RESUMEN
Pathological aggregation of amyloid-ß (Aß) is a main hallmark of Alzheimer's disease (AD). Recent genetic association studies have linked innate immune system actions to AD development, and current evidence suggests profound gender differences in AD pathogenesis. Here, we characterise gender-specific pathologies in the APP23 AD-like mouse model and find that female mice show stronger amyloidosis and astrogliosis compared with male mice. We tested the gender-specific effect of lack of IL12p40, the shared subunit of interleukin (IL)-12 and IL-23, that we previously reported to ameliorate pathology in APPPS1 mice. IL12p40 deficiency gender specifically reduces Aß plaque burden in male APP23 mice, while in female mice, a significant reduction in soluble Aß1-40 without changes in Aß plaque burden is seen. Similarly, plasma and brain cytokine levels are altered differently in female versus male APP23 mice lacking IL12p40, while glial properties are unchanged. These data corroborate the therapeutic potential of targeting IL-12/IL-23 signalling in AD, but also highlight the importance of gender considerations when studying the role of the immune system and AD.
Asunto(s)
Enfermedad de Alzheimer , Interleucina-12/deficiencia , Subunidad p19 de la Interleucina-23/deficiencia , Enfermedad de Alzheimer/genética , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Femenino , Interleucina-12/genética , Subunidad p40 de la Interleucina-12/deficiencia , Subunidad p40 de la Interleucina-12/genética , Subunidad p19 de la Interleucina-23/genética , Masculino , Ratones , Ratones Transgénicos , Placa AmiloideRESUMEN
The chronic skin inflammation psoriasis is crucially dependent on the IL-23/IL-17 cytokine axis. Although IL-23 is expressed by psoriatic keratinocytes and immune cells, only the immune cell-derived IL-23 is believed to be disease relevant. Here we use a genetic mouse model to show that keratinocyte-produced IL-23 is sufficient to cause a chronic skin inflammation with an IL-17 profile. Furthermore, we reveal a cell-autonomous nuclear function for the actin polymerizing molecule N-WASP, which controls IL-23 expression in keratinocytes by regulating the degradation of the histone methyltransferases G9a and GLP, and H3K9 dimethylation of the IL-23 promoter. This mechanism mediates the induction of IL-23 by TNF, a known inducer of IL-23 in psoriasis. Finally, in keratinocytes of psoriatic lesions a decrease in H3K9 dimethylation correlates with increased IL-23 expression, suggesting relevance for disease. Taken together, our data describe a molecular pathway where epigenetic regulation of keratinocytes can contribute to chronic skin inflammation.
Asunto(s)
Epigénesis Genética , N-Metiltransferasa de Histona-Lisina/genética , Subunidad p19 de la Interleucina-23/genética , Psoriasis/genética , Piel/metabolismo , Proteína Neuronal del Síndrome de Wiskott-Aldrich/genética , Adulto , Animales , Modelos Animales de Enfermedad , Genes Reporteros , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Células HEK293 , N-Metiltransferasa de Histona-Lisina/deficiencia , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Inflamación , Interleucina-17/genética , Interleucina-17/metabolismo , Subunidad p19 de la Interleucina-23/deficiencia , Queratinocitos/metabolismo , Queratinocitos/patología , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Cultivo Primario de Células , Regiones Promotoras Genéticas , Psoriasis/metabolismo , Psoriasis/patología , Transducción de Señal , Piel/patología , Proteína Neuronal del Síndrome de Wiskott-Aldrich/deficienciaRESUMEN
Our objective was to determine the role of the inflammatory cytokine interleukin-23 (IL-23) in promoting neutrophil recruitment, inflammatory cytokine expression and intestinal histopathology in response to Clostridium difficile infection. Wild-type (WT) and p19(-/-) (IL-23KO) mice were pre-treated with cefoperazone in their drinking water for 5 days, and after a 2-day recovery period were challenged with spores from C. difficile strain VPI 10463. Interleukin-23 deficiency was associated with significant defects in both the recruitment of CD11b(High) Ly6G(H) (igh) neutrophils to the colon and the expression of neutrophil chemoattractants and stabilization factors including Cxcl1, Cxcl2, Ccl3 and Csf3 within the colonic mucosa as compared with WT animals. Furthermore, the expression of inflammatory cytokines including Il33, Tnf and Il6 was significantly reduced in IL-23-deficient animals. There was also a trend towards less severe colonic histopathology in the absence of IL-23. The induction of Il17a and Il22 was also significantly abrogated in IL-23KO mice. Inflammatory cytokine expression and neutrophilic inflammation were not reduced in IL-17a-deficient mice or in mice treated with anti-IL-22 depleting monoclonal antibody. However, induction of RegIIIg was significantly reduced in animals treated with anti-IL-22 antibody. Taken together, these data indicate that IL-23, but not IL-17a or IL-22, promotes neutrophil recruitment and inflammatory cytokine and chemokine expression in the colon in response to C. difficile infection.
Asunto(s)
Clostridioides difficile/inmunología , Colon/inmunología , Enterocolitis Seudomembranosa/inmunología , Inmunidad Innata , Mediadores de Inflamación/inmunología , Interleucina-17/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Interleucinas/inmunología , Mucosa Intestinal/inmunología , Infiltración Neutrófila , Neutrófilos/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Clostridioides difficile/patogenicidad , Colon/efectos de los fármacos , Colon/metabolismo , Colon/patología , Modelos Animales de Enfermedad , Enterocolitis Seudomembranosa/microbiología , Enterocolitis Seudomembranosa/patología , Femenino , Inmunidad Innata/efectos de los fármacos , Mediadores de Inflamación/metabolismo , Interleucina-17/deficiencia , Interleucina-17/genética , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/genética , Interleucinas/antagonistas & inhibidores , Interleucinas/metabolismo , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Proteínas Asociadas a Pancreatitis , Proteínas/inmunología , Proteínas/metabolismo , Transducción de Señal , Interleucina-22RESUMEN
Our laboratory's investigations into mechanisms of protective immunity against Francisella tularensis Live Vaccine Strain (LVS) have uncovered mediators important in host defense against primary infection, as well as those correlated with successful vaccination. One such potential correlate was IL-12p40, a pleiotropic cytokine that promotes Th1 T cell function as part of IL-12p70. LVS-infected IL-12p40 deficient knockout (KO) mice maintain a chronic infection, but IL-12p35 KO mice clear LVS infection; thus the role that IL-12p40 plays in immunity to LVS is independent of the IL-12p70 heterodimer. IL-12p40 can also partner with IL-23p19 to create the heterodimeric cytokine IL-23. Here, we directly tested the role of IL-23 in LVS resistance, and found IL-23 to be largely dispensable for immunity to LVS following intradermal or intranasal infection. IL-23p19 KO splenocytes were fully competent in controlling intramacrophage LVS replication in an in vitro overlay assay. Further, antibody responses in IL-23p19 KO mice were similar to those of normal wild type mice after LVS infection. IL-23p19 KO mice or normal wild type mice that survived primary LVS infection survived maximal doses of LVS secondary challenge. Thus p40 has a novel role in clearance of LVS infection that is unrelated to either IL-12 or IL-23.
Asunto(s)
Vacunas Bacterianas , Coinfección/metabolismo , Francisella tularensis/fisiología , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/genética , Tularemia/metabolismo , Animales , Coinfección/genética , Coinfección/inmunología , Femenino , Francisella tularensis/inmunología , Subunidad p19 de la Interleucina-23/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tularemia/genética , Tularemia/inmunología , Vacunas AtenuadasRESUMEN
INTRODUCTION: Rheumatoid arthritis (RA) is a chronic inflammatory disease with striking heterogeneity in (i) clinical presentation, (ii) autoantibody profiles and (iii) responses to treatment suggesting that distinct molecular mechanisms may underlie the disease process. Proteoglycan-induced arthritis (PGIA) is induced by two pathways either by intraperitoneal (i.p.) or subcutaneous (s.c.) exposure to PG. CD4+ T cells primed by the i.p. route are T helper (Th)1 cells expressing interferon gamma (IFN-γ) whereas CD4+ T cells primed by the s.c. route are Th17 cells expressing interleukin (IL)-17. IL-23 is necessary for maintaining the phenotype of Th17 cells; however, IL-23 is inflammatory independent of IL-17. The aim of this study was to determine if PGIA induced by different routes of immunization is dependent on IL-23. METHODS: BALB/c wild type (WT), IL-12p40-/- and IL-23p19-/- littermate mice were immunized with recombinant G1 (rG1) domain of human PG in adjuvant either i.p. or s.c. and development of arthritis monitored. Joint histology was assessed. CD4+ T cell cytokines in spleen, lymph node (LN), and joint were assessed by intracellular staining and cytokine enzyme-linked immunosorbent assay. RNA transcripts for cytokines and transcription factors were examined. RESULTS: PGIA was suppressed in the p40-/- and p19-/- mice immunized by the s.c. route but only inhibited in p40-/- mice by the i.p. route. The joints of s.c. but not i.p. sensitized mice contained a population of CD4+ T cells expressing single positive IFN-γ and IL-17 and double positive IFN-γ/IL-17 which were dependent on IL-23 expression. The IFN-γ and IL-17 response in spleen and inguinal LN was inhibited in p19-/- mice and p40-/- mice after s.c. immunization, whereas in i.p. immunized p19-/- mice, IL-17 but not IFN-γ was reduced. Inguinal LN CD11c+ dendritic cells (DC) from s.c. immunized, but not spleen DC from i.p. immunized mice, produced IL-23, IL-1ß, and IL-6 and activated T cells to produce IL-17. CONCLUSION: IL-23 is necessary for the activity of Th17 after s.c. immunization and does not play a role independent of IL-17 after i.p. immunization. These data demonstrate that the molecular pathways IL-23/17 and IL-12/IFN-γ may represent subtypes of arthritis determined by the mode of induction.
Asunto(s)
Artritis Experimental/inmunología , Linfocitos T CD4-Positivos/inmunología , Interleucina-23/inmunología , Especificidad de Órganos/inmunología , Animales , Artritis Experimental/inducido químicamente , Antígeno CD11c/inmunología , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Citometría de Flujo , Humanos , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Interferón gamma/inmunología , Subunidad p40 de la Interleucina-12/deficiencia , Subunidad p40 de la Interleucina-12/genética , Subunidad p40 de la Interleucina-12/inmunología , Interleucina-17/inmunología , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/inmunología , Articulaciones/inmunología , Articulaciones/metabolismo , Ratones Endogámicos BALB C , Ratones Noqueados , Proteoglicanos/administración & dosificación , Proteoglicanos/inmunología , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
OBJECTIVE: Interleukin-17A (IL-17A) signals through the IL-17 receptor (IL-17R) A/C heterodimer. IL-17RA serves as a common receptor subunit for several IL-17 cytokine family members. Lack of IL-17RA signaling may therefore have additional effects beyond those of lack of IL-17A alone. The present study was undertaken to determine the role of IL-17RA signaling in autoimmune arthritis. METHODS: Disease incidence and severity were scored in type II collagen-treated wild-type, IL-17RA-deficient, and IL-23p19-deficient mice. T helper cell profiles and humoral immune responses were analyzed at several time points. Pathogenicity of T cells and total splenocytes was determined by in vitro functional assay. IL-17RA signaling was blocked in vivo in mice with antigen-induced arthritis (AIA). RESULTS: Comparable to the findings in IL-23p19-deficient mice, IL-17RA-deficient mice were completely protected against the development of collagen-induced arthritis (CIA). However, IL-17RA-deficient mice exhibited an increased number of IL-4-producing CD4+ T cells, distinct from IL-17A+CD4+ T cells. This was associated with fewer plasma cells, lower production of pathogenic IgG2c antibody, and increased production of IgG1 antibody. Both isolated CD4+ T cells and total splenocytes from IL-17RA-deficient mice had a reduced ability to induce IL-6 production by synovial fibroblasts in the setting of CIA, in a functional in vitro assay. Furthermore, blocking of IL-17RA signaling in AIA reduced synovial inflammation. CONCLUSION: These results demonstrate that absence of IL-17RA leads to a Th2-like phenotype characterized by IL-4 production and suggest that IL-17RA signaling plays a critical role in the regulation of IL-4 in CIA and the development of autoimmune inflammation of the joint.
Asunto(s)
Artritis Experimental/patología , Enfermedades Autoinmunes/prevención & control , Inflamación/prevención & control , Articulaciones/patología , Fenotipo , Receptores de Interleucina-17/deficiencia , Transducción de Señal/fisiología , Células Th2/patología , Animales , Artritis Experimental/fisiopatología , Enfermedades Autoinmunes/fisiopatología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Modelos Animales de Enfermedad , Inflamación/fisiopatología , Interleucina-17/metabolismo , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/fisiología , Interleucina-4/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Células Plasmáticas/patología , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/fisiología , Índice de Severidad de la EnfermedadRESUMEN
Primary biliary cirrhosis (PBC) is considered a model autoimmune disease, with the most highly directed and specific autoantibody in both murine and human autoimmunity, the anti-mitochondrial autoantibody (AMA). However, therapeutic advances in this disease have lagged behind. Herein we have taken advantage of our unique model of murine PBC in which mice immunized with 2-octynoic acid coupled to BSA (2OA-BSA), a compound identified by quantitative structure activity relationships (QSAR) of human AMA binding, develop an intense inflammatory cholangitis with striking similarities to humans with PBC. In particular, we have constructed several unique gene-deleted mice, including mice deleted of IL-12p40, IL-12p35, IFN-γ, IL-23p19, IL-17A, IL-17F and IL-22, immunized these animals with 2OA-BSA and followed the natural history of immunopathology to identify key pathways that might provide clues for successful therapy. Our data indicate that whereas both IL-12/Th1 and IL-23/Th17 are involved in cholangitis, it is the IL-12/Th1 signaling pathway that elicits pathology. In fact, deletion of IFN-γ prevents disease and suppresses autoantibodies. Importantly, deletion of the Th17 cytokines IL-17A and IL-22, but not IL-17F, reduces biliary damage; IL-17A-knockout mice have reduced levels of anti-mitochondrial antibody. We further demonstrate that the production of IFN-γ is significantly decreased in the liver of IL-23p19(-/-), IL-17A(-/-) and IL-22(-/-) mice compared with controls. However, the ability of T cells to produce IFN-γ was not affected in Th17 cytokine-deficient mice. Our data indicate that a deficient Th17 pathway suppresses the accumulation of IFN-γ producing cells in liver during the early phase of cholangitis. In conclusion, whereas IFN-γ has a pivotal role in the early events involved in the pathogenesis of autoimmune cholangitis induced by 2OA-BSA, the IL-23/Th17 pathway potentiates the effects of IL-12/IFN-γ-mediated immunopathology.
Asunto(s)
Autoanticuerpos/biosíntesis , Colangitis/genética , Subunidad p35 de la Interleucina-12/inmunología , Cirrosis Hepática Biliar/genética , Hígado/metabolismo , Transducción de Señal/inmunología , Animales , Autoinmunidad , Colangitis/inducido químicamente , Colangitis/inmunología , Colangitis/patología , Modelos Animales de Enfermedad , Ácidos Grasos Monoinsaturados/química , Ácidos Grasos Monoinsaturados/inmunología , Regulación de la Expresión Génica , Humanos , Inmunoconjugados/administración & dosificación , Inmunoconjugados/inmunología , Interferón gamma/deficiencia , Interferón gamma/genética , Interferón gamma/inmunología , Subunidad p35 de la Interleucina-12/deficiencia , Subunidad p35 de la Interleucina-12/genética , Interleucina-17/deficiencia , Interleucina-17/genética , Interleucina-17/inmunología , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/inmunología , Interleucinas/deficiencia , Interleucinas/genética , Interleucinas/inmunología , Hígado/inmunología , Hígado/patología , Cirrosis Hepática Biliar/inducido químicamente , Cirrosis Hepática Biliar/inmunología , Cirrosis Hepática Biliar/patología , Ratones , Ratones Noqueados , Mitocondrias/inmunología , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/inmunología , Balance Th1 - Th2 , Interleucina-22RESUMEN
Resolution of acute of infection caused by capsular Streptococcus pneumoniae infection in the absence of effective antibiotic therapy requires tight regulation of immune and inflammatory responses. To provide new mechanistic insight of the requirements needed for innate host defenses against acute S. pneumoniae infection, we examined how IL-23 deficiency mediated acute pulmonary resistance. We found that IL-23 deficient mice were more susceptible to bacterial colonization in the lungs corresponding with greater bacterial dissemination. The lack of IL-23 was found to decrease IL-6 and IL-12p70 cytokine levels in bronchiolar lavage within the initial day after infection. Pulmonary leukocytes isolated from infected IL-23 deficient mice demonstrated a dramatic decrease in IL-17A and IFN-γ in response to heat-killed organisms. These findings corresponded with significant abrogation of neutrophilic infiltrate in the lungs compared to IL-23 competent mice. Whereas previous studies have shown opposing influences of IL-12/IL-23 regulation, our findings suggest a concordant dependency of IL-23 expression on Th1 and Th17-related responses.
Asunto(s)
Subunidad p19 de la Interleucina-23/deficiencia , Infecciones Neumocócicas/inmunología , Streptococcus pneumoniae/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Células Cultivadas , Femenino , Inmunidad Innata , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Interleucina-17/metabolismo , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/inmunología , Interleucina-6/metabolismo , Pulmón/inmunología , Pulmón/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunologíaRESUMEN
Choroidal neovascularization (CNV) is a characteristic of age-related macular degeneration. Genome-wide association studies have provided evidence that the immune system is involved in the pathogenesis of age-related macular degeneration; however, the role of inflammatory cytokines in CNV has not been established. In this study, we demonstrated that IL-17 had a strong potential for promoting neovascularization in a vascular endothelial growth factor-independent manner in laser-induced experimental CNV in mice. Infiltrated γδT cells and Thy-1(+) innate lymphoid cells, but not Th17 cells, were the main sources of IL-17 in injured eyes. IL-23 was dispensable for IL-17 induction in the eye. Instead, we found that IL-1ß and high-mobility group box 1 strongly promoted IL-17 expression by γδT cells. Suppression of IL-1ß and high-mobility group box 1, as well as depletion of γδT cells, reduced IL-17 levels and ameliorated experimental CNV. Our findings suggest the existence of a novel inflammatory cytokine network that promotes neovascularization in the eye.
Asunto(s)
Neovascularización Coroidal/inmunología , Interleucina-17/biosíntesis , Subunidad p19 de la Interleucina-23/fisiología , Linfocitos/inmunología , Animales , Neovascularización Coroidal/genética , Neovascularización Coroidal/patología , Modelos Animales de Enfermedad , Inmunidad Innata/genética , Interleucina-17/antagonistas & inhibidores , Interleucina-17/fisiología , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/genética , Rayos Láser/efectos adversos , Linfocitos/metabolismo , Linfocitos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores de Antígenos de Linfocitos T gamma-delta/biosíntesis , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
BACKGROUND: Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, smooth muscle activation and matrix degradation. This study tests the hypothesis that CD4+ T-cell-produced IL-17 modulates inflammation and smooth muscle cell activation, leading to the pathogenesis of AAA and that human mesenchymal stem cell (MSC) treatment can attenuate IL-17 production and AAA formation. METHODS AND RESULTS: Human aortic tissue demonstrated a significant increase in IL-17 and IL-23 expression in AAA patients compared with control subjects as analyzed by RT-PCR and ELISA. AAA formation was assessed in C57BL/6 (wild-type; WT), IL-23(-/-) or IL-17(-/-) mice using an elastase-perfusion model. Heat-inactivated elastase was used as control. On days 3, 7, and 14 after perfusion, abdominal aorta diameter was measured by video micrometry, and aortic tissue was analyzed for cytokines, cell counts, and IL-17-producing CD4+ T cells. Aortic diameter and cytokine production (MCP-1, RANTES, KC, TNF-α, MIP-1α, and IFN-γ) was significantly attenuated in elastase-perfused IL-17(-/-) and IL-23(-/-) mice compared with WT mice on day 14. Cellular infiltration (especially IL-17-producing CD4+ T cells) was significantly attenuated in elastase-perfused IL-17(-/-) mice compared with WT mice on day 14. Primary aortic smooth muscle cells were significantly activated by elastase or IL-17 treatment. Furthermore, MSC treatment significantly attenuated AAA formation and IL-17 production in elastase-perfused WT mice. CONCLUSIONS: These results demonstrate that CD4+ T-cell-produced IL-17 plays a critical role in promoting inflammation during AAA formation and that immunomodulation of IL-17 by MSCs can offer protection against AAA formation.
Asunto(s)
Aneurisma de la Aorta Abdominal/fisiopatología , Aneurisma de la Aorta Abdominal/cirugía , Linfocitos T CD4-Positivos/metabolismo , Interleucina-17/fisiología , Trasplante de Células Madre Mesenquimatosas , Animales , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/patología , Cruzamientos Genéticos , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Inmunomodulación , Interleucina-17/biosíntesis , Interleucina-17/deficiencia , Interleucina-17/genética , Subunidad p19 de la Interleucina-23/biosíntesis , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/fisiopatología , Elastasa Pancreática/toxicidad , Trasplante HeterólogoRESUMEN
CD40 ligand (CD40L) transduction of antigen-pulsed dendritic cells (DCs) can result in antigen-specific humoral immune responses even in CD4(+) T-cell-depleted settings. Here, we show that CD40L transduction of DCs results in the induction of interleukin-12p40 (IL-12p40), IL-12p70, and IL-23. Using DCs that were deficient in IL-12p40, IL-12p35, or IL-23p19, we show that these molecules are dispensable for primary IgG1 responses to Pneumocystis, but IgG2c was dependent on IL-12p40 and IL-23p19 but not IL-12p35. Antigen-specific recall responses in CD4-deficient mice were critically dependent on IL-12p40 and IL-23p19 expression in DCs and were not affected by the lack of IL-12p35. To confirm that this defect in recall was due to IL-23, transduction of IL-12p40(-/-) DCs with a recombinant adenovirus expressing functional IL-23 restored recall responses in DC-vaccinated CD4-deficient mice. These data show that DC-produced IL-23 is critical for vaccine-induced antigen-specific IgG2c and recall antibody responses in the setting of CD4(+) T-cell depletion.
Asunto(s)
Células Dendríticas/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Interleucina-23/inmunología , Pneumocystis/inmunología , Receptores de IgG/inmunología , Adenoviridae/genética , Animales , Antígenos CD4/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Ligando de CD40/genética , Ligando de CD40/inmunología , Ligando de CD40/metabolismo , Células Dendríticas/metabolismo , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/inmunología , Subunidad p35 de la Interleucina-12/deficiencia , Subunidad p35 de la Interleucina-12/inmunología , Subunidad p40 de la Interleucina-12/biosíntesis , Subunidad p40 de la Interleucina-12/deficiencia , Subunidad p40 de la Interleucina-12/inmunología , Interleucina-23/metabolismo , Subunidad p19 de la Interleucina-23/deficiencia , Activación de Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de IgG/biosíntesis , Receptores de IgG/metabolismo , Transducción Genética , VacunaciónRESUMEN
The role of IL-23 in the development of arthritis and bone metabolism was studied using systemic IL-23 exposure in adult mice via hydrodynamic delivery of IL-23 minicircle DNA in vivo and in mice genetically deficient in IL-23. Systemic IL-23 exposure induced chronic arthritis, severe bone loss, and myelopoiesis in the bone marrow and spleen, which resulted in increased osteoclast differentiation and systemic bone loss. The effect of IL-23 was partly dependent on CD4(+) T cells, IL-17A, and TNF, but could not be reproduced by overexpression of IL-17A in vivo. A key role in the IL-23-induced arthritis was made by the expansion and activity of myeloid cells. Bone marrow macrophages derived from IL-23p19(-/-) mice showed a slower maturation into osteoclasts with reduced tartrate-resistant acid phosphatase-positive cells and dentine resorption capacity in in vitro osteoclastogenesis assays. This correlated with fewer multinucleated osteoclast-like cells and more trabecular bone volume and number in 26-wk-old male IL-23p19(-/-) mice compared with control animals. Collectively, our data suggest that systemic IL-23 exposure induces the expansion of a myeloid lineage osteoclast precursor, and targeting IL-23 pathway may combat inflammation-driven bone destruction as observed in rheumatoid arthritis and other autoimmune arthritides.
Asunto(s)
Artritis Experimental/inmunología , Artritis Experimental/patología , Resorción Ósea/inmunología , Diferenciación Celular/inmunología , Subunidad p19 de la Interleucina-23/fisiología , Osteoclastos/inmunología , Osteoclastos/patología , Animales , Artritis Experimental/genética , Resorción Ósea/genética , Resorción Ósea/patología , Células CHO , Diferenciación Celular/genética , Enfermedad Crónica , Cricetinae , Cricetulus , ADN de Cinetoplasto/biosíntesis , ADN de Cinetoplasto/genética , Células HEK293 , Humanos , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/aislamiento & purificación , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Índice de Severidad de la Enfermedad , Bazo/inmunología , Bazo/metabolismo , Bazo/patologíaRESUMEN
IL-23 is an important molecular driver of Th17 cells and has strong tumor-promoting proinflammatory activity postulated to occur via adaptive immunity. Conversely, more recently it has been reported that IL-17A elicits a protective inflammation that promotes the activation of tumor-specific CD8(+) T cells. Here we show the much broader impact of IL-23 in antagonizing antitumor immune responses primarily mediated by innate immunity. Furthermore, the majority of this impact was independent of IL-17A, which did not appear critical for many host responses to tumor initiation or metastases. IL-23-deficient mice were resistant to experimental tumor metastases in three models where host NK cells controlled disease. Immunotherapy with IL-2 was more effective in mice lacking IL-23, and again the protection afforded was NK cell mediated and independent of IL-17A. Further investigation revealed that loss of IL-23 promoted perforin and IFN-gamma antitumor effector function in both metastasis models examined. IL-23-deficiency also strikingly protected mice from tumor formation in two distinct mouse models of carcinogenesis where the dependence on host IL-12p40 and IL-17A was quite different. Notably, in the 3'-methylcholanthrene (MCA) induction of fibrosarcoma model, this protection was completely lost in the absence of NK cells. Overall, these data indicate the general role that IL-23 plays in suppressing natural or cytokine-induced innate immunity, promoting tumor development and metastases independently of IL-17A.
Asunto(s)
Inmunidad Innata , Interleucina-17/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Miocardio/inmunología , Neoplasias/inmunología , Neoplasias/patología , Animales , Línea Celular Tumoral , Femenino , Inmunoterapia , Interferón gamma/inmunología , Interleucina-2/inmunología , Subunidad p19 de la Interleucina-23/deficiencia , Células Asesinas Naturales/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Metástasis de la Neoplasia , Perforina/inmunologíaRESUMEN
Listeria monocytogenes (LM) is a Gram-positive, intracellular bacterium that can induce spontaneous abortion, septicemia, and meningitis. Although it is known that neutrophils are required for elimination of the bacteria and for survival of the host, the mechanisms governing the recruitment of neutrophils to LM-infected tissues are not fully understood. We demonstrate here that IL-23 and the IL-17 receptor A (IL-17RA), which mediates both IL-17A and IL-17F signaling, are necessary for resistance against systemic LM infection. LM-infected IL-23p19 knockout (KO) mice have decreased production of IL-17A and IL-17F, while IFN-gamma production is not altered by the lack of IL-23. LM induces the production of IL-17A from gammadelta T cells, but not CD4, CD8, or NK cells. Furthermore, a lack of efficient neutrophil recruitment to the liver is evident in both IL-23p19 KO and IL-17RA KO mice during LM infection. Immunocytochemical analysis of infected livers revealed that neutrophils were able to localize with LM in IL-23p19 KO and IL-17RA KO mice, indicating that IL-23 and IL-17RA do not regulate the precise localization of neutrophils with LM. The importance of IL-23-induced IL-17A was demonstrated by injecting IL-23p19 KO mice with recombinant IL-17A. These mice had reduced LM bacterial burdens compared with IL-23p19 KO mice that did not receive IL-17A. These results indicate that during LM infection, IL-23 regulates the production of IL-17A and IL-17F from gammadelta T cells, resulting in optimal liver neutrophil recruitment and enhanced bacterial clearance.
Asunto(s)
Interleucina-23/fisiología , Listeriosis/inmunología , Listeriosis/prevención & control , Animales , Interleucina-17/deficiencia , Interleucina-17/genética , Interleucina-17/fisiología , Interleucina-23/genética , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/fisiología , Listeria monocytogenes/inmunología , Listeriosis/microbiología , Hígado/inmunología , Hígado/microbiología , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/genética , Infiltración Neutrófila/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/biosíntesis , Receptores de Interleucina-17/deficiencia , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/fisiología , Transducción de Señal/genética , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
In infection with the trematode helminth Schistosoma mansoni, the severity of CD4 T cell-mediated hepatic granulomatous and fibrosing inflammation against parasite eggs varies considerably in humans and among mouse strains. In mice, either the natural high pathology, or high pathology induced by concomitant immunization with schistosome egg Ags (SEA) in CFA (SEA/CFA), results from a failure to contain a net proinflammatory cytokine environment. We previously demonstrated that the induction of severe immunopathology was dependent on the IL-12/IL-23 common p40 subunit, and correlated with an increase in IL-17, thus implying IL-23 in the pathogenesis. We now show that mice lacking the IL-23-specific subunit p19 are impaired in developing severe immunopathology following immunization with SEA/CFA, which is associated with a marked drop of IL-17 in the granulomas, but not in the draining mesenteric lymph nodes, and with a markedly suppressed SEA-specific IFN-gamma response regulated by a striking increase in IL-10. The granulomas are characterized by a significant reduction in Gr-1(+) cell recruitment and by alternative macrophage activation. Taken together, these results demonstrate that IL-23 per se is not necessary for the generation of IL-17-producing T cells, but is essential for the development of severe schistosome egg-induced immunopathology, and its absence cannot be overcome with other possible compensatory mechanisms.
Asunto(s)
Interleucina-17/biosíntesis , Interleucina-17/genética , Subunidad p19 de la Interleucina-23/fisiología , Óvulo/inmunología , Schistosoma mansoni/inmunología , Esquistosomiasis mansoni/inmunología , Esquistosomiasis mansoni/patología , Animales , Antígenos Helmínticos/administración & dosificación , Antígenos Helmínticos/inmunología , Células Cultivadas , Regulación de la Expresión Génica/inmunología , Interleucina-17/antagonistas & inhibidores , Subunidad p19 de la Interleucina-23/deficiencia , Subunidad p19 de la Interleucina-23/genética , Parasitosis Hepáticas/inmunología , Parasitosis Hepáticas/metabolismo , Parasitosis Hepáticas/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/parasitología , Ganglios Linfáticos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Esquistosomiasis mansoni/genética , Esquistosomiasis mansoni/mortalidad , Índice de Severidad de la Enfermedad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/parasitología , Subgrupos de Linfocitos T/patologíaRESUMEN
Experimental autoimmune encephalomyelitis (EAE), a T cell-mediated inflammatory disease of the CNS, is a rodent model of human multiple sclerosis. IL-23 is one of the critical cytokines in EAE development and is currently believed to be involved in the maintenance of encephalitogenic responses during the tissue damage effector phase of the disease. In this study, we show that encephalitogenic T cells from myelin oligodendrocyte glycopeptide (MOG)-immunized wild-type (WT) mice caused indistinguishable disease when adoptively transferred to WT or IL-23-deficient (p19 knockout (KO)) recipient mice, demonstrating that once encephalitogenic cells have been generated, EAE can develop in the complete absence of IL-23. Furthermore, IL-12/23 double-deficient (p35/p19 double KO) recipient mice developed EAE that was indistinguishable from WT recipients, indicating that IL-12 did not compensate for IL-23 deficiency during the effector phase of EAE. In contrast, MOG-specific T cells from p19KO mice induced EAE with delayed onset and much lower severity when transferred to WT recipient mice as compared with the EAE that was induced by cells from WT controls. MOG-specific T cells from p19KO mice were highly deficient in the production of IFN-gamma, IL-17A, and TNF, indicating that IL-23 plays a critical role in development of encephalitogenic T cells and facilitates the development of T cells toward both Th1 and Th17 pathways.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Subunidad p35 de la Interleucina-12/inmunología , Subunidad p19 de la Interleucina-23/inmunología , Esclerosis Múltiple/inmunología , Células TH1/inmunología , Animales , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/patología , Femenino , Humanos , Subunidad p35 de la Interleucina-12/deficiencia , Subunidad p19 de la Interleucina-23/deficiencia , Masculino , Ratones , Ratones Noqueados , Esclerosis Múltiple/patología , Proteínas de la Mielina , Glicoproteína Asociada a Mielina/inmunología , Glicoproteína Asociada a Mielina/toxicidad , Glicoproteína Mielina-Oligodendrócito , Células TH1/patología , Células TH1/trasplanteRESUMEN
Interleukin-23 (IL-23), a member of the IL-12 family, is a heterodimeric cytokine that is composed of the p40 subunit of IL-12 plus a unique p19 subunit. IL-23 is critical for autoimmune inflammation, in part due to its stimulation of the proinflammatory cytokine IL-17A. It is less clear, however, if IL-23 is required during the immune response to pathogens. We examined the role of IL-23 during Mycobacterium bovis BCG infection. We found that IL-23 reduces the bacterial burden and promotes granuloma formation when IL-12 is absent. However, IL-23 does not contribute substantially to host resistance when IL-12 is present, as the ability to control bacterial growth and form granulomata is not affected in IL-23p19-deficient mice and mice treated with a specific anti-IL-23p19 antibody. IL-23p19-deficient mice are also able to mount an effective memory response to secondary infection with BCG. While IL-23p19-deficient mice do not produce IL-17A, this cytokine is not necessary for effective control of infection, and antibody blocking of IL-17A in both wild-type and IL-12-deficient mice also has little effect on the bacterial burden. These data suggest that IL-23 by itself does not play an essential role in the protective immune response to BCG infection; however, the presence of IL-23 can partially compensate for the absence of IL-12. Furthermore, neutralization of IL-23 or IL-17A does not increase susceptibility to mycobacterial BCG infection.