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1.
Nat Immunol ; 22(3): 279-286, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33495652

RESUMEN

The constituents of the gut microbiome are determined by the local habitat, which itself is shaped by immunological pressures, such as mucosal IgA. Using a mouse model of restricted antibody repertoire, we identified a role for antibody-microbe interactions in shaping a community of bacteria with an enhanced capacity to metabolize L-tyrosine. This model led to increased concentrations of p-cresol sulfate (PCS), which protected the host against allergic airway inflammation. PCS selectively reduced CCL20 production by airway epithelial cells due to an uncoupling of epidermal growth factor receptor (EGFR) and Toll-like receptor 4 (TLR4) signaling. Together, these data reveal a gut microbe-derived metabolite pathway that acts distally on the airway epithelium to reduce allergic airway responses, such as those underpinning asthma.


Asunto(s)
Anticuerpos/metabolismo , Bacterias/metabolismo , Cresoles/metabolismo , Microbioma Gastrointestinal , Intestinos/microbiología , Pulmón/metabolismo , Neumonía/prevención & control , Hipersensibilidad Respiratoria/prevención & control , Ésteres del Ácido Sulfúrico/metabolismo , Tirosina/metabolismo , Administración Oral , Alérgenos , Animales , Anticuerpos/inmunología , Diversidad de Anticuerpos , Bacterias/inmunología , Células Cultivadas , Quimiocina CCL20/metabolismo , Técnicas de Cocultivo , Cresoles/administración & dosificación , Modelos Animales de Enfermedad , Receptores ErbB/metabolismo , Femenino , Interacciones Huésped-Patógeno , Inyecciones Intravenosas , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Neumonía/inmunología , Neumonía/metabolismo , Neumonía/microbiología , Hipersensibilidad Respiratoria/inmunología , Hipersensibilidad Respiratoria/metabolismo , Hipersensibilidad Respiratoria/microbiología , Transducción de Señal , Ésteres del Ácido Sulfúrico/administración & dosificación , Receptor Toll-Like 4/metabolismo , Tirosina/administración & dosificación
2.
Nat Immunol ; 18(6): 675-682, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28436956

RESUMEN

Immunoglobulin A (IgA) maintains a symbiotic equilibrium with intestinal microbes. IgA induction in the gut-associated lymphoid tissues (GALTs) is dependent on microbial sampling and cellular interaction in the subepithelial dome (SED). However it is unclear how IgA induction is predominantly initiated in the SED. Here we show that previously unrecognized mesenchymal cells in the SED of GALTs regulate bacteria-specific IgA production and diversify the gut microbiota. Mesenchymal cells expressing the cytokine RANKL directly interact with the gut epithelium to control CCL20 expression and microfold (M) cell differentiation. The deletion of mesenchymal RANKL impairs M cell-dependent antigen sampling and B cell-dendritic cell interaction in the SED, which results in a reduction in IgA production and a decrease in microbial diversity. Thus, the subepithelial mesenchymal cells that serve as M cell inducers have a fundamental role in the maintenance of intestinal immune homeostasis.


Asunto(s)
Microbioma Gastrointestinal/inmunología , Inmunoglobulina A/inmunología , Tejido Linfoide/inmunología , Células Madre Mesenquimatosas/inmunología , Ligando RANK/inmunología , Animales , Linfocitos B/inmunología , Biodiversidad , Diferenciación Celular/inmunología , Quimiocina CCL20/inmunología , Células Dendríticas/inmunología , Citometría de Flujo , Microbioma Gastrointestinal/genética , Centro Germinal , Tejido Linfoide/citología , Células Madre Mesenquimatosas/ultraestructura , Ratones , Microscopía Electrónica , Ligando RANK/genética , ARN Ribosómico 16S/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
3.
Cell ; 148(3): 447-57, 2012 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-22304915

RESUMEN

Although it is believed that neural activation can affect immune responses, very little is known about the neuroimmune interactions involved, especially the regulators of immune traffic across the blood-brain barrier which occurs in neuroimmune diseases such as multiple sclerosis (MS). Using a mouse model of MS, experimental autoimmune encephalomyelitis, we show that autoreactive T cells access the central nervous system via the fifth lumbar spinal cord. This location is defined by IL-6 amplifier-dependent upregulation of the chemokine CCL20 in associated dorsal blood vessels, which in turn depends on gravity-induced activation of sensory neurons by the soleus muscle in the leg. Impairing soleus muscle contraction by tail suspension is sufficient to reduce localized chemokine expression and block entry of pathogenic T cells at the fifth lumbar cord, suggesting that regional neuroimmune interactions may offer therapeutic targets for a variety of neurological diseases.


Asunto(s)
Barrera Hematoencefálica , Linfocitos T CD4-Positivos/citología , Encefalomielitis Autoinmune Experimental/inmunología , Animales , Movimiento Celular , Quimiocina CCL20/inmunología , Encefalomielitis Autoinmune Experimental/patología , Gravitación , Interleucina-6/inmunología , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Músculo Esquelético/inervación , Neuroinmunomodulación , Médula Espinal/irrigación sanguínea
4.
FASEB J ; 38(2): e23407, 2024 01 31.
Artículo en Inglés | MEDLINE | ID: mdl-38197598

RESUMEN

This study investigated the role of the axis involving chemokine receptor 6 (CCR6) and its ligand chemokine (C-C motif) ligand 20 (CCL20) in acute kidney disease (AKD) using an ischemia-reperfusion injury (IRI) model. The model was established by clamping the unilateral renal artery pedicle of C57BL/6 mice for 30 min, followed by evaluation of CCL20/CCR6 expression at 4 weeks post-IRI. In vitro studies were conducted to examine the effects of hypoxia and H2 O2 -induced oxidative stress on CCL20/CCR6 expression in kidney tissues of patients with AKD and chronic kidney disease (CKD). Tubular epithelial cell apoptosis was more severe in C57BL/6 mice than in CCL20 antibody-treated mice, and CCR6, NGAL mRNA, and IL-8 levels were higher under hypoxic conditions. CCL20 blockade ameliorated apoptotic damage in a dose-dependent manner under hypoxia and reactive oxygen species injury. CCR6 expression in IRI mice indicated that the disease severity was similar to that in patients with the AKD phenotype. Morphometry of CCL20/CCR6 expression revealed a higher likelihood of CCR6+ cell presence in CKD stage 3 patients than in stage 1-2 patients. Kidney tissues of patients with CKD frequently contained CCL20+ cells, which were positively correlated with interstitial inflammation. CCL20/CCR6 levels were increased in fibrotic kidneys at 4 and 8 weeks after 5/6 nephrectomy. These findings suggest that modulating the CCL20/CCR6 pathway is a potential therapeutic strategy for managing the progression of AKD to CKD.


Asunto(s)
Lesión Renal Aguda , Insuficiencia Renal Crónica , Humanos , Animales , Ratones , Ratones Endogámicos C57BL , Ligandos , Riñón , Células Epiteliales , Arteria Renal , Hipoxia , Receptores CCR6/genética , Quimiocina CCL20/genética
5.
Nature ; 565(7738): 246-250, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30602786

RESUMEN

In addition to maintaining immune tolerance, FOXP3+ regulatory T (Treg) cells perform specialized functions in tissue homeostasis and remodelling1,2. However, the characteristics and functions of brain Treg cells are not well understood because there is a low number of Treg cells in the brain under normal conditions. Here we show that there is massive accumulation of Treg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain Treg cells are similar to Treg cells in other tissues such as visceral adipose tissue and muscle3-5, they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT7. The amplification of brain Treg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain Treg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that Treg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.


Asunto(s)
Astrocitos/patología , Isquemia Encefálica/inmunología , Isquemia Encefálica/patología , Gliosis/patología , Neuroprotección/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Animales , Encéfalo/citología , Encéfalo/inmunología , Movimiento Celular , Proliferación Celular , Quimiocina CCL1/inmunología , Quimiocina CCL20/inmunología , Interleucina-2/inmunología , Interleucina-33/inmunología , Interleucina-6/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/inmunología , Receptores CCR/metabolismo , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Factor de Transcripción STAT3/metabolismo , Serotonina/metabolismo , Transducción de Señal , Linfocitos T Reguladores/metabolismo
6.
J Infect Dis ; 230(3): 741-753, 2024 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-38271258

RESUMEN

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS), a lethal tick-borne hemorrhagic fever, prompted our investigation into prognostic predictors and potential drug targets using plasma Olink Proteomics. METHODS: Employing the Olink assay, we analyzed 184 plasma proteins in 30 survivors and 8 nonsurvivors of SFTS. Validation was performed in a cohort of 154 patients with SFTS via enzyme-linked immunosorbent assay. We utilized the Drug-Gene Interaction Database to identify protein-drug interactions. RESULTS: Nonsurvivors exhibited 110 differentially expressed proteins as compared with survivors, with functional enrichment in the cell chemotaxis-related pathway. Thirteen differentially expressed proteins-including C-C motif chemokine 20 (CCL20), calcitonin gene-related peptide alpha, and pleiotrophin-were associated with multiple-organ dysfunction syndrome. CCL20 emerged as the top predictor of death, demonstrating an area under the curve of 1 (P = .0004) and 0.9033 (P < .0001) in the discovery and validation cohorts, respectively. Patients with CCL20 levels exceeding 45.74 pg/mL exhibited a fatality rate of 45.65%, while no deaths occurred in those with lower CCL20 levels. Furthermore, we identified 202 Food and Drug Administration-approved drugs targeting 37 death-related plasma proteins. CONCLUSIONS: Distinct plasma proteomic profiles characterize SFTS cases with different outcomes, with CCL20 emerging as a novel, sensitive, accurate, and specific biomarker for predicting SFTS prognosis.


Asunto(s)
Quimiocina CCL20 , Proteómica , Síndrome de Trombocitopenia Febril Grave , Humanos , Quimiocina CCL20/sangre , Femenino , Pronóstico , Masculino , Síndrome de Trombocitopenia Febril Grave/sangre , Síndrome de Trombocitopenia Febril Grave/virología , Proteómica/métodos , Anciano , Persona de Mediana Edad , Biomarcadores/sangre , Adulto , Anciano de 80 o más Años , Estudios de Cohortes
7.
J Proteome Res ; 23(8): 3674-3681, 2024 Aug 02.
Artículo en Inglés | MEDLINE | ID: mdl-39028944

RESUMEN

INTRODUCTION: It is crucial to investigate the distinct proteins that contribute to the advancement of lung cancer. MATERIAL AND METHODS: We analyzed the expression levels of 92 immuno-oncology-related proteins in 96 pairs of lung adenocarcinoma tissue samples using Olink proteomics. The differentially expressed proteins (DEPs) were successively screened in tumor and paraneoplastic groups, early and intermediate-late groups by a nonparametric rank sum test, and the distribution and expression levels of DEPs were determined by volcano and heat maps, etc., and the area under the curve was calculated. RESULTS: A total of 24 DEPs were identified in comparisons between tumor and paracancerous tissues. Among them, interleukin-8 (IL8) and chemokine (C-C motif) ligand 20 (CCL20) as potential markers for distinguishing tumor tissues. Through further screening, it was found that interleukin-6 (IL6) and vascular endothelial growth factor A (VEGFA) may be able to lead to tumor progression through the JaK-STAT signaling pathway, Toll-like receptor signaling pathway and PI3K/AKT signaling pathway. Interestingly, our study revealed a down-regulation of IL6 and VEGFA in tumor tissues compared to paracancerous tissues. CONCLUSIONS: IL8 + CCL20 (AUC: 0.7056) have the potential to differentiate tumor tissue from paracancerous tissue; IL6 + VEGFA (AUC: 0.7531) are important protein markers potentially responsible for tumor progression.


Asunto(s)
Adenocarcinoma del Pulmón , Biomarcadores de Tumor , Quimiocina CCL20 , Progresión de la Enfermedad , Interleucina-8 , Neoplasias Pulmonares , Proteómica , Factor A de Crecimiento Endotelial Vascular , Humanos , Proteómica/métodos , Biomarcadores de Tumor/metabolismo , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Quimiocina CCL20/metabolismo , Interleucina-8/metabolismo , Interleucina-6/metabolismo , Transducción de Señal , Femenino , Fosfatidilinositol 3-Quinasas/metabolismo , Masculino , Regulación Neoplásica de la Expresión Génica
8.
J Cell Mol Med ; 28(10): e18391, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38809918

RESUMEN

TH1L (also known as NELF-C/D) is a member of the Negative Elongation Factor (NELF) complex, which is a metazoan-specific factor that regulates RNA Polymerase II (RNAPII) pausing and transcription elongation. However, the function and molecular mechanisms of TH1L in cancer progression are still largely unknown. In this study, we found that TH1L was highly expressed in colorectal cancer (CRC) tissues and the faeces of CRC patients. Overexpression of TH1L significantly enhanced the proliferation and migration of CRC cells, while its knockdown markedly suppressed these processes. In mechanism, RNA sequencing revealed that CCL20 was upregulated in TH1L-overexpressed CRC cells, leading to activation of the NF-κB signalling pathway. Rescue assays showed that knockdown of CCL20 could impair the tumour-promoting effects of THIL in CRC cells. Taken together, these results suggest that TH1L may play a vital role via the CCL20/NF-κB signalling pathway in CRC proliferation and migration and may serve as a potential target for diagnosis and therapy of CRC.


Asunto(s)
Movimiento Celular , Proliferación Celular , Quimiocina CCL20 , Neoplasias Colorrectales , Regulación Neoplásica de la Expresión Génica , FN-kappa B , Transducción de Señal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Línea Celular Tumoral , Movimiento Celular/genética , Quimiocina CCL20/metabolismo , Quimiocina CCL20/genética , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , FN-kappa B/metabolismo
9.
J Cell Mol Med ; 28(10): e18445, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38801403

RESUMEN

Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS), a prevalent urological ailment, exerts a profound influence upon the well-being of the males. Autoimmunity driven by Th17 cells has been postulated as a potential factor in CP/CPPS pathogenesis. Nonetheless, elucidating the precise mechanisms governing Th17 cell recruitment to the prostate, triggering inflammation, remained an urgent inquiry. This study illuminated that CCL20 played a pivotal role in attracting Th17 cells to the prostate, thereby contributing to prostatitis development. Furthermore, it identified prostate stromal cells and immune cells as likely sources of CCL20. Additionally, this research unveiled that IL-17A, released by Th17 cells, could stimulate macrophages to produce CCL20 through the NF-κB/MAPK/PI3K pathway. The interplay between IL-17A and CCL20 establishes a positive feedback loop, which might serve as a critical mechanism underpinning the development of chronic prostatitis, thus adding complexity to its treatment challenges.


Asunto(s)
Enfermedades Autoinmunes , Quimiocina CCL20 , Quimiotaxis , Interleucina-17 , Prostatitis , Células Th17 , Masculino , Prostatitis/inmunología , Prostatitis/patología , Prostatitis/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Quimiocina CCL20/metabolismo , Quimiocina CCL20/genética , Animales , Interleucina-17/metabolismo , Interleucina-17/inmunología , Ratones , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Enfermedades Autoinmunes/patología , Macrófagos/metabolismo , Macrófagos/inmunología , Modelos Animales de Enfermedad , FN-kappa B/metabolismo , Transducción de Señal , Humanos , Ratones Endogámicos C57BL , Próstata/patología , Próstata/metabolismo , Próstata/inmunología , Fosfatidilinositol 3-Quinasas/metabolismo , Autoinmunidad
10.
Funct Integr Genomics ; 24(3): 112, 2024 Jun 08.
Artículo en Inglés | MEDLINE | ID: mdl-38849609

RESUMEN

BACKGROUND: Hepatocellular carcinoma (HCC), a globally common cancer, often presents late and shows high resistance to chemotherapy, resulting in suboptimal treatment efficacy. Components from traditional Chinese medicines have been recognized for their anti-cancer properties. OBJECTIVE: Exploring the mechanism of Schisandra chinensis lignans and acteoside in suppressing Epithelial-Mesenchymal Transition (EMT) in hepatoma cells through the Extracellular signal-Regulated Kinases (ERK)1/2 pathway and identifying biomarkers, molecular subtypes, and targets via multi-omics for precision oncology. METHODS: Proliferation was assessed using cell counting kit-8 (CCK-8) assays, with scratch and transwell assays for evaluating invasion and migration. Flow cytometry quantified apoptosis rates. Expression levels of CCL20, p-ERK1/2, c-Myc, Vimentin, and E-cadherin/N-cadherin were analyzed by real-time PCR and Western blot. Tumor volume was calculated with a specific formula, and growth. RESULTS: The Schisandra chinensis lignans and acteoside combination decreased CCL20 expression, inhibited hepatoma proliferation and migration, and enhanced apoptosis in a dose- and time-dependent manner. Molecular analysis revealed increased E-cadherin and decreased N-cadherin, p-ERK1/2, c-Myc, and Vimentin expression, indicating ERK1/2 pathway modulation. In vivo, treated nude mice showed significantly reduced tumor growth and volume. CONCLUSION: Schisandra chinensis lignans and acteoside potentially counteract CCL20-induced EMT, invasion, and migration in hepatocellular carcinoma cells via the ERK1/2 pathway, enhancing apoptosis. Multi-omics analysis further aids in pinpointing novel biomarkers for precision cancer therapy.


Asunto(s)
Apoptosis , Carcinoma Hepatocelular , Proliferación Celular , Transición Epitelial-Mesenquimal , Glucósidos , Lignanos , Neoplasias Hepáticas , Sistema de Señalización de MAP Quinasas , Fenoles , Schisandra , Transición Epitelial-Mesenquimal/efectos de los fármacos , Humanos , Lignanos/farmacología , Schisandra/química , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Animales , Ratones , Proliferación Celular/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Fenoles/farmacología , Glucósidos/farmacología , Apoptosis/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Ratones Desnudos , Línea Celular Tumoral , Quimiocina CCL20/metabolismo , Quimiocina CCL20/genética , Ratones Endogámicos BALB C , Células Hep G2 , Multiómica , Polifenoles
11.
Nat Immunol ; 13(8): 744-52, 2012 Jun 24.
Artículo en Inglés | MEDLINE | ID: mdl-22729248

RESUMEN

Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1(hi) monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.


Asunto(s)
Quimiocinas/biosíntesis , Folículo Piloso/inmunología , Células de Langerhans/fisiología , Estrés Fisiológico , Alopecia , Animales , Movimiento Celular , Quimiocina CCL20/biosíntesis , Quimiocina CCL8/biosíntesis , Quimiocinas/metabolismo , Folículo Piloso/metabolismo , Humanos , Queratinocitos/metabolismo , Células de Langerhans/inmunología , Ratones , Ratones Pelados , Receptores CCR2/metabolismo , Receptores CCR6/metabolismo , Receptores CCR8/metabolismo , Piel/inmunología
12.
Cell Commun Signal ; 22(1): 224, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38600588

RESUMEN

BACKGROUND: Activation of VDR pathway was a promising anti-tumor therapy strategy. However, numerous clinical studies have demonstrated the effect of activating VDR is limited, which indicates that VDR plays a complex role in vivos. METHODS: We analyzed the TCGA database to examine the association between VDR expression and immune cell infiltration in pancreatic adenocarcinoma (PAAD). Western blot, ELISA, ChIP, and dual-luciferase reporter assays were performed to determine the mechanism of VDR regulating CCL20. Migration assay and immunofluorescence were used to investigate the role of CCL20 in M2 macrophage polarization and recruitment. We employed multiplexed immunohistochemical staining and mouse models to validate the correlation of VDR on macrophages infiltration in PAAD. Flow cytometry analysis of M2/M1 ratio in subcutaneous graft tumors. RESULTS: VDR is extensively expressed in PAAD, and patients with elevated VDR levels exhibited a significantly reduced overall survival. VDR expression in PAAD tissues was associated with increased M2 macrophages infiltration. PAAD cells overexpressing VDR promote macrophages polarization towards M2 phenotype and recruitment in vitro and vivo. Mechanistically, VDR binds to the CCL20 promoter and up-regulates its transcription. The effects of polarization and recruitment on macrophages can be rescued by blocking CCL20. Finally, the relationship between VDR and M2 macrophages infiltration was evaluated using clinical cohort and subcutaneous graft tumors. A positive correlation was demonstrated between VDR/CCL20/CD163 in PAAD tissues and mouse models. CONCLUSION: High expression of VDR in PAAD promotes M2 macrophage polarization and recruitment through the secretion of CCL20, which activates tumor progression. This finding suggests that the combination of anti-macrophage therapy may improve the efficacy of VDR activation therapy in PAAD.


Asunto(s)
Adenocarcinoma , Quimiocina CCL20 , Neoplasias Pancreáticas , Receptores de Calcitriol , Animales , Humanos , Ratones , Adenocarcinoma/patología , Línea Celular Tumoral , Quimiocina CCL20/metabolismo , Macrófagos/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Fenotipo , Receptores de Calcitriol/metabolismo , Microambiente Tumoral , Macrófagos Asociados a Tumores
13.
Cell Biol Toxicol ; 40(1): 56, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-39042313

RESUMEN

Programmed cell death ligand 2 (PD-L2), a ligand for the receptor programmed cell death 1 (PD-1), has an identity of 34% with its twin ligand PD-L1 and exhibits higher binding affinity with PD-1 than PD-L1. However, the role of PD-L2 in non-small cell lung cancer (NSCLC) progression, especially tobacco-induced cancer progression, has not been fully understood. Here, we found that PD-L2 promoted tumor growth in murine models with recruitment of regulatory T cells (Tregs). In patients with NSCLC, PD-L2 expression level in tumor samples was higher than in counterpart normal controls and was positively associated with patients' response to anti-PD-1 treatment. Mechanismly, PD-L2 bound its receptor Repulsive guidance molecule B (RGMB) on cancer cells and activated extracellular signal-regulated kinase (Erk) and nuclear factor κB (NFκB), leading to increased production of chemokine CCL20, which recruited Tregs and contributed to NSCLC progression. Consistently, knockdown of RGMB or NFκB p65 inhibited PD-L2-induced CCL20 production, and silencing of PD-L2 repressed Treg recruitment by NSCLC cells. Furthermore, cigarette smoke and carcinogen benzo(a)pyrene (BaP) upregulated PD-L2 in lung epithelial cells via aryl hydrocarbon receptor (AhR)-mediated transcription activation, whose deficiency markedly suppressed BaP-induced PD-L2 upregulation. These results suggest that PD-L2 mediates tobacco-induced recruitment of Tregs via the RGMB/NFκB/CCL20 cascade, and targeting this pathway might have therapeutic potentials in NSCLC.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Quimiocina CCL20 , Neoplasias Pulmonares , FN-kappa B , Proteína 2 Ligando de Muerte Celular Programada 1 , Linfocitos T Reguladores , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Humanos , FN-kappa B/metabolismo , Animales , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Proteína 2 Ligando de Muerte Celular Programada 1/metabolismo , Proteína 2 Ligando de Muerte Celular Programada 1/genética , Quimiocina CCL20/metabolismo , Quimiocina CCL20/genética , Ratones , Fumar Tabaco/efectos adversos , Transducción de Señal , Línea Celular Tumoral , Masculino , Femenino
14.
J Pediatr Gastroenterol Nutr ; 78(2): 211-216, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38374573

RESUMEN

BACKGROUND: Food protein-induced allergic proctocolitis (FPIAP) is a nonimmunoglobulin (IgE)-mediated food hypersensitivity and the exact mechanisms that cause FPIAP are unknown. Chemokines play crucial roles in the development of allergic diseases. OBJECTIVE: To examine serum levels of a group of chemokines in infants with FPIAP. METHODS: In 67 infants with FPIAP and 65 healthy infants, we measured serum levels of mucosa-associated epithelial chemokine (MEC/CCL28), thymus-expressed chemokine (TECK/CCL25), CX3CL1 and macrophage inflammatory protein (MIP)-3a/CCL20. RESULTS: Infants with FPIAP had a lower median value of MIP3a/CCL20 than healthy infants [0.7 (0-222) vs. 4 (0-249) pg/mL, respectively] (p < 0.001). Infants with MIP3a/CCL20 levels ≤0.95 pg/mL have 13.93 times more risk of developing FPIAP than infants with MIP3a/CCL20 levels >0.95 pg/mL. Serum MEC/CCL28, TECK/CCL25, and CX3CL1 levels were similar between the infants with FPIAP and the control group. CONCLUSION: MIP3a/CCL20 serum levels were reduced in infants with FPIAP compared with healthy controls. Whether this finding has a role in pathogenesis remains to be determined.


Asunto(s)
Quimiocina CCL20 , Hipersensibilidad a los Alimentos , Proctocolitis , Humanos , Lactante , Hipersensibilidad a los Alimentos/complicaciones , Proteínas Inflamatorias de Macrófagos , Membrana Mucosa , Quimiocina CCL20/sangre , Quimiocina CCL20/química
15.
BMC Psychiatry ; 24(1): 677, 2024 Oct 11.
Artículo en Inglés | MEDLINE | ID: mdl-39394574

RESUMEN

BACKGROUND: Major psychotic disorders (MPD), including schizophrenia (SCZ) and schizoaffective disorder (SAD), are severe neuropsychiatric conditions with unclear causes. Understanding their pathophysiology is essential for better diagnosis, treatment, and prognosis. Recent research highlights the role of inflammation and the immune system, particularly the Interleukin 17 (IL-17) family, in these disorders. Elevated IL-17 levels have been found in MPD, and human IL-17 A antibodies are available. Changes in chemokine levels, such as CCL20, are also noted in SCZ. This study investigates the relationship between serum levels of IL-17 A and CCL20 in MPD patients and their clinical characteristics. METHOD: We conducted a case-control study at the Ibn Sina Psychiatric Hospital (Mashhad, Iran) in 2023. The study involved 101 participants, of which 71 were MPD patients and 30 were healthy controls (HC). The Positive and Negative Symptom Scale (PANSS) was utilized to assess the symptoms of MPD patients. Serum levels of CCL20 and IL-17 A were measured using Enzyme-Linked Immunosorbent Assay (ELISA) kits. We also gathered data on lipid profiles and Fasting Blood Glucose (FBS). RESULTS: The mean age of patients was 41.04 ± 9.93 years. The median serum levels of CCL20 and IL-17 A were significantly elevated in MPD patients compared to HC (5.8 (4.1-15.3) pg/mL and 4.2 (3-5) pg/mL, respectively; p < 0.001). Furthermore, CCL20 and IL-17 A levels showed a positive correlation with the severity of MPD. MPD patients also had significantly higher FBS, cholesterol, and Low-Density Lipoprotein (LDL) levels, and lower High-Density Lipoprotein (HDL) levels compared to HC. No significant relationship was found between PANSS components and blood levels of IL17 and CCL20. CONCLUSION: The current study revealed that the serum levels of IL-17 A and CCL20 in schizophrenia patients are higher than those in the control group. Metabolic factors such as FBS, cholesterol, HDL, and LDL also showed significant differences between MPD and HC. In conclusion, the findings suggest that these two inflammatory factors could serve as potential therapeutic targets and prognostic biomarkers for schizophrenia.


Asunto(s)
Biomarcadores , Quimiocina CCL20 , Interleucina-17 , Trastornos Psicóticos , Esquizofrenia , Humanos , Interleucina-17/sangre , Quimiocina CCL20/sangre , Masculino , Estudios de Casos y Controles , Femenino , Trastornos Psicóticos/sangre , Trastornos Psicóticos/diagnóstico , Biomarcadores/sangre , Adulto , Esquizofrenia/sangre , Esquizofrenia/diagnóstico , Persona de Mediana Edad , Irán
16.
Eur J Oral Sci ; 132(5): e13019, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39302740

RESUMEN

In response to pro-inflammatory cytokines such as interleukin (IL)-1ß, dental pulp fibroblasts produce various inflammatory mediators, including IL-6, IL-8, CC chemokine ligand 20 (CCL20), and CXC chemokine ligand 10 (CXCL10), leading to the progression of pulpitis. IL-17/IL-17A (IL-17A) is a pro-inflammatory cytokine secreted by T helper (Th) 17 cells following their recruitment to inflamed sites; however, the roles of IL-17A during pulpitis remain unclear. The purpose of this study was to investigate the effect of IL-17A on IL-6, IL-8, CCL20 and CXCL10 production by human dental pulp fibroblasts (HDPFs) in vitro. IL-17A at a concentration of 100 ng/ml induced the production of 10 times more IL-8 and 4 times more CXCL10, but not IL-6 and CCL20, compared to controls. Co-stimulation of HDPFs with IL-17A and IL-1ß synergistically enhanced the production of IL-6, CCL20, IL-8 and CXCL10. IL-1ß increased expression of IL-17 receptor/IL-17RA (IL-17R) on HDPFs. Moreover, the cell signal pathways of p38 mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) were more potently activated by simultaneous stimulation with IL-17A and IL-1ß. These findings suggest that IL-17A participates in the progression of dental pulp inflammation through the enhanced production of inflammatory mediators in HDPFs.


Asunto(s)
Quimiocina CXCL10 , Pulpa Dental , Fibroblastos , Interleucina-17 , Interleucina-1beta , Interleucina-6 , Interleucina-8 , Humanos , Pulpa Dental/citología , Pulpa Dental/metabolismo , Pulpa Dental/efectos de los fármacos , Interleucina-17/farmacología , Interleucina-17/metabolismo , Fibroblastos/metabolismo , Fibroblastos/efectos de los fármacos , Interleucina-1beta/metabolismo , Quimiocina CXCL10/metabolismo , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Mediadores de Inflamación/metabolismo , Quimiocina CCL20/metabolismo , Pulpitis/metabolismo , Células Cultivadas , FN-kappa B/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Receptores de Interleucina-17/metabolismo
17.
Environ Toxicol ; 39(5): 3211-3224, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38356310

RESUMEN

Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by lung inflammation and high mortality rates. Lung cancer, specifically lung adenocarcinoma (LUAD), is a major cause of cancer-related deaths worldwide. Patients with LUAD, particularly those undergoing chemotherapy, are more likely to develop ARDS. ARDS inflicts major malfunctioning in the immune system. We suspected a certain shared pathogenic mechanism between these diseases. This study analyzed 503 LUAD patients from the TCGA-LUAD cohort as the training set, 85 LUAD cases from the GSE30219 cohort as the validation set, and 24 RNA-seq samples from ARDS mice model and control groups in the GSE2411 cohort. The differentially expressed genes (DEGs) of ARDS were analyzed using the limma package and screened by Cox and Lasso analysis. ssGSEA and xCell algorithms were utilized for immune landscaping. RT-qPCR analysis was used to determine the mRNA levels of key genes in both the LPS-induced ARDS model and human LUAD cell lines. We identified DEGs between ARDS and control groups, which were highly associated with cytokine production and leukocyte migration. A prognosis model for LUAD patients was developed based on the expressions of the key genes in the ARDS-derived DEGs, including FMO3, IL1R2, CCL20, CFTR, and GADD45G. A satisfactory efficacy was observed in both the training and validation cohorts. The model demonstrated increased effectiveness in predicting the intratumor immune profile and mutation status of LUAD. Moreover, we utilized LPS to induce the ARDS model, which resulted in elevated expressions of IL1R2 and CCL20. Additionally, CCL20 was upregulated in cancerous LUAD cell lines. We developed an ARDS-based model for stratifying LUAD prognosis. CCL20 was found to be elevated in both the ARDS model and LUAD, suggesting a shared underlying mechanism of these two diseases.


Asunto(s)
Adenocarcinoma del Pulmón , Adenocarcinoma , Neoplasias Pulmonares , Animales , Ratones , Humanos , Lipopolisacáridos , Adenocarcinoma del Pulmón/genética , Neoplasias Pulmonares/genética , Línea Celular , Quimiocina CCL20
18.
Int J Mol Sci ; 25(15)2024 Jul 24.
Artículo en Inglés | MEDLINE | ID: mdl-39125633

RESUMEN

Epstein-Barr virus (EBV) infection and various chemokines, including CCL20, CXCL8 and CXCL10 are considered to participate in the pathogenesis of multiple sclerosis (MS), and several studies point to a direct regulatory effect of EBV on the expression of these chemokines. In our study we hypothesized that serum concentrations of CCL20, CXCL8 and CXCL0 are induced in patients with relapsing-remitting MS (RRMS) in comparison to healthy individuals, and that they are associated with EBV infection. Serum concentrations of CXCL8 and CXCL10 were lower in RRMS patients in relapse in comparison to healthy controls. Although potential effects of corticosteroid therapy introduced in a subgroup of RRMS patients prior to sampling were excluded by subgroup comparison, this possibility has to be considered while interpreting the results. We found an inverse association between serum concentrations of CXCL8 and anti-Epstein-Barr Virus Nuclear Antigen (EBNA) IgG and decreased expression of CXCL8 in peripheral blood mononuclear cells (PBMC) in relapse compared to remission. Lower serum concentrations of CXCL8 and CXCL10 in RRMS patients and decreased peripheral production of CXCL8 in relapse may indicate compensatory anti-inflammatory counter-regulation in MS.


Asunto(s)
Quimiocina CCL20 , Quimiocina CXCL10 , Herpesvirus Humano 4 , Interleucina-8 , Esclerosis Múltiple Recurrente-Remitente , Humanos , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/inmunología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/virología , Femenino , Quimiocina CXCL10/sangre , Adulto , Masculino , Herpesvirus Humano 4/inmunología , Quimiocina CCL20/sangre , Interleucina-8/sangre , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Infecciones por Virus de Epstein-Barr/sangre , Infecciones por Virus de Epstein-Barr/inmunología , Infecciones por Virus de Epstein-Barr/virología , Persona de Mediana Edad , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/inmunología , Estudios de Casos y Controles
19.
Cancer Sci ; 114(4): 1479-1490, 2023 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-36479732

RESUMEN

The suppression of androgen receptor (AR) expression exacerbates the migration potential of prostate cancer. This study identified a previously unrecognized regulation of the AR-controlled pathway that promotes migration potential in prostate cancer cells. Prostate cancer cells that pass through a transwell membrane (mig cells) have a higher migration potential with a decreased AR expression than parental cells. In this study, we aimed to elucidate the mechanism of migration enhancement associated with the suppression of AR signaling. Expression of C-C motif ligand 20 (CCL20) is upregulated in mig cells, unlike in the parental cells. Knockdown of AR with small interfering RNA (siAR) in LNCaP and C4-2B cells increased CCL20 secretion and enhanced the migration of cancer cells. Mig cells, CCL20-treated cells, and siAR cells promoted cell migration with an enhancement of AKT phosphorylation and Snail expression, while the addition of a C-C chemokine receptor 6 (CCR6, the specific receptor of CCL20) inhibitor, anti-CCL20 antibody, and AKT inhibitor suppressed the activation of AKT and Snail. With 59 samples of prostate cancer tissue, CCL20 secretion was profuse in metastatic cases despite low AR expression levels. Snail expression was associated with the expression of CCL20 and CCR6. A xenograft study showed that the anti-CCL20 antibody significantly inhibited Snail expression, thereby suggesting a new therapeutic approach for castration-resistant prostate cancer with the inhibition of the axis between CCL20 and CCR6.


Asunto(s)
Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-akt , Masculino , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Receptores Androgénicos , Transducción de Señal , Quimiocina CCL20/genética , Quimiocina CCL20/metabolismo , Línea Celular Tumoral , Receptores CCR6/genética , Proliferación Celular
20.
Kidney Int ; 104(1): 74-89, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36924892

RESUMEN

Previous studies have identified a unique Treg population, which expresses the Th17 characteristic transcription factor RORγt. These RORγt+ Tregs possess enhanced immunosuppressive capacity, which endows them with great therapeutic potential. However, as a caveat, they are also capable of secreting pro-inflammatory IL-17A. Since the sum function of RORγt+ Tregs in glomerulonephritis (GN) remains unknown, we studied the effects of their absence. Purified CD4+ T cell populations, containing or lacking RORγt+ Tregs, were transferred into immunocompromised RAG1 knockout mice and the nephrotoxic nephritis model of GN was induced. Absence of RORγt+ Tregs significantly aggravated kidney injury, demonstrating overall kidney-protective properties. Analyses of immune responses showed that RORγt+ Tregs were broadly immunosuppressive with no preference for a particular type of T cell response. Further characterization revealed a distinct functional and transcriptional profile, including enhanced production of IL-10. Expression of the chemokine receptor CCR6 marked a particularly potent subset, whose absence significantly worsened GN. As an underlying mechanism, we found that chemokine CCL20 acting through receptor CCR6 signaling mediated expansion and activation of RORγt+ Tregs. Finally, we also detected an increase of CCR6+ Tregs in kidney biopsies, as well as enhanced secretion of chemokine CCL20 in 21 patients with anti-neutrophil cytoplasmic antibody associated GN compared to that of 31 healthy living donors, indicating clinical relevance. Thus, our data characterize RORγt+ Tregs as anti-inflammatory mediators of GN and identify them as promising target for Treg directed therapies.


Asunto(s)
Glomerulonefritis , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares , Ratones , Animales , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Linfocitos T Reguladores , Quimiocina CCL20/genética , Quimiocina CCL20/metabolismo , Riñón/patología , Ratones Noqueados , Células Th17 , Receptores CCR6/genética , Receptores CCR6/metabolismo
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