RESUMO
As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs can induce both immune activation and immune tolerance according to the peripheral cues. Recent work has established that DCs comprise several phenotypically and functionally heterogeneous subsets that differentially regulate T lymphocyte differentiation. This review summarizes both mouse and human DC subset phenotypes, development, diversification, and function. We focus on advances in our understanding of how different DC subsets regulate distinct CD4+ T helper (Th) cell differentiation outcomes, including Th1, Th2, Th17, T follicular helper, and T regulatory cells. We review DC subset intrinsic properties, local tissue microenvironments, and other immune cells that together determine Th cell differentiation during homeostasis and inflammation.
Assuntos
Tolerância Imunológica , Ativação Linfocitária , Animais , Células Dendríticas , Humanos , Camundongos , Linfócitos T Reguladores , Células Th17RESUMO
Allergic conjunctivitis is a chronic inflammatory disease that is characterized by severe itch in the conjunctiva, but how neuro-immune interactions shape the pathogenesis of severe itch remains unclear. We identified a subset of memory-type pathogenic Th2 cells that preferentially expressed Il1rl1-encoding ST2 and Calca-encoding calcitonin-gene-related peptide (CGRP) in the inflammatory conjunctiva using a single-cell analysis. The IL-33-ST2 axis in memory Th2 cells controlled the axonal elongation of the peripheral sensory C-fiber and the induction of severe itch. Pharmacological blockade and genetic deletion of CGRP signaling in vivo attenuated scratching behavior. The analysis of giant papillae from patients with severe allergic conjunctivitis revealed ectopic lymphoid structure formation with the accumulation of IL-33-producing epithelial cells and CGRP-producing pathogenic CD4+ T cells accompanied by peripheral nerve elongation. Thus, the IL-33-ST2-CGRP axis directs severe itch with neuro-reconstruction in the inflammatory conjunctiva and is a potential therapeutic target for severe itch in allergic conjunctivitis.
Assuntos
Conjuntivite Alérgica , Neuropeptídeos , Humanos , Interleucina-33/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Peptídeo Relacionado com Gene de Calcitonina , Conjuntivite Alérgica/patologia , Células Th2 , Calcitonina , Prurido/patologia , Túnica Conjuntiva/patologia , NeurôniosRESUMO
Type 2 lymphocytes promote both physiologic tissue remodeling and allergic pathology, yet their physical tissue niches are poorly described. Here, we used quantitative imaging to define the tissue niches of group 2 innate lymphoid cells (ILC2s), which are critical instigators of type 2 immunity. We identified a dominant adventitial niche around lung bronchi and larger vessels in multiple tissues, where ILC2s localized with subsets of dendritic and regulatory T cells. However, ILC2s were most intimately associated with adventitial stromal cells (ASCs), a mesenchymal fibroblast-like subset that expresses interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP). In vitro, ASCs produced TSLP that supported ILC2 accumulation and activation. ILC2s and IL-13 drove reciprocal ASC expansion and IL-33 expression. During helminth infection, ASC depletion impaired lung ILC2 and Th2 cell accumulation and function, which are in part dependent on ASC-derived IL-33. These data indicate that adventitial niches are conserved sites where ASCs regulate type 2 lymphocyte expansion and function.
Assuntos
Imunidade Inata/imunologia , Linfócitos/imunologia , Células Estromais/imunologia , Animais , Brônquios/imunologia , Citocinas/imunologia , Interleucina-13/imunologia , Interleucina-33/imunologia , Camundongos , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Linfopoietina do Estroma do TimoRESUMO
Memory T cells provide long-lasting protective immunity, and distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes remain unknown. We found that interleukin-33 (IL-33) enhanced amphiregulin production by the IL-33 receptor, ST2hi memory T helper 2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and osteopontin-producing eosinophils. Thus, the IL-33-amphiregulin-osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.
Assuntos
Anfirregulina/imunologia , Eosinófilos/imunologia , Osteopontina/metabolismo , Fibrose Pulmonar/imunologia , Transdução de Sinais/imunologia , Células Th2/imunologia , Anfirregulina/biossíntese , Anfirregulina/metabolismo , Anfirregulina/farmacologia , Animais , Modelos Animais de Doenças , Receptores ErbB/metabolismo , Feminino , Memória Imunológica/imunologia , Imunomodulação , Interleucina-33/metabolismo , Camundongos , Rinite/imunologia , Rinite/patologia , Sinusite/imunologia , Sinusite/patologia , Transcrição Gênica/efeitos dos fármacosRESUMO
The local regulation of type 2 immunity relies on dialog between the epithelium and the innate and adaptive immune cells. Here we found that alarmin-induced expression of the co-stimulatory molecule OX40L on group 2 innate lymphoid cells (ILC2s) provided tissue-restricted T cell co-stimulation that was indispensable for Th2 and regulatory T (Treg) cell responses in the lung and adipose tissue. Interleukin (IL)-33 administration resulted in organ-specific surface expression of OX40L on ILC2s and the concomitant expansion of Th2 and Treg cells, which was abolished upon deletion of OX40L on ILC2s (Il7raCre/+Tnfsf4fl/fl mice). Moreover, Il7raCre/+Tnfsf4fl/fl mice failed to mount effective Th2 and Treg cell responses and corresponding adaptive type 2 pulmonary inflammation arising from Nippostrongylus brasiliensis infection or allergen exposure. Thus, the increased expression of OX40L in response to IL-33 acts as a licensing signal in the orchestration of tissue-specific adaptive type 2 immunity, without which this response fails to establish.
Assuntos
Imunidade Adaptativa/imunologia , Imunidade Inata/imunologia , Glicoproteínas de Membrana/imunologia , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Fatores de Necrose Tumoral/imunologia , Animais , Diferenciação Celular/imunologia , Interleucina-33/imunologia , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Camundongos , Ligante OX40RESUMO
Conventional dendritic cells (cDCs) can integrate multiple stimuli from the environment and provide three separate outputs in terms of antigen presentation, costimulation, and cytokine production; this guides the activation, expansion, and differentiation of distinct functional T helper subsets. Accordingly, the current dogma posits that T helper cell specification requires these three signals in sequence. Data show that T helper 2 (Th2) cell differentiation requires antigen presentation and costimulation from cDCs but does not require polarizing cytokines. In this opinion article, we propose that the 'third signal' driving Th2 cell responses is, in fact, the absence of polarizing cytokines; indeed, the secretion of the latter is actively suppressed in cDCs, concomitant with acquired pro-Th2 functions.
Assuntos
Citocinas , Células Th2 , Humanos , Linfócitos T Auxiliares-Indutores , Diferenciação Celular , Células Th1RESUMO
CD4+ memory T cells are central to long-lasting protective immunity and are involved in shaping the pathophysiology of chronic inflammation. While metabolic reprogramming is critical for the generation of memory T cells, the mechanisms controlling the redox metabolism in memory T cell formation remain unclear. We found that reactive oxygen species (ROS) metabolism changed dramatically in T helper-2 (Th2) cells during the contraction phase in the process of memory T cell formation. Thioredoxin-interacting protein (Txnip), a regulator of oxidoreductase, regulated apoptosis by scavenging ROS via the nuclear factor erythroid 2-related factor 2 (Nrf2)-biliverdin reductase B (Blvrb) pathway. Txnip regulated the pathology of chronic airway inflammation in the lung by controlling the generation of allergen-specific pathogenic memory Th2 cells in vivo. Thus, the Txnip-Nrf2-Blvrb axis directs ROS metabolic reprogramming in Th2 cells and is a potential therapeutic target for intractable chronic inflammatory diseases.
Assuntos
Células T de Memória , Fator 2 Relacionado a NF-E2 , Humanos , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Oxirredução , Inflamação , Tiorredoxinas/genética , Tiorredoxinas/metabolismoRESUMO
CD4+T cells play a central role in orchestrating the immune response in asthma, with dysregulated ion channel profiles and altered metabolic signatures contributing to disease progression and severity. An important classification of asthma is based on the presence of T-helper cell type 2 (Th2) inflammation, dividing patients into Th2-high and Th2-low endotypes. These distinct endotypes have implications for disease severity, treatment response, and prognosis. By elucidating how ion channels and the energy metabolism control Th cells in asthma, this review contributes to the pathophysiological understanding and the prospective development of personalized therapeutic treatment strategies for patients suffering from distinct asthma endotypes.
RESUMO
BACKGROUND: Asthma is a common immune disease with high morbidity in children. Type 2 inflammation is the center of asthma development, and mainly mediated by a subset of CD4 + T cells, T helper 2 (Th2) cells. Excess Th2 differentiation was generally associated with asthmatic attack. Casitas B-lineage lymphoma (c-CBL) was reported to involved in T cell development and databank showed its decreased expression in CD4 + T cells from peripheral blood of asthmatic children. This study aims to investigate the role of c-CBL in childhood asthma and Th2 differentiation, and explore the underlying mechanism. METHODS: We collected peripheral blood samples from clinical childhood asthma cases and healthy controls, and determined c-CBL expression in CD4 + T cells. Asthma was induced in neonatal mice by ovalbumin (OVA) intraperitoneal injection and aerosol inhalation, and c-CBL expression in CD4 + T cells from peripheral blood and spleen was measured. Gain-of-function experiments was performed to confirm the effects of c-CBL on Th2 differentiation in vitro. Finally, c-CBL was delivered into asthmatic mice via lentivirus infection to verify its effects on experimental asthma. RESULTS: c-CBL was lowly expressed in CD4 + T cells from asthmatic children than those of healthy controls. Similarly, it was downregulated in CD4 + T cells from peripheral blood and spleen of asthma mice. Overexpression of c-CBL restrained lung pathological injury and type 2 inflammation in experimental asthmatic mice. Gain-of-function experiments demonstrated that c-CBL inhibited Th2 differentiation of CD4 + T cells from healthy children, and mediated the ubiquitination of lymphocyte cell-specific protein-tyrosine kinase (LCK). LCK acted as a kinase to phosphorylate and activate c-JUN, which was predicted to bind promoter sequence of CD28 by bioinformatic analysis. Dual-luciferase reporter assay verified that c-JUN and ETS1 synergically enhanced transcription of CD28, and this transcription activation was aggravated by LCK overexpression. CONCLUSION: c-CBL alleviated asthma and suppressed Th2 differentiation by facilitating LCK ubiquitination, interrupting c-JUN activation and CD28 expression in vivo and in vitro. c-CBL/LCK/c-JUN/ETS1/CD28 axis was partially involved in childhood asthma, and may provide novel insights for clinical treatment for asthma.
Assuntos
Asma , Antígenos CD28 , Diferenciação Celular , Proteína Proto-Oncogênica c-ets-1 , Proteínas Proto-Oncogênicas c-cbl , Células Th2 , Asma/metabolismo , Asma/imunologia , Asma/genética , Animais , Proteínas Proto-Oncogênicas c-cbl/metabolismo , Proteínas Proto-Oncogênicas c-cbl/genética , Humanos , Células Th2/metabolismo , Células Th2/imunologia , Camundongos , Criança , Masculino , Feminino , Proteína Proto-Oncogênica c-ets-1/metabolismo , Proteína Proto-Oncogênica c-ets-1/genética , Antígenos CD28/metabolismo , Antígenos CD28/genética , Modelos Animais de Doenças , Transdução de Sinais , Pré-EscolarRESUMO
Parasitic nematodes infect more than 1 billion people in the global south. The development of effective antihelminthic vaccines is a crucial tool for their future elimination. Protective immune responses to nematodes depend on Gata3+ Th2 cells, which can also be induced by nematode-released products. Whether these nematode products induce antigen-specific long-lived memory T cells and thereby confer protection against a challenge infection is not known yet. Hence, we set out to characterize the formation of memory Th2 cells induced by immunization with Heligmosomoides polygyrus excretory-secretory (HES) products, infection-induced versus immunization-induced recall responses to a challenge infection, and whether HES-induced memory T cells show protective properties following adoptive transfer. Our results show that 8 weeks postimmunization, HES induces long-lived functional memory Th2 cells at the site of immunization in the peritoneal cavity. Following a H. polygyrus challenge infection, HES-immunized mice display MHC-II-dependent antigen-specific Th2 cytokine responses in the gut-draining lymph nodes, comparable to those induced by a prior natural infection. Moreover, adoptive transfer of sorted memory CD4+ T cells from HES-immunized donors reduces female worm fecundity following a challenge H. polygyrus infection in recipient mice, highlighting a protective role for immunization-induced memory T cells.
Assuntos
Nematoides , Nematospiroides dubius , Infecções por Strongylida , Camundongos , Feminino , Animais , Células Th2 , Imunização , Citocinas , Vacinação , Camundongos Endogâmicos BALB CRESUMO
T helper 2 (Th2) cells stochastically express from the Il4 locus but it has not been determined whether allelic expression is linked or independent. Here, we provide evidence that alleles are independently activated and inactivated. We compared Il4 locus expression in T cells from hemizygous IL-4 reporter mice in culture and in vivo following exposure to type 2 immunogens. In culture, Il4 alleles had independent, heritable expression probabilities. Modeling showed that in co-expressors, dual allele transcription occurs for only short periods, limiting per-cell mRNA variation in individual cells within a population of Th2 cells. In vivo profiles suggested that early in the immune response, IL-4 output was derived predominantly from single alleles, but co-expression became more frequent over time and were tuned by STAT6, supporting the probabilistic regulation of Il4 alleles in vivo among committed IL-4 producers. We suggest an imprinted probability of expression from individual alleles with a short transcriptional shutoff time controls the magnitude of T cell IL-4 output, but the amount produced per allele is amplified by STAT6 signaling. This form of regulation may be a relevant general mechanism governing cytokine expression.
Assuntos
Interleucina-4 , Células Th2 , Animais , Camundongos , Alelos , Citocinas , RNA Mensageiro/genéticaRESUMO
Modelling atopic dermatitis (AD) in vitro is paramount to understand the disease pathophysiology and identify novel treatments. Previous studies have shown that the Th2 cytokines IL-4 and IL-13 induce AD-like features in keratinocytes in vitro. However, it has not been systematically researched whether the addition of Th2 cells, their supernatants or a 3D structure is superior to model AD compared to simple 2D cell culture with cytokines. For the first time, we investigated what in vitro option most closely resembles the disease in vivo based on single-cell RNA sequencing data (scRNA-seq) obtained from skin biopsies in a clinical study and published datasets of healthy and AD donors. In vitro models were generated with primary fibroblasts and keratinocytes, subjected to cytokine treatment or Th2 cell cocultures in 2D/3D. Gene expression changes were assessed using qPCR and Multiplex Immunoassays. Of all cytokines tested, incubation of keratinocytes and fibroblasts with IL-4 and IL-13 induced the closest in vivo-like AD phenotype which was observed in the scRNA-seq data. Addition of Th2 cells to fibroblasts failed to model AD due to the downregulation of ECM-associated genes such as POSTN. While keratinocytes cultured in 3D showed better stratification than in 2D, changes induced with AD triggers did not better resemble AD keratinocyte subtypes observed in vivo. Taken together, our comprehensive study shows that the simple model using IL-4 or IL-13 in 2D most accurately models AD in fibroblasts and keratinocytes in vitro, which may aid the discovery of novel treatment options.
Assuntos
Dermatite Atópica , Fibroblastos , Interleucina-13 , Interleucina-4 , Queratinócitos , Análise de Sequência de RNA , Análise de Célula Única , Células Th2 , Humanos , Fibroblastos/metabolismo , Interleucina-4/farmacologia , Interleucina-4/metabolismo , Interleucina-13/metabolismo , Interleucina-13/farmacologia , Citocinas/metabolismo , Técnicas de Cocultura , RNA-Seq , Células Cultivadas , Pele/patologiaRESUMO
Allergic rhinitis (AR) is characterized by nasal symptoms such as rubbing and sneezing, often triggered by allergen exposure. The purpose of this study is to dissect the roles of NLRP3-mediated immune modulation and macrophage pyroptosis in modulating T cell differentiation within the context of ovalbumin (OVA)-induced AR in mice. OVA-induced AR was established in mice, evaluating nasal symptoms, macrophage infiltration, cytokine levels, and T cell differentiation. Manipulations using NLRP3-/-, ASC-/- mice, clodronate liposome treatment, and NLRP3 inhibitor MCC950 were performed to assess their impact on AR symptoms and immune responses. Following OVA stimulation, increased nasal symptoms were observed in the OVA group along with augmented GATA3 expression and elevated IL-4 and IL-1b levels, indicative of Th2 polarization and cellular pyroptosis involvement. NLRP3-/- and ASC-/- mice exhibited reduced CD3+ T cells post OVA induction, implicating cellular pyroptosis in AR. Macrophage depletion led to decreased IgE levels, highlighting their involvement in allergic responses. Further investigations revealed enhanced macrophage pyroptosis, influencing Th1/Th2 differentiation in AR models. IL-18 released through NLRP3-mediated pyroptosis induced Th2 differentiation, distinct from IL-1b. Additionally, MCC950 effectively mitigated AR symptoms by modulating Th2 responses and reducing macrophage infiltration. This comprehensive study unravels the pivotal role of NLRP3-mediated immune modulation and macrophage pyroptosis in Th1/Th2 balance regulation in OVA-induced AR. Targeting NLRP3 pathways with MCC950 emerged as a promising strategy to alleviate AR symptoms, providing insights for potential therapeutic interventions in AR management.
Assuntos
Rinite Alérgica , Células Th2 , Camundongos , Animais , Células Th2/metabolismo , Interleucina-18/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Mucosa Nasal/metabolismo , Ovalbumina/metabolismo , Ovalbumina/farmacologia , Rinite Alérgica/tratamento farmacológico , Citocinas/metabolismo , Imunomodulação , Imunidade , Modelos Animais de Doenças , Camundongos Endogâmicos BALB CRESUMO
Protein regulator of cytokinesis 1 (PRC1) is involved in cytokinesis. Growing evidence suggests the association of PRC1 with multiple cancers. Here, we unveil that, in 28 cancer types, PRC1 is higher expressed in tumor tissues than in non-malignant tissues. Overexpression of PRC1 indicates unfavorable prognostic value, especially in ACC, LGG, KIRP, LICH, LUAD, MESO, PAAD, SARC and UCEC, while methylation of the PRC1 gene at sites associated with its inactivation has a favorable prognostic value in ACC, KIRP, LUAD, MESO, KIRP and LGG. Differentially expressed genes (DEGs) associated with high (> median) PRC1 expression contribute to key signaling pathways related with cell cycle, DNA damage and repair, EMT, cell migration, invasion and cell proliferation in most cancer types. More specifically, the DEGs involved in RAS/RAF/MAPK, PI3K/AKT, WNT, NOTCH, TGF-ß, integrin, EMT process, focal adhesion, RHO GTPase-related pathway or microtubule cytoskeleton regulation are upregulated when PRC1 expression is above median, as confirmed for most cancers. Most importantly, high expression of PRC1 appears to be associated with an overabundance of poor-prognosis TH2 cells. Furthermore, positive correlations of PRC1 and some immune checkpoint genes (CD274, CTLA4, HAVCR2, LAG3, PDCD1, PDCD1LG2, TIGIT, and CD86) were observed in several cancers, especially BLCA, BRCA, KIRC, LUAD, LIHC, PRAD and THCA. These findings plead in favor of further studies validating the diagnostic and prognostic impact of PRC1 as well as the elaboration of pharmacological strategies for targeting PRC1.
Assuntos
Citocinese , Neoplasias , Humanos , Fosfatidilinositol 3-Quinases , Neoplasias/genética , Proliferação de Células , Transdução de SinaisRESUMO
INTRODUCTION: Although IgE-mediated food allergy (FA) and eosinophilic gastrointestinal disorders (EGID) are clinically distinct and treated differently, pathogenic effector Th2 (peTh2) cells are implicated in the pathogenesis of both FA and EGID. The aim of this study was to better characterize peTh2 cells in the context of FA and EGID and the overlap between these two conditions. METHODS: Peripheral blood peTh2 cells (CD3+CD4+CD27-CD49d+CRTH2+CD161+) were profiled by intracellular cytokine flow cytometry in the following patient cohorts: patients with FA alone (n = 8), FA and food-triggered EGID (EGID+FA+FT, n = 7), food-triggered EGID alone (EGID+FT, n = 7), EGID without FA or specific food triggers (ONLY_EGID, n = 9), and healthy volunteers (HV, n = 7). Overnight peripheral blood mononuclear cell (PBMC) culture supernatants were assessed for cytokine production by multiplex analysis. RESULTS: CRTH2+CD161+ (peTh2) memory CD4+ T cells were significantly increased in both patients with FA and those with ALL_EGID (inclusive of EGID+FA+FT, EGID+FT and ONLY_EGID) when compared to HV. However, ALL_EGID patients, particularly those with EGID+FA+FT, had significantly elevated IL-5+IL-13+ peTh2 cells, whereas FA patients had significantly elevated IFN-γ or IL-17A-expressing peTh2 cells. This finding was supported by increased spontaneous IL-5 and IL-13 production in overnight cultures of PBMC from EGID+FA+FT patients compared to spontaneous IL-10 and IFN-γ production by PBMC from FA patients. FA patients had increased IL-9, IL-10, IL-17A, and IFN-γ production in overnight cultures of stimulated PBMC. CONCLUSIONS: EGID and IgE-mediated FA share a common cell subtype defined by specific surface markers and termed CRTH2+CD161+ (peTh2) memory CD4+ T cells. However, the cytokine profiles of these CRTH2+CD161+ (peTh2) memory CD4+ T cells are markedly different between the two disorders.
Assuntos
Hipersensibilidade Alimentar , Gastroenteropatias , Humanos , Linfócitos T CD4-Positivos , Interleucina-17/metabolismo , Interleucina-10 , Leucócitos Mononucleares/metabolismo , Interleucina-5 , Interleucina-13 , Citocinas/metabolismo , Imunoglobulina ERESUMO
BACKGROUND: Type 2-high asthma is characterized by elevated levels of circulating Th2 cells and eosinophils, cells that express chemoattractant-homologous receptor expressed on Th2 cells (CRTh2). Severe asthma is more common in women than men; however, the underlying mechanism(s) remain elusive. Here we examined whether the relationship between severe asthma and type 2 inflammation differs by sex and if estrogen influences Th2 cell response to glucocorticoid (GC). METHODS: Type 2 inflammation and the proportion of blood Th2 cells (CD4+ CRTh2+ ) were assessed in whole blood from subjects with asthma (n = 66). The effects of GC and estrogen receptor alpha (ERα) agonist on in vitro differentiated Th2 cells were examined. Expression of CRTh2, type 2 cytokines and degree of apoptosis (Annexin V+ , 7-AAD) were determined by flow cytometry, qRT-PCR, western blot and ELISA. RESULTS: In severe asthma, the proportion of circulating Th2 cells and hospitalizations were higher in women than men. Women with severe asthma also had more Th2 cells and serum IL-13 than women with mild/moderate asthma. Th2 cells, eosinophils and CRTh2 mRNA correlated with clinical characteristics associated with asthma control in women but not men. In vitro, GC and ERα agonist treated Th2 cells exhibited less apoptosis, more CRTh2 as well as IL-5 and IL-13 following CRTh2 activation than Th2 cells treated with GC alone. CONCLUSION: Women with severe asthma had higher levels of circulating Th2 cells than men, which may be due to estrogen modifying the effects of GC, enhancing Th2 cell survival and type 2 cytokine production.
Assuntos
Asma , Receptores de Glucocorticoides , Humanos , Feminino , Receptores de Glucocorticoides/metabolismo , Receptor alfa de Estrogênio/metabolismo , Interleucina-13/metabolismo , Receptores Imunológicos/genética , Receptores de Prostaglandina/genética , Inflamação/metabolismo , Asma/tratamento farmacológico , Células Th2/metabolismo , Glucocorticoides/uso terapêutico , Prostaglandina D2/metabolismoRESUMO
BACKGROUND: MicroRNA (miR)-185-5p participates in the pathology of asthma by regulating immune imbalance, inflammation, periostin synthesis, and smooth muscle contraction. This study intended to explore the dysregulation of miR-185p and its correlation with T-helper (Th)1, Th2 cells, and inflammatory cytokines in childhood asthma. METHODS: In 150 childhood asthma patients and 30 healthy controls (HCs), miR-185-5p from peripheral blood mononuclear cells was detected using reverse transcription-quantitative polymerase chain reaction, Th cells from peripheral blood samples were detected using flow cytometry, inflammatory cytokines from serum samples were detected using enzyme-linked immunosorbent assay. RESULTS: MiR-185-5p was increased in childhood asthma patients versus HCs [median (interquartile range (IQR)): 2.315 (1.770-3.855) versus 1.005 (0.655-1.520)] (P < 0.001). Meanwhile, miR-185-5p was negatively associated with Th1 cells (P = 0.035) but positively correlated with Th2 cells (P = 0.006) and IL-4 (P = 0.003) in childhood asthma patients; however, miR-185-5p was not linked to Th1 cells, Th2 cells, IFN-γ, or IL-4 in HCs (all P > 0.05). In addition, miR-185-5p was positively related to TNF-α (P < 0.001), IL-1ß (P = 0.015), and IL-6 (P = 0.008) in childhood asthma patients, miR-185-5p was only linked to TNF-α (P = 0.040) but not IL-1ß or IL-6 (both P > 0.05) in HCs. Moreover, miR-185-5p was increased in exacerbated childhood asthma patients versus remissive patients [median (IQR): 3.170 (2.070-4.905) versus 1.900 (1.525-2.615)] (P < 0.001). Besides, miR-185-5p was highest in patients with severe exacerbation followed by patients with moderate exacerbation, and lowest in patients with mild exacerbation (P = 0.010). CONCLUSION: MiR-185-5p is associated with imbalanced Th1/Th2 cells, increased inflammatory cytokines along with elevated exacerbation risk, and severity in childhood asthma patients.
Assuntos
Asma , MicroRNAs , Humanos , Células Th2 , Interleucina-4 , Fator de Necrose Tumoral alfa , Leucócitos Mononucleares , Interleucina-6 , Células Th1 , CitocinasRESUMO
Dendritic cell (DC) activation and cytokine production is tightly regulated. In this study, we found that Zbtb10 expression is activation dependent and it is essential for the immunogenic function of cDC1. Zbtb10 knockdown (KD) significantly reduced the expression of co-stimulatory genes CD80 and CD86 along with cytokines including IL-12, IL-6, and IL-10, in activated cDC1 Mutu-DC line. Consequently, the clonal expansion of CD44+ effector T cells in co-cultured CD4+ T cells was drastically reduced owing to significantly reduced IL-2. At the same time, these CD44+ effector T cells were unable to differentiate toward Tbet+ IFNγ+ Th1 subtype. Instead, an increased frequency of Th2 cells expressing GATA3+ and IL-13+ was observed. Interestingly, in Zbtb10 KD condition the co-cultured T cells depicted increased expression of PD1 and LAG3, the T-cell anergic markers. Moreover, the global transcriptome analysis identified that Zbtb10 is pertinent for DC activation and its depletion in cDC1 completely shuts down their immune responses. Mechanistic analysis revealed that Zbtb10 KD enhanced the expression of NKRF (NF-κB repressing factor) leading to drastic suppression of NF-κB related genes. Zbtb10 KD abrogated p65 and RelB nuclear translocation, thereby controlling the activation and maturation of cDC1 and the ensuing adaptive T cell responses.
Assuntos
Citocinas/biossíntese , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Fatores de Transcrição/metabolismo , Animais , Biomarcadores , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Linhagem Celular , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Ativação Linfocitária/imunologia , Camundongos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
A20 (Tnfaip3), a ubiquitin-editing enzyme, inhibits NF-κB signaling pathways in response to pro-inflammatory cytokines. Previous studies have proved the anti-inflammatory roles of A20 in various cell types, including T cells, B cells, dendritic cells, and intestinal epithelial cells. Moreover, recent studies have shown that A20 expressed in lung epithelial cells is required for LPS-induced protection from asthma. In humans, a single-nucleotide polymorphism in TNFAIP3 is associated with asthma risk. However, the role of A20 expressed in T cells in asthmatic responses has not been elucidated. We addressed this point by generating mice lacking A20 expression in T cells (CD4-CreA20 fl/fl mice). We found that house dust mite (HDM)-induced allergic airway inflammation, mucus production, airway hyperresponsiveness, and Th2 cytokine production were significantly exacerbated in CD4-CreA20 fl/fl mice compared with those in control A20 fl/fl mice. In vitro differentiation of Th2 cells but not of Th1 cells or Th17 cells was enhanced in CD4+ T cells by the absence of A20. Consistently, enforced expression of A20 inhibited the differentiation of Th2 cells but not of Th1 cells or Th17 cells. Notably, the expression of GATA3 was significantly enhanced in A20-deficient CD4+ T cells, and the enhanced GATA3 expression was partly canceled by IL-2 neutralization. These results suggest that A20 functions as a stabilizing factor maintaining GATA3 levels during the induction of Th2 cells to prevent excessive Th2 cell differentiation.
Assuntos
Asma , Células Th2 , Animais , Camundongos , Anti-Inflamatórios/metabolismo , Asma/genética , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Interleucina-2/metabolismo , Lipopolissacarídeos/metabolismo , NF-kappa B/metabolismo , Pyroglyphidae , Células Th1/metabolismo , Células Th17/metabolismo , Células Th2/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Ubiquitinas/metabolismo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Epidermal melanocyte loss in vitiligo, triggered by stresses ranging from trauma to emotional stress, chemical exposure or metabolite imbalance, to the unknown, can stimulate oxidative stress in pigment cells, which secrete damage-associated molecular patterns that then initiate innate immune responses. Antigen presentation to melanocytes leads to stimulation of autoreactive T-cell responses, with further targeting of pigment cells. Studies show a pathogenic basis for cellular stress, innate immune responses and adaptive immunity in vitiligo. Improved understanding of the aetiological mechanisms in vitiligo has already resulted in successful use of the Jak inhibitors in vitiligo. In this review, we outline the current understanding of the pathological mechanisms in vitiligo and locate loci to which therapeutic attack might be directed.