old (66 weeks) and young (8 weeks) mice received partial thickness thermal burns. Localized and systemic expression of nine chemokines (TNFalpha, MCP-1, MIP-2, S100A9, EGF, IL-10, RANTES, G-CSF, and EOTAXIN) were evaluated at day 3 after burn using Luminex analysis. Vimentin immunostaining was used to evaluate injury depth. RESULTS: Vimentin staining demonstrated increased burn depth in old mice (449±38µm) as compared to young (166±18µm) (p<0.05). Both groups exhibited increased localized expression of EOTAXIN after burn (p<0.05), however expression in old mice (83.6±6.1pg/ml) was lower than that of young (126.8±18.7pg/ml) (p<0.05). Systemically, however, old mice had increased baseline EOTAXIN expression (1332.40±110.78pg/ml) compared to young (666.12±45.8pg/ml) (p<0.005). CONCLUSIONS: EOTAXIN is one of the primary chemoattractants for selective eosinophilic recruitment and activation. While eosinophils are important for wound healing, a hyperactive eosinophilic response can result in tissue damage. We hypothesize that the increased baseline serum EOTAXIN in the old may prime their hyperactive response, and may contribute to their worse clinical outcomes. Long-term eosinophil activation requires further study, however our findings indicate a role for EOTAXIN and eosinophils in burn response.
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Envejecimiento/inmunología , Quemaduras/inmunología , Quimiocina CCL11/inmunología , Quimiocina CCL24/inmunología , Quimiocina CCL26/inmunología , Eosinófilos/inmunología , Envejecimiento/metabolismo , Animales , Quemaduras/metabolismo , Quemaduras/patología , Calgranulina B/inmunología , Calgranulina B/metabolismo , Quimiocina CCL11/metabolismo , Quimiocina CCL2/inmunología , Quimiocina CCL2/metabolismo , Quimiocina CCL24/metabolismo , Quimiocina CCL26/metabolismo , Quimiocina CCL5/inmunología , Quimiocina CCL5/metabolismo , Quimiocina CXCL2/inmunología , Quimiocina CXCL2/metabolismo , Eosinófilos/metabolismo , Factor de Crecimiento Epidérmico/inmunología , Factor de Crecimiento Epidérmico/metabolismo , Factor Estimulante de Colonias de Granulocitos/inmunología , Factor Estimulante de Colonias de Granulocitos/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Interleucina-10/inmunología , Interleucina-10/metabolismo , Ratones , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
PURPOSE: To analyze the relationship between the seasonal allergic conjunctivitis (SAC), eotaxin-2, matrix metalloproteinase-9 (MMP-9), and the topographical findings in the keratoconus patients. METHODS: Thirty-four eyes of patients without SAC (Group 1), 34 eyes of patients with SAC (Group 2), and 20 eyes of control subjects (control group) were enrolled. Tear samples of the subjects were collected by Schirmer method. Corneal topography parameters, tear MMP-9, and tear eotaxin-2 levels were analyzed. RESULTS: The mean tear MMP-9 levels in Groups 1 and 2 were significantly higher than in the control group (p = 0.004). MMP-9 level exhibited a positive correlation with the keratoconus stage and a negative correlation with the thinnest corneal thickness (r = 0.294, p = 0.018, and r = - 0.302, p = 0.006, respectively). The tear eotaxin-2 level was higher in Group 2 than in Group 1 and control group which is not statistically significant (p = 0.17). CONCLUSION: The tear eotaxin-2 did not exhibit any difference in the presence of keratoconus. The tear MMP-9 level was higher in the keratoconic eyes, and it showed a correlation with the stage of the disease and the corneal thickness.
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Quimiocina CCL24/metabolismo , Conjuntivitis Alérgica/metabolismo , Córnea/patología , Topografía de la Córnea/métodos , Queratocono/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Lágrimas/metabolismo , Adolescente , Adulto , Biomarcadores/metabolismo , Conjuntivitis Alérgica/complicaciones , Conjuntivitis Alérgica/diagnóstico , Ensayo de Inmunoadsorción Enzimática , Femenino , Estudios de Seguimiento , Humanos , Queratocono/complicaciones , Queratocono/diagnóstico , Masculino , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: microRNA (miR)-218-5p is involved in cigarette smoke-induced airway inflammation. In our earlier asthma epithelial miRNA profiling data, miR-218-5p was the top 2 down-regulated miRNA. We hypothesize that miR-218-5p plays a role in asthma airway inflammation. OBJECTIVE: To unveil the role of miR-218-5p and its target gene in asthma airway inflammation. METHODS: We measured miR-218-5p expression in bronchial brushings of asthma patients (n = 50) and healthy controls (n = 15), and analysed the correlations between miR-218-5p expression and airway eosinophilia. We examined whether CTNND2 was a target of miR-218-5p, and the expression of 12 catenin family members in bronchial brushings, in cultured human bronchial epithelial (HBE) cells and BEAS-2B cells. We explored the role of miR-218-5p-CTNND2 pathway using a murine model of allergic airway inflammation. RESULTS: Epithelial miR-218-5p expression was significantly decreased and negatively correlated with eosinophils in induced sputum and bronchial biopsies, and other type 2 biomarkers in asthma patients. We verified that CTNND2 (encoding δ-catenin) was a target of miR-218-5p. Remarkably, CTNND2 was the most significantly up-regulated catenin compared with the other 11 catenin family members in bronchial brushings of asthma patients, IL-13-stimulated HBE and BEAS-2B cells. Moreover, epithelial CTNND2 expression positively correlated with airway eosinophilia in asthma. Airway mmu-miR-218-5p expression was also decreased, and Ctnnd2 expression was increased in a murine model of allergic airway inflammation. Intriguingly, mmu-miR-218-5p overexpression suppressed airway hyperresponsiveness, eosinophilic airway inflammation and Ctnnd2 up-regulation in the mouse model. Finally, perturbation of miR-218-5p or CTNND2 expression significantly altered chemokine CCL26 expression in the cell cultures and the mouse model. CONCLUSIONS AND CLINICAL RELEVANCE: Epithelial miR-218-5p plays a protective role in eosinophilic airway inflammation via targeting CTNND2, a novel catenin in asthma, and suppressing chemokine CCL26 expression.
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Asma/genética , Cateninas/genética , Quimiocina CCL26/metabolismo , Eosinofilia/genética , MicroARNs/genética , Animales , Asma/metabolismo , Bronquios/metabolismo , Estudios de Casos y Controles , Línea Celular , Células Cultivadas , Quimiocina CCL11/metabolismo , Quimiocina CCL24/metabolismo , Eosinofilia/metabolismo , Expresión Génica , Humanos , Ratones , Catenina deltaRESUMEN
OBJECTIVES: Eosinophilic esophagitis (EoE), a chronic food allergic disease, lacks sensitive and specific peripheral biomarkers. We hypothesized that levels of EoE-related biomarkers captured using a 1-hour minimally invasive Esophageal String Test (EST) would correlate with mucosal eosinophil counts and tissue concentrations of these same biomarkers. We aimed to determine whether a 1-hour EST accurately distinguishes active from inactive EoE or a normal esophagus. METHODS: In a prospective, multisite study, children and adults (ages 7-55 years) undergoing a clinically indicated esophagogastroduodenoscopy performed an EST with an esophageal dwell time of 1 hour. Subjects were divided into 3 groups: active EoE, inactive EoE, and normal esophageal mucosa. Eosinophil-associated protein levels were compared between EST effluents and esophageal biopsy extracts. Statistical modeling was performed to select biomarkers that best correlated with and predicted eosinophilic inflammation. RESULTS: One hundred thirty-four subjects (74 children, 60 adults) with active EoE (n = 62), inactive EoE (n = 37), and patient controls with a normal esophagus (n = 35) completed the study. EST-captured eosinophil-associated biomarkers correlated significantly with peak eosinophils/high-power field, endoscopic visual scoring, and the same proteins extracted from mucosal biopsies. Statistical modeling, using combined eotaxin-3 and major basic protein-1 concentrations, led to the development of EoE scores that distinguished subjects with active EoE from inactive EoE or normal esophagi. Eighty-seven percent of children, 95% of parents, and 92% of adults preferred the EST over endoscopy if it provided similar information. DISCUSSION: The 1-hour EST accurately distinguishes active from inactive EoE in children and adults and may facilitate monitoring of disease activity in a safe and minimally invasive fashion.
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Esofagitis Eosinofílica/diagnóstico , Eosinófilos , Mucosa Esofágica/citología , Esófago/citología , Adolescente , Adulto , Biomarcadores/análisis , Biomarcadores/metabolismo , Biopsia , Quimiocina CCL24/análisis , Quimiocina CCL24/metabolismo , Quimiocina CCL26/análisis , Quimiocina CCL26/metabolismo , Niño , Endoscopía del Sistema Digestivo , Esofagitis Eosinofílica/patología , Mucosa Esofágica/diagnóstico por imagen , Mucosa Esofágica/patología , Esófago/diagnóstico por imagen , Esófago/patología , Estudios de Factibilidad , Femenino , Humanos , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: The mechanisms underlying mucosal eosinophilia in chronic rhinosinusitis with nasal polyps (CRSwNP) remain poorly clarified. The nervous system and neuropeptides play an important role in the regulation of immune response. Herein we explore the expression and function of hemokinin-1 (HK-1), a newly identified tachykinin, along with its receptor neurokinin 1 receptor (NK1R) in CRSwNP. METHODS: HK-1, NK1R, and C-C motif chemokine ligand 24 (CCL24) expression in nasal tissues (53 eosinophilic CRSwNP, 32 non-eosinophilic CRSwNP, and 33 controls) was investigated by quantitative reverse transcript polymerase chain reaction (RT-PCR) and immunofluorescence staining. THP-1, a human monocytic leukemia cell line, and eosinophilic polyp tissues were stimulated with HK-1. Cells, tissues, and culture supernatants were subsequently collected for detection of the production of various inflammatory cytokines and chemokines by quantitative RT-PCR and enzyme-linked immunoassay. RESULTS: HK-1 and NK1R mRNA and protein expression were upregulated in eosinophilic and non-eosinophilic nasal polyps compared with control tissues, with eosinophilic polyps demonstrating a higher upregulation compared with that of non-eosinophilic polyps. Eosinophils constituted the major source of HK-1, whereas macrophages were the predominant cell type exhibiting NK1R in eosinophilic polyps. HK-1 induced CCL24 production from macrophages differentiated from THP-1 cells; this was abolished by an NK1R antagonist. HK-1 also induced CCL24 production from ex vivo-cultured eosinophilic nasal polyps. CCL24 was expressed by macrophages in eosinophilic but not non-eosinophilic polyps. The expression level of HK-1 correlated with CCL24 expression and tissue eosinophilia in eosinophilic nasal polyps. CONCLUSION: Eosinophil-derived HK-1 induces CCL24 production from macrophages and therefore exaggerates eosinophilic inflammation in CRSwNP.
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Eosinófilos/inmunología , Inflamación/inmunología , Macrófagos/inmunología , Pólipos Nasales/inmunología , Rinitis/inmunología , Sinusitis/inmunología , Taquicininas/metabolismo , Adulto , Quimiocina CCL24/metabolismo , Enfermedad Crónica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Receptores de Neuroquinina-1/metabolismo , Células THP-1 , Taquicininas/genética , Regulación hacia Arriba , Adulto JovenRESUMEN
Eosinophils are seen in a number of dermatologic conditions. While the extent of their function in these diseases remains to be fully elucidated, pathogenic activity in bullous pemphigoid suggests a more significant role than previously thought. Several dermatoses have a fairly characteristic histologic morphology of eosinophil infiltration. We hypothesized that epidermal expression of eotaxins and TSLP would differ by disease, perhaps explaining the different histologic morphologies. We performed a retrospective study of eosinophil rich dermatoses to perform immunohistochemistry. We collected 49 specimens composed of bullous pemphigoid (n = 15), atopic dermatitis (n = 12), drug rash (n = 8), arthropod assault (n = 5), and non-bullous pemphigoid eosinophilic spongiosis (n = 5). We used lichen planus (n = 4) as a control for lymphocyte-mediated inflammation. TSLP was diffusely expressed in all epidermal samples, whereas eotaxins demonstrated a weaker staining. Eotaxins and TSLP demonstrated a gradient between basal and spinous keratinocytes. The correlation between overall basal keratinocyte and spinous keratinocyte staining of eotaxins and TSLP with the number of eosinophils demonstrated a significant correlation between eotaxin-1 (R = 0.404, P = 0.004), eotaxin-2 (R = 0.576, P < 0.001), and eotaxin-3 (R = 0.512, P < 0.001), but not TSLP (R = 0.164, P = 0.251). These remained significant after correcting for multiple comparisons. While we were unable to detect significant differences in epidermal expression of eotaxins and TSLP in various eosinophil rich dermatoses, we identified a significant correlation of spinous keratinocyte eotaxin staining with tissue eosinophilia. Our identification of a correlation of spinous keratinocyte eotaxin staining with tissue eosinophilia may provide insight into local eosinophil chemotaxis.
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Quimiocina CCL11/metabolismo , Quimiocina CCL24/metabolismo , Quimiocina CCL26/metabolismo , Citocinas/metabolismo , Dermatitis/patología , Eosinofilia/patología , Quimiocina CCL11/análisis , Quimiocina CCL24/análisis , Quimiocina CCL26/análisis , Citocinas/análisis , Dermatitis/inmunología , Eosinofilia/inmunología , Eosinófilos/inmunología , Epidermis/inmunología , Epidermis/patología , Humanos , Inmunohistoquímica , Queratinocitos/inmunología , Queratinocitos/patología , Estudios RetrospectivosRESUMEN
Glucagon has been shown to be beneficial as a treatment for bronchospasm in asthmatics. Here, we investigate if glucagon would prevent airway hyperreactivity (AHR), lung inflammation, and remodeling in a murine model of asthma. Glucagon (10 and 100 µg/Kg, i.n.) significantly prevented AHR and eosinophilia in BAL and peribronchiolar region induced by ovalbumin (OVA) challenge, while only the dose of 100 µg/Kg of glucagon inhibited subepithelial fibrosis and T lymphocytes accumulation in BAL and lung. The inhibitory action of glucagon occurred in parallel with reduction of OVA-induced generation of IL-4, IL-5, IL-13, TNF-α, eotaxin-1/CCL11, and eotaxin-2/CCL24 but not MDC/CCL22 and TARC/CCL17. The inhibitory effect of glucagon (100 µg/Kg, i.n.) on OVA-induced AHR and collagen deposition was reversed by pre-treatment with indomethacin (10 mg/Kg, i.p.). Glucagon increased intracellular cAMP levels and inhibits anti-CD3 plus anti-CD28-induced proliferation and production of IL-2, IL-4, IL-10, and TNF- α from TCD4+ cells in vitro. These findings suggest that glucagon reduces crucial features of asthma, including AHR, lung inflammation, and remodeling, in a mechanism probably associated with inhibition of eosinophils accumulation and TCD4+ cell proliferation and function. Glucagon should be further investigated as an option for asthma therapy.
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Remodelación de las Vías Aéreas (Respiratorias)/efectos de los fármacos , Hiperreactividad Bronquial/prevención & control , Glucagón/farmacología , Ovalbúmina/farmacología , Neumonía/prevención & control , Animales , Asma/prevención & control , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Proliferación Celular/efectos de los fármacos , Quimiocina CCL24/metabolismo , Citocinas/metabolismo , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Ratones Endogámicos , Receptores de Glucagón/metabolismoRESUMEN
BACKGROUND: CCL11, CCL24 and CCL26 are potent chemokines for eosinophils. Since there has been no study reporting the association serum CCL11, CCL24 and CCL26 with fibrotic progression of PBC, the aim of this study is to explore the association. METHODS: One hundred and eight PBC patients, 52 patients with chronic hepatitis B (CHB) and 50 healthy controls (HC) were recruited. The sera were detected for CCL11, CCL24 and CCL26 using multiplex immunoassay. Other laboratory indicators were routinely measured. PBC was divided into four stages according to Scheuer's classification. RESULTS: Serum CCL11, CCL24 and CCL26 levels were significantly higher in PBC patients than those with CHB and HC (Pâ¯<â¯0.05). The ROC analyses showed that all of the three CCLs performed well for identification of PBC (all P< or =0.001). The multiple linear regression analysis showed an independent relationship of CCL26 with APRI and FIB-4 in PBC patients, but no relationship of CCL11 and CCL24 with fibrotic indicators. Additionally, serum CCL11 and CCL26 were negatively correlated with histological stage of PBC, while serum CCL24 showed no statistical correlation. CONCLUSION: Serum CCL11, CCL24 and CCL26 are upregulated in PBC. CCL11 and CCL26 are associated with fibrotic progression of PBC, but CCL24 is not.
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Quimiocina CCL11/sangre , Quimiocina CCL24/sangre , Quimiocina CCL26/sangre , Cirrosis Hepática Biliar/sangre , Cirrosis Hepática Biliar/metabolismo , Anciano , Biomarcadores , Quimiocina CCL11/metabolismo , Quimiocina CCL24/metabolismo , Quimiocina CCL26/metabolismo , Femenino , Regulación de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Regulación hacia ArribaRESUMEN
Minocycline/tetracycline is clinically used for the treatment of bullous pemphigoid (BP), and its clinical benefits are superior to those of prednisolone when considering adverse events. Although the clinical benefits of minocycline/tetracycline are well known, its immunosuppressive mechanisms are still unclear. In this study, we investigated the immunomodulatory effects of traditional anti-BP drugs (minocycline, nicotinic acid amide, dexamethasone and cyclosporine) on CD163+ M2 macrophages in vitro, with special focus on the production of CCL18 and CCL22, both of which are produced by CD163+ M2 macrophages in the lesional skin of BP and are increased in the serum of BP patients. Minocycline decreased the production of CCL22, CCL24 and CCL26 as well as CCL2 from M2 macrophages. CCL18 from M2 macrophages was decreased by dexamethasone and cyclosporine, but not decreased by minocycline. These data suggest that the clinical benefit of minocycline is partially explained by its suppressive effects against the production of specific Th2 chemokines from M2 macrophages, which should contribute to the recruitment of Th2 cells and eosinophils in the lesional skin of BP patients.