RESUMO
The Th17 cell-lineage-defining cytokine IL-17A contributes to host defense and inflammatory disease by coordinating multicellular immune responses. The IL-17 receptor (IL-17RA) is expressed by diverse intestinal cell types, and therapies targeting IL-17A induce adverse intestinal events, suggesting additional tissue-specific functions. Here, we used multiple conditional deletion models to identify a role for IL-17A in secretory epithelial cell differentiation in the gut. Paneth, tuft, goblet, and enteroendocrine cell numbers were dependent on IL-17A-mediated induction of the transcription factor ATOH1 in Lgr5+ intestinal epithelial stem cells. Although dispensable at steady state, IL-17RA signaling in ATOH1+ cells was required to regenerate secretory cells following injury. Finally, IL-17A stimulation of human-derived intestinal organoids that were locked into a cystic immature state induced ATOH1 expression and rescued secretory cell differentiation. Our data suggest that the cross talk between immune cells and stem cells regulates secretory cell lineage commitment and the integrity of the mucosa.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Mucosa Intestinal/citologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Interleucina-17/metabolismo , Células-Tronco/metabolismo , Animais , Comunicação Celular , Diferenciação Celular/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Colite/induzido quimicamente , Colite/metabolismo , Colite/patologia , Sulfato de Dextrana/efeitos adversos , Humanos , Interleucina-17/metabolismo , Interleucina-17/farmacologia , Mucosa Intestinal/metabolismo , Intestinos/efeitos dos fármacos , Intestinos/metabolismo , Intestinos/patologia , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Receptores de Interleucina-17/deficiência , Fatores de Transcrição SOX9/metabolismo , Transdução de Sinais , Células-Tronco/citologiaRESUMO
Aging is linked to greater susceptibility to chronic inflammatory diseases, several of which, including periodontitis, involve neutrophil-mediated tissue injury. Here we found that aging-associated periodontitis was accompanied by lower expression of Del-1, an endogenous inhibitor of neutrophil adhesion dependent on the integrin LFA-1, and by reciprocal higher expression of interleukin 17 (IL-17). Consistent with that, IL-17 inhibited gingival endothelial cell expression of Del-1, thereby promoting LFA-1-dependent recruitment of neutrophils. Young Del-1-deficient mice developed spontaneous periodontitis that featured excessive neutrophil infiltration and IL-17 expression; disease was prevented in mice doubly deficient in Del-1 and LFA-1 or in Del-1 and the IL-17 receptor. Locally administered Del-1 inhibited IL-17 production, neutrophil accumulation and bone loss. Therefore, Del-1 suppressed LFA-1-dependent recruitment of neutrophils and IL-17-triggered inflammatory pathology and may thus be a promising therapeutic agent for inflammatory diseases.
Assuntos
Perda do Osso Alveolar/imunologia , Proteínas de Transporte/metabolismo , Interleucina-17/antagonistas & inibidores , Interleucina-17/metabolismo , Infiltração de Neutrófilos/efeitos dos fármacos , Periodontite/metabolismo , Envelhecimento/imunologia , Animais , Proteínas de Ligação ao Cálcio , Proteínas de Transporte/imunologia , Proteínas de Transporte/farmacologia , Adesão Celular/efeitos dos fármacos , Moléculas de Adesão Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Feminino , Integrinas/antagonistas & inibidores , Integrinas/imunologia , Integrinas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular , Interleucina-17/imunologia , Antígeno-1 Associado à Função Linfocitária/imunologia , Antígeno-1 Associado à Função Linfocitária/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Atrofia Periodontal/imunologia , Atrofia Periodontal/metabolismo , Periodontite/imunologia , Periodontite/terapia , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/metabolismoRESUMO
BACKGROUND & AIMS: Chronic alcohol consumption is a leading risk factor for the development of hepatocellular carcinoma (HCC), which is associated with a marked increase in hepatic expression of pro-inflammatory IL-17A and its receptor IL-17RA. METHODS: Genetic deletion and pharmacological blocking were used to characterize the role of IL-17A/IL-17RA signaling in the pathogenesis of HCC in mouse models and human specimens. RESULTS: We demonstrate that the global deletion of the Il-17ra gene suppressed HCC in alcohol-fed diethylnitrosamine-challenged Il-17ra-/- and major urinary protein-urokinase-type plasminogen activator/Il-17ra-/- mice compared with wild-type mice. When the cell-specific role of IL-17RA signaling was examined, the development of HCC was decreased in both alcohol-fed Il-17raΔMΦ and Il-17raΔHep mice devoid of IL-17RA in myeloid cells and hepatocytes, but not in Il-17raΔHSC mice (deficient in IL-17RA in hepatic stellate cells). Deletion of Il-17ra in myeloid cells ameliorated tumorigenesis via suppression of pro-tumorigenic/inflammatory and pro-fibrogenic responses in alcohol-fed Il-17raΔMΦ mice. Remarkably, despite a normal inflammatory response, alcohol-fed Il-17raΔHep mice developed the fewest tumors (compared with Il-17raΔMΦ mice), with reduced steatosis and fibrosis. Steatotic IL-17RA-deficient hepatocytes downregulated the expression of Cxcl1 and other chemokines, exhibited a striking defect in tumor necrosis factor (TNF)/TNF receptor 1-dependent caspase-2-SREBP1/2-DHCR7-mediated cholesterol synthesis, and upregulated the production of antioxidant vitamin D3. The pharmacological blocking of IL-17A/Th-17 cells using anti-IL-12/IL-23 antibodies suppressed the progression of HCC (by 70%) in alcohol-fed mice, indicating that targeting IL-17 signaling might provide novel strategies for the treatment of alcohol-induced HCC. CONCLUSIONS: Overall, IL-17A is a tumor-promoting cytokine, which critically regulates alcohol-induced hepatic steatosis, inflammation, fibrosis, and HCC. LAY SUMMARY: IL-17A is a tumor-promoting cytokine, which critically regulates inflammatory responses in macrophages (Kupffer cells and bone-marrow-derived monocytes) and cholesterol synthesis in steatotic hepatocytes in an experimental model of alcohol-induced HCC. Therefore, IL-17A may be a potential therapeutic target for patients with alcohol-induced HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Hepatócitos/metabolismo , Interleucina-17/metabolismo , Células de Kupffer/metabolismo , Cirrose Hepática/complicações , Cirrose Hepática/metabolismo , Hepatopatias Alcoólicas/complicações , Hepatopatias Alcoólicas/metabolismo , Neoplasias Hepáticas/metabolismo , Transdução de Sinais/genética , Animais , Carcinogênese/induzido quimicamente , Carcinogênese/genética , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Modelos Animais de Doenças , Etanol/efeitos adversos , Deleção de Genes , Humanos , Cirrose Hepática/patologia , Hepatopatias Alcoólicas/patologia , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , TranscriptomaRESUMO
Although several interleukin-17 (IL-17) family members and their receptors have been recently appreciated as important regulators in inflammatory diseases, the function of other IL-17 cytokines and IL-17 receptor-like molecules is unclear. Here we show that an IL-17 cytokine family member, IL-17C, was induced in a Th17 cell-dependent autoimmune disease and was required for its pathogenesis. IL-17C bound to IL-17RE, a member of IL-17 receptor family whose full-length isoform was selectively expressed in Th17 cells and signaled via an IL-17RA-RE receptor complex and the downstream adaptor Act1. IL-17C-IL-17RE induced the expression of a nuclear IkappaB family member, IκBζ, in Th17 cells to potentiate the Th17 cell response. Thus, our work has identified a cytokine-receptor pair with important function in regulating proinflammatory responses. This pathway may be targeted to treat autoimmune diseases.
Assuntos
Encefalomielite Autoimune Experimental/imunologia , Interleucina-17/imunologia , Receptores de Interleucina-17/imunologia , Células Th17/imunologia , Animais , Diferenciação Celular , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Quinase I-kappa B/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/metabolismo , Transdução de Sinais , Células Th17/citologiaRESUMO
Interleukin-17A (IL-17A) is the signature cytokine of the recently identified T helper 17 (Th17) cell subset. IL-17 has six family members (IL-17A to IL-17F). Although IL-17A and IL-17F share the highest amino acid sequence homology, they perform distinct functions; IL-17A is involved in the development of autoimmunity, inflammation, and tumors, and also plays important roles in the host defenses against bacterial and fungal infections, whereas IL-17F is mainly involved in mucosal host defense mechanisms. IL-17E (IL-25) is an amplifier of Th2 immune responses. The functions of IL-17B, IL-17C, and IL-17D remain largely elusive. In this review, we describe the identified functions of each IL-17 family member and discuss the potential of these molecules as therapeutic targets.
Assuntos
Interleucina-17/fisiologia , Células Th17/imunologia , Animais , Autoimunidade/imunologia , Infecções Bacterianas/imunologia , Humanos , Imunidade nas Mucosas/imunologia , Inflamação/imunologia , Interleucina-17/biossíntese , Interleucina-17/química , Interleucina-17/genética , Interleucina-17/imunologia , Camundongos , Camundongos Knockout , Família Multigênica , Micoses/imunologia , Neoplasias/imunologia , Receptores de Interleucina-17/química , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/fisiologia , Homologia de Sequência de Aminoácidos , Transdução de Sinais , Células Th17/metabolismo , Células Th2/imunologiaRESUMO
Atopic dermatitis (AD) is a common inflammatory skin disease affecting up to 20% of children and 3% of adults worldwide and is associated with dysregulation of the skin barrier. Although type 2 responses are implicated in AD, emerging evidence indicates a potential role for the IL-17A signaling axis in AD pathogenesis. In this study we show that in the filaggrin mutant mouse model of spontaneous AD, IL-17RA deficiency (Il17ra-/- ) resulted in severe exacerbation of skin inflammation. Interestingly, Il17ra-/- mice without the filaggrin mutation also developed spontaneous progressive skin inflammation with eosinophilia, as well as increased levels of thymic stromal lymphopoietin (TSLP) and IL-5 in the skin. Il17ra-/- mice have a defective skin barrier with altered filaggrin expression. The barrier dysregulation and spontaneous skin inflammation in Il17ra-/- mice was dependent on TSLP, but not the other alarmins IL-25 and IL-33. The associated skin inflammation was mediated by IL-5-expressing pathogenic effector Th2 cells and was independent of TCRγδ T cells and IL-22. An absence of IL-17RA in nonhematopoietic cells, but not in the hematopoietic cells, was required for the development of spontaneous skin inflammation. Skin microbiome dysbiosis developed in the absence of IL-17RA, with antibiotic intervention resulting in significant amelioration of skin inflammation and reductions in skin-infiltrating pathogenic effector Th2 cells and TSLP. This study describes a previously unappreciated protective role for IL-17RA signaling in regulation of the skin barrier and maintenance of skin immune homeostasis.
Assuntos
Dermatite Atópica/imunologia , Receptores de Interleucina-17/imunologia , Receptores de Interleucina-17/metabolismo , Pele/crescimento & desenvolvimento , Pele/patologia , Animais , Citocinas/imunologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Disbiose , Eosinofilia/imunologia , Proteínas Filagrinas , Regulação da Expressão Gênica , Homeostase , Interleucina-33/imunologia , Interleucina-5/genética , Interleucina-5/imunologia , Interleucinas/genética , Interleucinas/imunologia , Proteínas de Filamentos Intermediários/deficiência , Proteínas de Filamentos Intermediários/genética , Camundongos , Microbiota , Mutação , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Transdução de Sinais , Pele/imunologia , Pele/microbiologia , Células Th2/imunologia , Linfopoietina do Estroma do Timo , Interleucina 22RESUMO
Chronic mucocutaneous candidiasis (CMC) is defined as recurrent or persistent infection of the skin, nails, and/or mucosae with commensal Candida species. The first genetic etiology of isolated CMC-autosomal recessive (AR) IL-17 receptor A (IL-17RA) deficiency-was reported in 2011, in a single patient. We report here 21 patients with complete AR IL-17RA deficiency, including this first patient. Each patient is homozygous for 1 of 12 different IL-17RA alleles, 8 of which create a premature stop codon upstream from the transmembrane domain and have been predicted and/or shown to prevent expression of the receptor on the surface of circulating leukocytes and dermal fibroblasts. Three other mutant alleles create a premature stop codon downstream from the transmembrane domain, one of which encodes a surface-expressed receptor. Finally, the only known missense allele (p.D387N) also encodes a surface-expressed receptor. All of the alleles tested abolish cellular responses to IL-17A and -17F homodimers and heterodimers in fibroblasts and to IL-17E/IL-25 in leukocytes. The patients are currently aged from 2 to 35 y and originate from 12 unrelated kindreds. All had their first CMC episode by 6 mo of age. Fourteen patients presented various forms of staphylococcal skin disease. Eight were also prone to various bacterial infections of the respiratory tract. Human IL-17RA is, thus, essential for mucocutaneous immunity to Candida and Staphylococcus, but otherwise largely redundant. A diagnosis of AR IL-17RA deficiency should be considered in children or adults with CMC, cutaneous staphylococcal disease, or both, even if IL-17RA is detected on the cell surface.
Assuntos
Infecções Bacterianas/imunologia , Candidíase/imunologia , Micoses/imunologia , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Alelos , Candida , Membrana Celular , Criança , Pré-Escolar , Saúde da Família , Feminino , Fibroblastos/metabolismo , Genes Recessivos , Estudo de Associação Genômica Ampla , Células HEK293 , Homozigoto , Humanos , Imunofenotipagem , Lactente , Recém-Nascido , Interleucina-17/metabolismo , Masculino , Mutação , Fases de Leitura Aberta , Linhagem , Receptores de Interleucina-17/metabolismo , Pele/microbiologia , Linfócitos T/citologiaRESUMO
The IL-17 cytokine family and the cognate receptors thereof have a unique role in organ-specific autoimmunity. Most studies have focused on the founding member of the IL-17 family, IL-17A, as the central mediator of diseases. Indeed, although pathogenic functions have been ascribed to IL-17A and IL-17F in the context of immune-mediated glomerular diseases, the specific functions of the other IL-17 family members in immunity and inflammatory kidney diseases is largely unknown. Here, we report that compared with healthy controls, patients with acute Anti-neutrophil cytoplasmatic antibody (ANCA)-associated crescentic glomerulonephritis (GN) had significantly elevated serum levels of IL-17C (but not IL-17A, F, or E). In mouse models of crescentic GN (nephrotoxic nephritis) and pristane-induced lupus nephritis, deficiency in IL-17C significantly ameliorated the course of GN in terms of renal tissue injury and kidney function. Deficiency of the unique IL-17C receptor IL-17 receptor E (IL-17RE) provided similar protection against crescentic GN. These protective effects associated with a reduced TH17 response. Bone marrow transplantation experiments revealed that IL-17C is produced by tissue-resident cells, but not by lymphocytes. Finally, IL-17RE was highly expressed by CD4+ TH17 cells, and loss of this expression prevented the TH17 responses and subsequent tissue injury in crescentic GN. Our findings indicate that IL-17C promotes TH17 cell responses and immune-mediated kidney disease via IL-17RE expressed on CD4+ TH17 cells. Targeting the IL-17C/IL-17RE pathway may present an intriguing therapeutic strategy for TH17-induced autoimmune disorders.
Assuntos
Doenças Autoimunes/imunologia , Linfócitos T CD4-Positivos/imunologia , Glomerulonefrite/imunologia , Interleucina-17/sangue , Interleucina-17/fisiologia , Receptores de Interleucina-17/fisiologia , Células Th17/imunologia , Animais , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Doenças Autoimunes/sangue , Doenças Autoimunes/patologia , Doenças Autoimunes/prevenção & controle , Glomerulonefrite/sangue , Glomerulonefrite/patologia , Glomerulonefrite/prevenção & controle , Humanos , Interleucina-17/biossíntese , Interleucina-17/deficiência , Interleucina-17/genética , Rim/imunologia , Rim/patologia , Nefrite Lúpica/induzido quimicamente , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Terapia de Alvo Molecular , RNA Mensageiro/biossíntese , Quimera por Radiação , Receptores de Interleucina-17/biossíntese , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Terpenos/toxicidade , Regulação para CimaRESUMO
T cells undergo homeostatic expansion and acquire an activated phenotype in lymphopenic microenvironments. Restoration of normal lymphocyte numbers typically re-establishes normal homeostasis, and proinflammatory cytokine production returns to baseline. Mice deficient in guanine nucleotide exchange factor RasGRP1 exhibit dysregulated homeostatic expansion, which manifests as lymphoproliferative disease with autoantibody production. Our previous work revealed that autoreactive B cells lacking RasGRP1 break tolerance early during development, as well as during germinal center responses, suggesting that T cell-independent and T cell-dependent mechanisms are responsible. Examination of whether a particular T cell subset is involved in the breach of B cell tolerance revealed increased Th17 cells in Rasgrp1-deficient mice relative to control mice. Rasgrp1-deficient mice lacking IL-17R had fewer germinal centers, and germinal centers that formed contained fewer autoreactive B cells, suggesting that IL-17 signaling is required for a break in B cell tolerance in germinal centers. Interestingly, a fraction of Th17 cells from Rasgrp1-deficient mice were CXCR5(+) and upregulated levels of CD278 coordinate with their appearance in germinal centers, all attributes of T follicular helper cells (Tfh17). To determine whether CD278-CD275 interactions were required for the development of Tfh17 cells and for autoantibody, Rasgrp1-deficient mice were crossed with CD275-deficient mice. Surprisingly, mice deficient in RasGRP1 and CD275 formed Tfh17 cells and germinal centers and produced similar titers of autoantibodies as mice deficient in only RasGRP1. Therefore, these studies suggest that requirements for Tfh cell development change in lymphopenia-associated autoimmune settings.
Assuntos
Autoimunidade , Centro Germinativo/imunologia , Ligante Coestimulador de Linfócitos T Induzíveis/imunologia , Interleucina-17/imunologia , Linfopenia/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Autoanticorpos/biossíntese , Autoanticorpos/imunologia , Linfócitos B/imunologia , Centro Germinativo/citologia , Fatores de Troca do Nucleotídeo Guanina/deficiência , Homeostase , Tolerância Imunológica/genética , Ligante Coestimulador de Linfócitos T Induzíveis/deficiência , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Interleucina-17/biossíntese , Camundongos , Receptores CXCR5/genética , Receptores de Interleucina-17/deficiência , Transdução de Sinais , Células Th17/imunologiaRESUMO
IL-25 promotes type 2 immunity by inducing the expression of Th2-associated cytokines. Although it is known that the IL-25R (IL-17RB) recruits the adaptor protein ACT1, the IL-25R signaling mechanism remains poorly understood. While screening for IL-25R components, we found that IL-25 responses were impaired in Traf4 (-/-) cells. Administering IL-25 to Traf4 (-/-) mice resulted in blunted airway eosinophilia and Th2 cytokine production. Notably, IL-25R recruitment of TRAF4 was required for the ACT1/IL-25R interaction. Mechanistically, TRAF4 recruited the E3-ligase SMURF2, to degrade the IL-25R-inhibitory molecule DAZAP2. Silencing Dazap2 increased ACT1/IL-25R interaction and IL-25 responsiveness. Moreover, a tyrosine within the IL-25R elicited DAZAP2 interference. This study indicates that TRAF4-SMURF2-mediated DAZAP2 degradation is a crucial initiating event for the IL-25 response.
Assuntos
Proteínas de Transporte/imunologia , Inflamação/imunologia , Receptores de Interleucina/imunologia , Sistema Respiratório/imunologia , Fator 4 Associado a Receptor de TNF/imunologia , Ubiquitina-Proteína Ligases/imunologia , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Immunoblotting , Inflamação/genética , Inflamação/metabolismo , Interleucinas/imunologia , Interleucinas/farmacologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Imunológicos , Mutação , Proteólise , Interferência de RNA , Proteínas de Ligação a RNA , Receptores de Interleucina/genética , Receptores de Interleucina/metabolismo , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologia , Sistema Respiratório/metabolismo , Sistema Respiratório/patologia , Transdução de Sinais/imunologia , Fator 4 Associado a Receptor de TNF/deficiência , Fator 4 Associado a Receptor de TNF/genética , Tirosina/genética , Tirosina/imunologia , Tirosina/metabolismo , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genéticaRESUMO
BACKGROUND: Data on patients affected by chronic mucocutaneous candidiasis underscore the preponderant role of IL-17 receptor A (IL-17RA) in preserving mucocutaneous immunity. Little is known about the role of adenosine deaminase (ADA) 2 in regulation of immune responses, although recent reports linked ADA2 deficiency with inflammation and vasculitis. OBJECTIVE: We sought to investigate the mechanisms of chronic inflammation and vasculitis in a child lacking IL-17RA and ADA2 to identify therapeutic targets. METHODS: We report a family with 2 siblings who have had recurrent mucocutaneous infections with Candida albicans and Staphylococcus aureus and chronic inflammatory disease and vasculitis since early childhood, which were refractory to classical treatments. Array-based comparative genomic hybridization analysis showed that both siblings are homozygous for a 770-kb deletion on chr22q11.1 encompassing both IL17RA and cat eye critical region 1 (CECR1). Immunologic studies were carried out by means of flow cytometry, ELISA, and RIA. RESULTS: As expected, in the affected child we found a lack of IL-17RA expression, which implies a severe malfunction in the IL-17 signaling pathway, conferring susceptibility to recurrent mucocutaneous infections. Surprisingly, we detected an in vitro and in vivo upregulation of proinflammatory cytokines, notably IL-1ß and TNF-α, which is consistent with the persistent systemic inflammation. CONCLUSIONS: This work emphasizes the utility of whole-genome analyses combined with immunologic investigation in patients with unresolved immunodeficiency. This approach is likely to provide an insight into immunologic pathways and mechanisms of disease. It also provides molecular evidence for more targeted therapies. In addition, our report further corroborates a potential role of ADA2 in modulating immunity and inflammation.
Assuntos
Adenosina Desaminase/deficiência , Adenosina Desaminase/genética , Candidíase Mucocutânea Crônica/genética , Inflamação/genética , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Peptídeos e Proteínas de Sinalização Intercelular/genética , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Vasculite/genética , Adenosina Desaminase/imunologia , Adolescente , Candidíase Mucocutânea Crônica/complicações , Candidíase Mucocutânea Crônica/imunologia , Criança , Pré-Escolar , Doença Crônica , Hibridização Genômica Comparativa , Evolução Fatal , Feminino , Humanos , Inflamação/complicações , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Receptores de Interleucina-17/imunologia , Deleção de Sequência , Irmãos , Vasculite/complicações , Vasculite/imunologiaRESUMO
Foodborne Listeria monocytogenes (LM) is a cause of serious illness and death in the US. The case-fatality rate of invasive LM infection in the elderly population is >50%. The goal of this study is to establish a murine model of oral LM infection that can be used as a surrogate for human foodborne listeriosis in the geriatric population. Adult C57BL/6 (wild-type, WT) and adult or old IL17R-KO (knock-out) mice were gavaged with a murinized LM strain (Lmo-InlAm) and monitored for body-weight loss and survivability. Tissues were collected and assayed for bacterial burden, histology, and cytokine responses. When compared to WT mice, adult IL17R-KO mice are more susceptible to LM infection and showed increased LM burden and tissue pathology and a higher mortality rate. Older LM-infected KO-mice lost significantly (p < 0.02, ANOVA) more body-weight and had a higher bacterial burden in the liver (p = 0.03) and spleen as compared to adult mice. Uninfected, aged KO-mice showed a higher baseline pro-inflammatory response when compared to uninfected adult-KO mice. After infection, the pro-inflammatory cytokine, IFN-γ, mRNA in the liver was higher in the adult mice as compared to the old mice. The anti-inflammatory cytokine, IL-10, mRNA and regulatory T-cells (CD4+CD25+h or CD4+Foxp3+) cells in the aged mice increased significantly after infection as compared to adult mice. Expression of the T-cell activation marker, CD25 (IL-2Rα) in the aged mice did not increase significantly over baseline. These data suggest that aged IL17R-KO mice can be used as an in vivo model to study oral listeriosis and that aged mice are more susceptible to LM infection due to dysregulation of pro- and anti-inflammatory responses compared to adult mice, resulting in a protracted clearance of the infection.
Assuntos
Modelos Animais de Doenças , Suscetibilidade a Doenças , Listeria monocytogenes/crescimento & desenvolvimento , Listeriose/microbiologia , Listeriose/patologia , Receptores de Interleucina-17/deficiência , Administração Oral , Fatores Etários , Estruturas Animais/microbiologia , Estruturas Animais/patologia , Animais , Carga Bacteriana , Peso Corporal , Citocinas/análise , Histocitoquímica , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-2/análise , Camundongos Endogâmicos C57BL , Camundongos Knockout , Análise de Sobrevida , Linfócitos T Reguladores/imunologiaRESUMO
Oropharyngeal candidiasis (OPC), caused by the commensal fungus Candida albicans, is an opportunistic infection associated with infancy, AIDS, and IL-17-related primary immunodeficiencies. The Th17-associated cytokines IL-23 and IL-17 are crucial for immunity to OPC, but the mechanisms by which they mediate immunity are poorly defined. IL-17RA-deficient humans and mice are strongly susceptible to OPC, with reduced levels of CXC chemokines and concomitantly impaired neutrophil recruitment to the oral mucosa. Paradoxically, humans with isolated neutropenia are typically not susceptible to candidiasis. To determine whether immunity to OPC is mediated via neutrophil recruitment, mice lacking CXCR2 were subjected to OPC and were found to be highly susceptible, although there was no dissemination of fungi to peripheral organs. To assess whether the entire neutrophil response is IL-17 dependent, IL-17RA(-/-) and IL-23(-/-) mice were administered neutrophil-depleting Abs and subjected to OPC. These mice displayed increased oral fungal burdens compared with IL-17RA(-/-) or IL-23(-/-) mice alone, indicating that additional IL-17-independent signals contribute to the neutrophil response. WT mice treated with anti-Gr-1 Abs exhibited a robust infiltrate of CD11b(+)Ly-6G(low)F4/80(-) cells to the oral mucosa but were nonetheless highly susceptible to OPC, indicating that this monocytic influx is insufficient for host defense. Surprisingly, Ly-6G Ab treatment did not induce the same strong susceptibility to OPC in WT mice. Thus, CXCR2(+) and Gr-1(+) neutrophils play a vital role in host defense against OPC. Moreover, defects in the IL-23/17 axis cause a potent but incomplete deficiency in the neutrophil response to oral candidiasis.
Assuntos
Candidíase Bucal/imunologia , Interleucina-17/metabolismo , Subunidade p19 da Interleucina-23/genética , Neutrófilos/imunologia , Receptores de Interleucina-17/imunologia , Animais , Antígenos de Diferenciação/metabolismo , Antígenos Ly/metabolismo , Antígeno CD11b/metabolismo , Candida albicans/imunologia , Candidíase Bucal/microbiologia , Interleucina-17/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mucosa Bucal/imunologia , Mucosa Bucal/microbiologia , Infiltração de Neutrófilos , Receptores de Quimiocinas/imunologia , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-8B/deficiência , Receptores de Interleucina-8B/genética , Células Th17/imunologia , Células Th17/metabolismoRESUMO
Multiple sclerosis (MS) is an autoimmune disease in which inflammatory lesions lead to tissue injury in the brain and/or spinal cord. The specific sites of tissue injury are strong determinants of clinical outcome in MS, but the pathways that determine whether damage occurs in the brain or spinal cord are not understood. Previous studies in mouse models of MS demonstrated that IFN-γ and IL-17 regulate lesion localization within the brain; however, the mechanisms by which these cytokines mediate their effects have not been identified. In the present study, we show that IL-17 promoted, but IFN-γ inhibited, ELR(+) chemokine-mediated neutrophil recruitment to the brain, and that neutrophil infiltration was required for parenchymal tissue damage in the brain. In contrast, IFN-γ promoted ELR(+) chemokine expression and neutrophil recruitment to the spinal cord. Surprisingly, tissue injury in the spinal cord did not exhibit the same dependence on neutrophil recruitment that was observed for the brain. Our results demonstrate that the brain and spinal cord exhibit distinct sensitivities to cellular mediators of tissue damage, and that IL-17 and IFN-γ differentially regulate recruitment of these mediators to each microenvironment. These findings suggest an approach toward tailoring therapies for patients with distinct patterns of neuroinflammation.
Assuntos
Encéfalo/imunologia , Citocinas/imunologia , Encefalomielite Autoimune Experimental/imunologia , Mielite/imunologia , Infiltração de Neutrófilos/imunologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/genética , Encefalomielite Autoimune Experimental/metabolismo , Citometria de Fluxo , Humanos , Camundongos , Camundongos Endogâmicos C3H , Camundongos Knockout , Camundongos Transgênicos , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Glicoproteína Mielina-Oligodendrócito/imunologia , Mielite/genética , Mielite/metabolismo , Fragmentos de Peptídeos/imunologia , Ratos , Receptores de Interferon/deficiência , Receptores de Interferon/genética , Receptores de Interferon/imunologia , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/imunologia , Receptores de Interleucina-8B/imunologia , Receptores de Interleucina-8B/metabolismo , Receptor de Interferon gamaRESUMO
Recently, a number of studies have reported the presence of interleukin 17 (IL-17) in patients with Lyme disease, and several murine studies have suggested a role for this cytokine in the development of Lyme arthritis. However, the role of IL-17 has not been studied using the experimental Lyme borreliosis model of infection of C3H mice with Borrelia burgdorferi. In the current study, we investigated the role of IL-17 in the development of experimental Lyme borreliosis by infecting C3H mice devoid of the common IL-17 receptor A subunit (IL-17RA) and thus deficient in most IL-17 signaling. Infection of both C3H and C3H IL-17RA(-/-) mice led to the production of high levels of IL-17 in the serum, low levels in the heart tissue, and no detectable IL-17 in the joint tissue. The development and severity of arthritis and carditis in the C3H IL-17RA(-/-) mice were similar to what was seen in wild-type C3H mice. In addition, development of antiborrelia antibodies and clearance of spirochetes from tissues were similar for the two mouse strains. These results demonstrate a limited role for IL-17 signaling through IL-17RA in the development of disease following infection of C3H mice with B. burgdorferi.
Assuntos
Artrite/imunologia , Artrite/patologia , Doença de Lyme/imunologia , Doença de Lyme/patologia , Miocardite/imunologia , Miocardite/patologia , Receptores de Interleucina-17/deficiência , Animais , Borrelia burgdorferi/crescimento & desenvolvimento , Feminino , Interleucina-17/sangue , Camundongos Endogâmicos C3H , Camundongos Knockout , Índice de Gravidade de DoençaRESUMO
Inflammatory signals present in demyelinated multiple sclerosis lesions affect the reparative remyelination process conducted by oligodendrocyte progenitor cells (OPCs). Interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 have differing effects on the viability and growth of OPCs, however the effects of IL-17A are largely unknown. Primary murine OPCs were stimulated with IL-17A and their viability, proliferation, and maturation were assessed in culture. IL-17A-stimulated OPCs exited the cell cycle and differentiated with no loss in viability. Expression of the myelin-specific protein, proteolipid protein, increased in a cerebellar slice culture assay in the presence of IL-17A. Downstream, IL-17A activated ERK1/2 within 15 min and induced chemokine expression in 2 days. These results demonstrate that IL-17A exposure stimulates OPCs to mature and participate in the inflammatory response.
Assuntos
Diferenciação Celular/efeitos dos fármacos , Encefalomielite Autoimune Experimental/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Oligodendroglia/efeitos dos fármacos , Oligodendroglia/enzimologia , Células-Tronco/efeitos dos fármacos , Animais , Células Cultivadas , Cerebelo/citologia , Cerebelo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Citometria de Fluxo , Adjuvante de Freund/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Técnicas In Vitro , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteína Proteolipídica de Mielina/genética , Glicoproteína Mielina-Oligodendrócito/toxicidade , Técnicas de Cultura de Órgãos , Fragmentos de Peptídeos/toxicidade , Receptores de Interleucina-17/deficiência , Receptores de Interleucina-17/genética , Células-Tronco/fisiologiaRESUMO
Germinal centers (GCs) provide a microenvironment that promotes and regulates the interactions of B cells with follicular Th (TFH) cells. In this study, we show that there are significantly higher frequencies of CXCR5(+)ICOS(+) TFH cells in autoimmune BXD2 mice, and these cells express both IL-21R and IL-17RA. Although IL-17 and IL-21 are both important for the formation of spontaneous GCs and development of pathogenic autoantibodies, IL-21, but not IL-17, is required for the proper development of TFH cells in BXD2 mice. The total numbers of TFH cells and their ability to induce B cell responses in vitro were not affected by a deficiency of IL-17RA in BXD2-Il17ra(-/-) mice, the majority of CXCR5(+) TFH cells from BXD2-Il17ra(-/-) mice were, however, not localized in the GC light zone (LZ). Interruption of IL-17 signaling, either acutely by AdIL-17R:Fc or chronically by Il17ra(-/-), disrupted TFH-B interactions and abrogated the generation of autoantibody-forming B cells in BXD2 mice. IL-17 upregulated the expression of regulator of G-protein signaling 16 (RGS16) to promote the ability of TFH to form conjugates with B cells, which was abolished in TFH cells from BXD2-Rgs16(-/-) mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on postdifferentiated IL-17RA(+) TFH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that TFH differentiation and its stabilization in the LZ are two separate checkpoints and that IL-21 and IL-17 act at each checkpoint to enable pathogenic GC development.
Assuntos
Autoanticorpos/biossíntese , Subpopulações de Linfócitos B/imunologia , Centro Germinativo/imunologia , Interleucina-17/imunologia , Interleucinas/imunologia , Receptores de Interleucina-17/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Transferência Adotiva , Animais , Movimento Celular , Microambiente Celular/imunologia , Técnicas de Cocultura , Cruzamentos Genéticos , Centro Germinativo/ultraestrutura , Haptenos/imunologia , Imunoglobulina G/imunologia , Rim/patologia , Cooperação Linfocítica/imunologia , Linfopoese , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrofenóis/imunologia , Fenilacetatos/imunologia , Receptores de Interleucina-17/deficiênciaRESUMO
IL-17 is a pleiotropic cytokine produced by Th17 T cells that induces a myriad of proinflammatory mediators. However, different models of inflammation report opposite functional roles of IL-17 signal in terms of its effects on bone destruction. In this study we determined the role of IL-17RA signal in bone resorption stimulated by dentoalveolar infections. Infrabony resorptive lesions were induced by surgical pulp exposure and microbial infection of mouse molar teeth. IL-17 was strongly induced in periapical tissues in wild-type (WT) mice by 7 d after the infection but was not expressed in uninfected mice. Dentoalveolar infections of IL-17RA knockout (KO) mice demonstrated significantly increased bone destruction and more abscess formation in the apical area compared with WT mice. Infected IL-17RA KO mice exhibited significantly increased neutrophils and macrophages compared with the WT littermates at day 21, suggesting a failure of transition from acute to chronic inflammation in the IL-17RA KO mice. The expression of IL-1 (both α and ß isoforms) and MIP2 were significantly upregulated in the IL-17RA KO compared with WT mice at day 21 postinfection. The development of periapical lesions in IL-17RA KO mice was significantly attenuated by neutralization of IL-1ß and MIP2. Taken together, these results demonstrate that IL-17RA signal seems to be protective against infection-induced periapical inflammation and bone destruction via suppression of neutrophil and mononuclear inflammation.
Assuntos
Perda do Osso Alveolar/prevenção & controle , Reabsorção Óssea/prevenção & controle , Interleucina-17/fisiologia , Macrófagos Peritoneais/imunologia , Neutrófilos/imunologia , Periodontite Periapical/patologia , Receptores de Interleucina-17/fisiologia , Perda do Osso Alveolar/etiologia , Perda do Osso Alveolar/imunologia , Animais , Reabsorção Óssea/etiologia , Reabsorção Óssea/imunologia , Quimiocina CXCL2/biossíntese , Quimiocina CXCL2/genética , Doença Crônica , Coinfecção , Citocinas/biossíntese , Citocinas/genética , Regulação da Expressão Gênica/imunologia , Interleucina-17/biossíntese , Interleucina-17/genética , Interleucina-1alfa/biossíntese , Interleucina-1alfa/genética , Interleucina-1beta/biossíntese , Interleucina-1beta/genética , Masculino , Mandíbula , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Dente Molar , Receptores de Interleucina-17/deficiênciaRESUMO
Liver fibrosis is a severe, life-threatening clinical condition resulting from nonresolving hepatitis of different origins. IL-17A is critical in inflammation, but its relation to liver fibrosis remains elusive. We find increased IL-17A expression in fibrotic livers from HBV-infected patients undergoing partial hepatectomy because of cirrhosis-related early-stage hepatocellular carcinoma in comparison with control nonfibrotic livers from uninfected patients with hepatic hemangioma. In fibrotic livers, IL-17A immunoreactivity localizes to the inflammatory infiltrate. In experimental carbon tetrachloride-induced liver fibrosis of IL-17RA-deficient mice, we observe reduced neutrophil influx, proinflammatory cytokines, hepatocellular necrosis, inflammation, and fibrosis as compared with control C57BL/6 mice. IL-17A is produced by neutrophils and T lymphocytes expressing the Th17 lineage-specific transcription factor Retinoic acid receptor-related orphan receptor γt. Furthermore, hepatic stellate cells (HSCs) isolated from naive C57BL/6 mice respond to IL-17A with increased IL-6, α-smooth muscle actin, collagen, and TGF-ß mRNA expression, suggesting an IL-17A-driven fibrotic process. Pharmacologic ERK1/2 or p38 inhibition significantly attenuated IL-17A-induced HSC activation and collagen expression. In conclusion, IL-17A(+) Retinoic acid receptor-related orphan receptor γt(+) neutrophils and T cells are recruited into the injured liver driving a chronic, fibrotic hepatitis. IL-17A-dependent HSC activation may be critical for liver fibrosis. Thus, blockade of IL-17A could potentially benefit patients with chronic hepatitis and liver fibrosis.
Assuntos
Células Estreladas do Fígado/metabolismo , Interleucina-17/fisiologia , Cirrose Hepática/etiologia , Actinas/biossíntese , Actinas/genética , Adulto , Animais , Intoxicação por Tetracloreto de Carbono/complicações , Carcinoma Hepatocelular/química , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/cirurgia , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Colágeno/biossíntese , Colágeno/genética , Citocinas/biossíntese , Citocinas/genética , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/imunologia , Hemangioma/química , Hemangioma/cirurgia , Hepatectomia , Células Estreladas do Fígado/patologia , Hepatite B Crônica/complicações , Hepatite Animal/induzido quimicamente , Hepatite Animal/metabolismo , Hepatite Animal/patologia , Humanos , Interleucina-17/análise , Interleucina-17/biossíntese , Interleucina-17/genética , Interleucina-17/farmacologia , Cirrose Hepática/complicações , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/química , Neoplasias Hepáticas/cirurgia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Neutrófilos/fisiologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/análise , Inibidores de Proteínas Quinases/farmacologia , Receptores de Interleucina-17/deficiência , Proteínas Recombinantes/farmacologia , Células Th17/imunologia , Células Th17/metabolismo , Fator de Crescimento Transformador beta/biossínteseRESUMO
The protozoan parasite Giardia duodenalis (Giardia lamblia) is one of the most commonly found intestinal pathogens in mammals, including humans. In the current study, a Giardia muris-mouse model was used to analyze cytokine transcription patterns and histological changes in intestinal tissue at different time points during infection in C57BL/6 mice. Since earlier work revealed the upregulation of peroxisome proliferator-activated receptors (PPARs) in Giardia-infected calves, a second aim was to investigate the potential activation of PPARs in the intestines of infected mice. The most important observation in all mice was a strong upregulation of il17a starting around 1 week postinfection. The significance of interleukin 17A (IL-17A) in orchestrating a protective immune response was further demonstrated in an infection trial or experiment using IL-17 receptor A (IL-17RA) knockout (KO) mice: whereas in wild-type (WT) mice, cyst secretion dropped significantly after 3 weeks of infection, the IL-17RA KO mice were unable to clear the infection. Analysis of the intestinal response further indicated peroxisome proliferator-activated receptor alpha (PPARα) induction soon after the initial contact with the parasite, as characterized by the transcriptional upregulation of ppara itself and several downstream target genes such as pltp and cpt1. Overall, PPARα did not seem to have any influence on the immune response against G. muris, since PPARα KO animals expressed il-17a and could clear the infection similar to WT controls. In conclusion, this study shows for the first time the importance of IL-17 production in the clearance of a G. muris infection together with an early induction of PPARα. The effect of the latter, however, is still unclear.