RESUMEN
Pathogenic Th17 cells play a crucial role in autoimmune diseases like uveitis and its animal model, experimental autoimmune uveitis (EAU). Dimethyl itaconate (DMI) possesses potent anti-inflammatory effects. However, there is still a lack of knowledge about the role of DMI in regulating pathogenic Th17 cells and EAU. Here, we reported that intraperitoneal administration of DMI significantly inhibited the severity of EAU via selectively suppressing Th17 cell responses. In vitro antigen stimulation studies revealed that DMI dramatically decreased the frequencies and function of antigen-specific Th17, but not Th1, cells. Moreover, DMI hampered the differentiation of naive CD4+ T cells toward pathogenic Th17 cells. DMI-treated DCs produced less IL-1ß, IL-6, and IL-23, and displayed an impaired ability to stimulate antigen-specific Th17 activation. Mechanistically, DMI activated the NRF2/HO-1 pathway and suppressed STAT3 signaling, which subsequently restrains p-STAT3 nuclear translocation, leading to decreased pathogenic Th17 cell responses. Thus, we have identified an important role for DMI in regulating pathogenic Th17 cells, supporting DMI as a promising therapy in Th17 cell-driven autoimmune diseases including uveitis.
Asunto(s)
Enfermedades Autoinmunes , Succinatos , Uveítis , Animales , Ratones , Células Th17 , Factor 2 Relacionado con NF-E2/metabolismo , Inflamación/metabolismo , Enfermedades Autoinmunes/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Células TH1RESUMEN
Sjögren's syndrome (SS) dry eye can cause ocular surface inflammation and lacrimal gland (LG) damage, leading to discomfort and potential vision problems. The existing treatment options for SS dry eye are currently constrained. We investigated the possible therapeutic effect and the underlying mechanism of AS101 in autoimmune dry eye. AS101 was injected subconjunctivally into a rabbit model of autoimmune dacryoadenitis and its therapeutic effects were determined by evaluating clinical and histological scores. The expressions of effector T cells (Teff)/regulatory T cells (Treg)-related transcription factors and cytokines, inflammation mediators, and transcription factor NFATc2 were measured by quantitative real-time PCR and/or Western blot both in vivo and in vitro. Additionally, the role of NFATc2 in the immunomodulatory effects of AS101 on T cells was explored by co-culturing activated peripheral blood lymphocytes (PBLs) transfected with NFATc2 overexpression lentiviral plasmid with AS101. AS101 treatment potently ameliorated the clinical severity and reduced the inflammation of LG. Further investigation revealed that AS101 treatment led to decreased expression of Th1-related genes (T-bet and IFN-γ) and Th17-related genes (RORC, IL-17A, IL-17F, and GM-CSF) and increased expression of Treg-related gene Foxp3 in vivo and in vitro. Meanwhile, AS101 suppressed the expression of TNF-α, IL-1ß, IL-23, IL-6, MMP-2, and MMP-9. Mechanistically, AS101 downregulated the expression of NFATc2 in inflamed LGs. Overexpression of NFATc2 in activated PBLs partially blunted the effect of AS101 on Teff suppression and Treg promotion. In conclusion, AS101 is a potential regulator of Teff/Treg cell balance and could be an effective treatment agent for SS dry eye.
Asunto(s)
Dacriocistitis , Factores de Transcripción NFATC , Síndrome de Sjögren , Animales , Femenino , Conejos , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/metabolismo , Western Blotting , Citocinas/metabolismo , Dacriocistitis/tratamiento farmacológico , Dacriocistitis/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Aparato Lagrimal/metabolismo , Aparato Lagrimal/patología , Factores de Transcripción NFATC/metabolismo , Factores de Transcripción NFATC/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Linfocitos T Reguladores/inmunología , Síndrome de Sjögren/tratamiento farmacológicoRESUMEN
Pathogenic Th17 cells are critical drivers of multiple autoimmune diseases, including uveitis and its animal model, experimental autoimmune uveitis (EAU). However, how innate immune signals modulate pathogenic Th17 responses remains largely unknown. Here, we showed that miR-338-3p endowed dendritic cells (DCs) with an increased ability to activate interphotoreceptor retinoid-binding protein (IRBP)1-20 -specific Th17 cells by promoting the production of IL-6, IL-1ß, and IL-23. In vivo administration of LV-miR-338-infected DCs promoted pathogenic Th17 responses and exacerbated EAU development. Mechanistically, dual-specificity phosphatase 16 (Dusp16) was a molecular target of miR-338-3p. miR-338-3p repressed Dusp16 and therefore strengthened the mitogen-activated protein kinase (MAPK) p38 signaling, resulting in increased production of Th17-polarizing cytokines and subsequent pathogenic Th17 responses. In addition, methyltransferase like 3 (Mettl3), a key m6A methyltransferase, mediated the upregulation of miR-338-3p in activated DCs. Together, our findings identify a vital role for Mettl3/miR-338-3p/Dusp16/p38 signaling in DCs-driven pathogenic Th17 responses and suggest a potential therapeutic avenue for uveitis and other Th17 cell-related autoimmune disorders.
Asunto(s)
Enfermedades Autoinmunes , MicroARNs , Uveítis , Animales , Células Th17 , Enfermedades Autoinmunes/genética , Metiltransferasas , Proteínas Quinasas p38 Activadas por Mitógenos/genética , Uveítis/genética , Células Dendríticas , MicroARNs/genéticaRESUMEN
γδ T cells are important immunoregulatory cells in experimental autoimmune uveitis (EAU), and the activation status of γδ T cells determines their disease-enhancing or inhibitory effects. Because γδ T cells can be activated via various pathways, we questioned whether the nature of their activation might impact their function. In this study, we show that γδ T cells activated under different inflammatory conditions differ greatly in their functions. Whereas anti-CD3 treatment activated both IFN-γ+ and IL-17+ γδ T cells, cytokines preferentially activated IL-17+ γδ T cells. γδ T cells continued to express high levels of surface CD73 after exposure to inflammatory cytokines, but they downregulated surface CD73 after exposure to dendritic cells. Although both CD73high and CD73low cells have a disease-enhancing effect, the CD73low γδ T cells are less inhibitory. We also show that polarized activation not only applies to αß T cells and myeloid cells, but also to γδ T cells. After activation under Th17-polarizing conditions, γδ T cells predominantly expressed IL-17 (gdT17), but after activation under Th1 polarizing conditions (gdT1) they mainly expressed IFN-γ. The pro-Th17 activity of γδ T cells was associated with gdT17, but not gdT1. Our results demonstrate that the functional activity of γδ T cells is strikingly modulated by their activation level, as well as the pathway through which they were activated.
Asunto(s)
Interferón gamma/inmunología , Interleucina-17/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Células Th17/inmunología , Uveítis/inmunología , 5'-Nucleotidasa/metabolismo , Animales , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Citocinas/inmunología , Células Dendríticas/inmunología , Femenino , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Subgrupos de Linfocitos T/inmunología , Células TH1/inmunología , Uveítis/inducido químicamente , Uveítis/patologíaRESUMEN
Adenosine is an important regulatory molecule of the immune response. We have previously reported that treatment of experimental autoimmune uveitis (EAU)-prone mice with an adenosine-degrading enzyme (adenosine deaminase) prohibited EAU development by inhibiting Th17 pathogenic T cell responses. To further validate that the targeting of adenosine or adenosine receptors effectively modulates Th17 responses, we investigated the effect of adenosine receptor antagonists. In this study, we show that the A2AR antagonist SCH 58261 (SCH) effectively modulates aberrant Th17 responses in induced EAU. However, timing of the treatment is important. Whereas SCH inhibits EAU when administered during the active disease stage, it did not do so if administered during quiescent disease stages, thus implying that the existing immune status influences the therapeutic effect. Mechanistic studies showed that inhibition of γδ T cell activation is crucially involved in adenosine-based treatment. Adenosine is an important costimulator of γδ T cell activation, which is essential for promoting Th17 responses. During ongoing disease stages, adenosine synergizes with existing high levels of cytokines, leading to augmented γδ T cell activation and Th17 responses, but in quiescent disease stages, when existing cytokine levels are low, adenosine does not enhance γδ T cell activation. Our results demonstrated that blockade of the synergistic effect between adenosine and inflammatory cytokines at active disease stages can ameliorate high-degree γδ T cell activation and, thus, suppress Th17 pathogenic T cell responses.
Asunto(s)
Adenosina/inmunología , Enfermedades Autoinmunes/inmunología , Uveítis/inmunología , Animales , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Short chain fatty acids (SCFAs) are produced by gut microbiota as fermentation products of digestion-resistant oligosaccharides and fibers. Their primary roles are functioning as major energy sources for colon cells and assisting in gut homeostasis by immunomodulation. Recent evidence suggests that they affect various organs both at cellular and molecular levels, and regulate functions in distance sites including gene expression, cell proliferation, cell differentiation, apoptosis and inflammation. In this study, we examined whether SCFAs are present in the mouse eye and whether SCFAs affect inflammatory responses of the eye and retinal astrocytes (RACs). We observed that intra-peritoneal injected SCFAs were detected in the eye and reduced intraocular inflammation induced by lipopolysaccharide (LPS). Moreover, SCFAs displayed two disparate effects on LPS-stimulated RACs - namely, cytokine and chemokine production was reduced, but the ability to activate T cells was enhanced. Our results support the existence of gut-eye cross talk and suggest that SCFAs can cross the blood-eye-barrier via the systemic circulation. If applied at high concentrations, SCFAs may reduce inflammation and impact cellular functions in the intraocular milieu.
Asunto(s)
Astrocitos/patología , Ácidos Grasos Volátiles/farmacología , Inflamación/terapia , Células Ganglionares de la Retina/patología , Uveítis/terapia , Animales , Proliferación Celular , Modelos Animales de Enfermedad , Endotoxinas/toxicidad , Femenino , Inflamación/metabolismo , Inflamación/patología , Ratones , Ratones Endogámicos C57BL , Uveítis/metabolismo , Uveítis/patologíaRESUMEN
BACKGROUND: Exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including autoimmune development. The role of circulating exosomes in the development of autoimmune uveitis is unknown. In this study, using the rat model of experimental autoimmune uveitis, which has clinical and histological features of pan uveitis in man, we evaluated the immunoregulatory function of circulating exosomes. METHODS: Experimental autoimmune uveitis was induced in Lewis rats either immunised with interphotoreceptor retinoid-binding protein R16 peptides or injected with activated R16-specific T cells. The disease incidence and severity were examined by indirect fundoscopy and flow cytometry. Circulating exosomes were isolated from peripheral blood of naïve and Day 14 R16 immunised Lewis rats. The effect of exosomes on specific T cells was evaluated by R16-specific T cell proliferation, cytokine production and recurrent uveitis induction. RESULTS: Circulating exosomes derived from active immunised uveitis rats selectively inhibited immune responses of R16-specific T cells in vitro. Vaccination of naïve rats with these exosomes reduced the incidence of recurrent uveitis in an antigen-specific manner. Antigen-specific uveitogenic T cells reduced IFN-γ production and increased IL-10 after vaccination. CONCLUSIONS: Circulating exosomes in autoimmune uveitis have the potential to be a novel treatment for recurrent autoimmune uveitis.
Asunto(s)
Enfermedades Autoinmunes , Exosomas , Uveítis , Animales , Enfermedades Autoinmunes/prevención & control , Modelos Animales de Enfermedad , Proteínas del Ojo , Inflamación , Ratas , Ratas Endogámicas Lew , Uveítis/prevención & control , VacunaciónRESUMEN
Mesenchymal stem cells (MSCs) exhibit beneficial effects on autoimmune dacryoadenitis. However, the underlying mechanisms are not fully understood. In this study, we investigated the therapeutic effect of human umbilical cord mesenchymal stem cells (hUC-MSCs) on rabbit autoimmune dacryoadenitis, an animal model of Sjögren's syndrome (SS) dry eye, and explored whether the effects of MSCs were related to their modulation on macrophage polarization. We have showed that systemic infusion of hUC-MSCs after disease onset efficiently diminished the chronic inflammation in diseased LGs and improved the clinical symptoms. Further analysis revealed that hUC-MSC treatment significantly inhibited the expression of pro-inflammatory M1 macrophage markers iNOS, TNF-α and IL-6, and promoted the expression of anti-inflammatory M2 macrophage markers Arg1, CD206, IL-10, IL-4 and TGF-ß in LGs. Mechanistically, hUC-MSCs activated AKT pathway in macrophages, resulting in upregulation of M2-associated molecule Arg1, which was partly abolished by PI3K inhibitor, LY294002. Together, our data indicated that hUC-MSCs can skew macrophages into an M2 phenotype via affecting AKT pathway. These data may provide a new insight into the mechanisms of hUC-MSCs in the therapy of SS dry eye.
Asunto(s)
Antiinflamatorios/metabolismo , Enfermedades Autoinmunes/prevención & control , Dacriocistitis/prevención & control , Macrófagos/inmunología , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas/fisiología , Cordón Umbilical/citología , Animales , Enfermedades Autoinmunes/inmunología , Western Blotting , Técnicas de Cultivo de Célula , Dacriocistitis/inmunología , Modelos Animales de Enfermedad , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Activación de Macrófagos , Fenotipo , Conejos , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Pathogenic T helper (Th)17 cells are key mediators of autoimmune diseases such as uveitis and its animal model, experimental autoimmune uveitis (EAU). However, the contribution of microRNAs (miRs) to the intrinsic control of pathogenic Th17 cells in EAU remains largely unknown. Here, we have reported that miR-223-3p was significantly up-regulated in interphotoreceptor retinoid-binding protein-specific Th17 cells, and its expression was enhanced by IL-23-signal transducer and activator of transcription 3 signaling. Knockdown of miR-223-3p decreased the pathogenicity of Th17 cells in a T-cell transfer model of EAU. Mechanistic studies showed that miR-223-3p directly repressed the expression of forkhead box O3 (FOXO3), and FOXO3 negatively regulated pathogenic Th17 cell responses partially via suppression of IL-23 receptor expression. Thus, our results reveal an important role for miR-223-3p in autoreactive Th17 cell responses and suggest a potential therapeutic avenue for uveitis.-Wei, Y., Chen, S., Sun, D., Li, X., Wei, R., Li, X., Nian, H. miR-223-3p promotes autoreactive Th17 cell responses in experimental autoimmune uveitis (EAU) by inhibiting transcription factor FOXO3 expression.
Asunto(s)
Enfermedades Autoinmunes/metabolismo , Proteína Forkhead Box O3/metabolismo , MicroARNs/metabolismo , Células Th17/metabolismo , Uveítis/metabolismo , Animales , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/fisiología , Ratones , Ratones Endogámicos C57BL , Receptores de Interleucina/metabolismo , Transducción de Señal/fisiología , Regulación hacia Arriba/fisiologíaRESUMEN
Th17-type autoreactive T cells contribute to pathogenicity in autoimmune diseases, including autoimmune uveitis. However, the mechanisms of regulation of Th17 cell activities remain unsolved and are likely to be tissue- and disease specific. In this review, we have summarized our studies from the murine model of experimental autoimmune uveitis (EAU). The resultsdemonstrate that γδ T cells have a regulatory effect on Th17 response. The regulatory effects of γδ T cells depend on their action state. Activated γδ T cells express significantly high levels of adenosine receptor A2 (A2AR) but low CD73. Both molecules are crucially involved in adenosine generation, thus modifying T cell responses. While the increased expression of A2AR-allows activated γδ T cells to bind adenosine more effectively than other immune cells, the decreased CD73 restricts their ability to convert AMP to adenosine. Adenosine affects Th1 and Th17 autoimmune responses differently. Its activation of γδ T cells shifts the Th1/Th17 balance towards the Th17 autoreactivity.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Células Th17/inmunología , Uveítis/inmunología , Animales , Humanos , Linfocitos T Reguladores/inmunología , Células TH1/inmunologíaRESUMEN
Regulatory effects of γδ T-cells on immune responses have been studied for years. We have investigated the regulatory effect of γδ T-cells on Th1 and Th17 autoimmune responses, and have studied molecular and cellular mechanisms by which γδ T-cells enhance or inhibit immune responses, exploiting a well-characterized murine model of experimental autoimmune uveitis (EAU). Our results show that (1) aberrant γδ T-cell activation is an important pathogenic event in EAU; (2) γδ T-cells have a unique regulatory effect on Th17 autoimmune responses, which is shaped by the activation status of γδ T-cells; and (3) γδ-mediated immunoregulation is closely linked with the extracellular adenosine metabolism. Reciprocal interactions between γδ T-cells and extracellular adenosine partially determine the development of EAU.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T Reguladores/inmunología , Células TH1/inmunología , Células Th17/inmunología , Uveítis/inmunología , Adenosina , Animales , Modelos Animales de Enfermedad , Humanos , Ratones , Modelos Animales , Receptores de Antígenos de Linfocitos T gamma-delta/genéticaRESUMEN
We have previously shown that activated γδ T cells have a much stronger proinflammatory effect in the development of experimental autoimmune uveitis than their nonactivated counterparts. Our present study explored γδ T cell subsets are functionally distinct in autoimmune pathogenesis and determined the pathogenic contribution of biased Vγ4+ γδ T cell activation in this disease. By systematically comparing two major peripheral γδ T cell subsets, the Vγ1+ and the Vγ4+ cells, we found that the Vγ4+ cells were readily activated in B6 mice during experimental autoimmune uveitis development, whereas Vγ1+ cells remained nonactivated. Cytokines that were abundantly found in the serum of immunized mice activated Vγ4+, but did not activate Vγ1+, cells. The Vγ4+ cells had a strong proinflammatory activity, whereas the Vγ1+ cells remained nonactivated when tested immediately after isolation from immunized mice. However, when the Vγ1+ cells were activated in vitro, they promoted inflammation. Our results demonstrated that activation is a major factor in switching the enhancing and inhibiting effects of both Vγ1+ and Vγ4+ γδ T cell subsets, and that γδ T cell subsets differ greatly in their activation requirements. Whether the enhancing or inhibiting function of γδ T cells is dominant is mainly determined by the proportion of the γδ T cells that are activated versus the proportion not activated.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Activación de Linfocitos , Receptores de Antígenos de Linfocitos T gamma-delta , Subgrupos de Linfocitos T/inmunología , Uveítis/inmunología , Animales , Enfermedades Autoinmunes/fisiopatología , Citocinas/sangre , Citocinas/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
γδ T cells located near the epithelial barrier are integral components of local inflammatory and innate immune responses. We have previously reported the presence of choroidal γδ T cells in a model of chronic degeneration of the retinal pigment epithelium (RPE). The goals of the current study were to further define the functions of choroidal γδ T cells and to explore the underlying mechanisms of their action. Our data demonstrate that choroidal γδ T cells are activated by RPE injury in response to NaIO3 treatment, and that they express genes that encode immunosuppressive cytokines, such as IL-4 and IL-10. γδ-T-cell-deficient mice developed profound RPE and retinal damage at doses that caused minimal effects in wild-type mice, and adoptive transfer of γδ T cells prevented sensitization. Intravitreal injection of IL-4 and IL-10 ameliorated RPE toxicity that was induced by NaIO3Ex vivo coculture of γδ T cells with RPE explants activated the production of anti-inflammatory cytokines via an aryl hydrocarbon receptor (AhR)-dependent mechanism. AhR deficiency abolished the protective effects of γδ T cells after adoptive transfer. Collectively, these findings define important roles for choroid γδ T cells in maintaining tissue homeostasis in the outer retina.-Zhao, Z., Liang, Y., Liu, Y., Xu, P., Flamme-Wiese, M. J., Sun, D., Sun, J., Mullins, R. F., Chen, Y., Cai, J. Choroidal γδ T cells in protection against retinal pigment epithelium and retinal injury.
Asunto(s)
Traslado Adoptivo , Distrofias Hereditarias de la Córnea/inmunología , Distrofias Hereditarias de la Córnea/terapia , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Epitelio Pigmentado de la Retina/inmunología , Linfocitos T/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Distrofias Hereditarias de la Córnea/inducido químicamente , Distrofias Hereditarias de la Córnea/genética , Interleucina-10/genética , Interleucina-10/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Yodatos/toxicidad , Ratones , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/inmunología , Epitelio Pigmentado de la Retina/lesiones , Linfocitos T/patología , Linfocitos T/trasplanteRESUMEN
Adenosine is an important regulator of the immune response, and adenosine deaminase (ADA) inhibits this regulatory effect by converting adenosine into functionally inactive molecules. Studies showed that adenosine receptor agonists can be anti- or proinflammatory. Clarification of the mechanisms that cause these opposing effects should provide a better guide for therapeutic intervention. In this study, we investigated the effect of ADA on the development of experimental autoimmune uveitis (EAU) induced by immunizing EAU-prone mice with a known uveitogenic peptide, IRBP1-20. Our results showed that the effective time to administer a single dose of ADA to suppress induction of EAU was 8-14 d postimmunization, shortly before EAU expression; however, ADA treatment at other time points exacerbated disease. ADA preferentially inhibited Th17 responses, and this effect was γδ T cell dependent. Our results demonstrated that the existing immune status strongly influences the anti- or proinflammatory effects of ADA. Our observations should help to improve the design of ADA- and adenosine receptor-targeted therapies.
Asunto(s)
Adenosina Desaminasa/administración & dosificación , Enfermedades Autoinmunes/tratamiento farmacológico , Factores Inmunológicos/administración & dosificación , Células Th17/efectos de los fármacos , Uveítis/tratamiento farmacológico , Animales , Enfermedades Autoinmunes/inmunología , Células Cultivadas , Proteínas del Ojo/inmunología , Femenino , Humanos , Inmunización , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Terapia Molecular Dirigida , Fragmentos de Péptidos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Proteínas de Unión al Retinol/inmunología , Células Th17/inmunología , Uveítis/inmunologíaRESUMEN
In this study, we showed that TLR7 activation significantly promoted interphotoreceptor retinoid-binding protein (IRBP)-specific Th17 responses by upregulating RORγt, IL-17, GM-CSF, and IL-23R expression in experimental autoimmune uveitis mice. In vivo administration of CL097 activated dendritic cells (DCs) and endowed them with an increased ability to activate IRBP-specific Th17 cells. CL097-treated DCs (CL097-DCs) formed a cytokine milieu that favored the generation and maintenance of Th17 cells by stimulating IL-1ß, IL-6, and IL-23 expression. Furthermore, IRBP-specific T cells from immunized mice injected with CL097-DCs produced more IL-17 and transferred more severe experimental autoimmune uveitis than did those from mice injected with DCs. The enhanced immunostimulatory activities of CL097-DCs depended on JNK, ERK, and p38 activation. Blockade of ERK, but not p38 or JNK, completely abolished the Th17 responses induced by CL097-DCs. Collectively, our findings suggest that CL097 treatment significantly promotes autoreactive IL-17+ T cell responses through enhancing DC activation, which is mediated, at least in part, via the activation of ERK signaling.
Asunto(s)
Células Dendríticas/inmunología , Sistema de Señalización de MAP Quinasas , Glicoproteínas de Membrana/inmunología , Glicoproteínas de Membrana/metabolismo , Células Th17/inmunología , Receptor Toll-Like 7/inmunología , Receptor Toll-Like 7/metabolismo , Animales , Autoinmunidad , Diferenciación Celular , Citocinas/inmunología , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Modelos Animales de Enfermedad , Proteínas del Ojo/inmunología , Imidazoles/farmacología , Interleucina-17/genética , Interleucina-6/inmunología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Quinolinas/farmacología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Receptores de Interleucina/genética , Proteínas de Unión al Retinol/inmunología , Transducción de Señal , Células Th17/efectos de los fármacos , Uveítis/inmunologíaRESUMEN
To prevent potentially damaging inflammatory responses, the eye actively promotes local immune tolerance via a variety of mechanisms. Owing to trauma, infection, or other ongoing autoimmunity, these mechanisms sometimes fail, and an autoimmune disorder may develop in the eye. In mice of the C57BL/10 (B10) background, autoimmune keratitis often develops spontaneously, particularly in the females. Its incidence is greatly elevated in the absence of γδ T cells, such that â¼80% of female B10.TCRδ(-/-) mice develop keratitis by 18 wk of age. In this article, we show that CD8(+) αß T cells are the drivers of this disease, because adoptive transfer of CD8(+), but not CD4(+), T cells to keratitis-resistant B10.TCRß/δ(-/-) hosts induced a high incidence of keratitis. This finding was unexpected because in other autoimmune diseases, more often CD4(+) αß T cells, or both CD4(+) and CD8(+) αß T cells, mediate the disease. Compared with wild-type B10 mice, B10.TCRδ(-/-) mice also show increased percentages of peripheral memory phenotype CD8(+) αß T cells, along with an elevated frequency of CD8(+) αß T cells biased to produce inflammatory cytokines. In addition, B10.TCRδ-/- mice have fewer peripheral CD4(+) CD25(+) Foxp3(+) αß regulatory T cells (Tregs), which express lower levels of receptors needed for Treg development and function. Together, these observations suggest that in B10 background mice, γδ T cells are required to generate adequate numbers of CD4(+) CD25(+) Foxp3(+) Tregs, and that in B10.TCRδ(-/-) mice a Treg deficiency allows dysregulated effector or memory CD8(+) αß T cells to infiltrate the cornea and provoke an autoimmune attack.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Córnea/inmunología , Queratitis/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Linfocitos T Reguladores/inmunología , Animales , Linfocitos T CD8-positivos/metabolismo , Progresión de la Enfermedad , Femenino , Factores de Transcripción Forkhead , Memoria Inmunológica , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfocitos T gamma-delta/genéticaRESUMEN
A 1q42 deletion is a rare structure variation that commonly harbours various deletion breakpoints along with diversified phenotypes. In our study, we found a de novo 1q42 deletion in a boy who did not have a cleft palate or a congenital diaphragmatic hernia but presented with psychomotor retardation. A 1.9 Mb deletion located within 1q42.11-q42.12 was validated at the molecular cytogenetic level. This is the first report of a 1q42.11-q42.12 deletion in a patient with onlypsychomotor retardation. The precise break points could facilitate the discovery of potential causative genes, such as LBR, EPHX1, etc. The correlation between the psychomotor retardation and the underlying genetic factors could not only shed light on the diagnosis of psychomotor retardation at the genetic level but also provide potential therapeutic targets.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 1/genética , Discapacidades del Desarrollo/genética , Preescolar , Bandeo Cromosómico , Humanos , Hibridación Fluorescente in Situ , Masculino , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo de Nucleótido SimpleRESUMEN
Adenosine is a key endogenous signaling molecule that regulates a wide range of physiological functions, including immune system function and inflammation. Studies have shown that adenosine receptor (AR) agonists can be either anti-inflammatory or proinflammatory in immune responses and in inflammation, and the clarification of the mechanisms causing these opposing effects should provide a better guide for therapeutic intervention. Whereas previous studies mostly examined the effects of AR agonists on Th1-type immune responses, in this study, we compared their effect on Th17 and Th1 autoimmune responses in experimental autoimmune uveitis, a mouse model of human uveitis induced by immunization with the human interphotoreceptor retinoid-binding protein peptides 1-20. We showed that injection of mice with a nonselective AR agonist, 5'-N-ethylcarboxamidoadenosine (NECA), at an early stage after immunization had an inhibitory effect on both Th1 and Th17 responses, whereas injection of the same amount of NECA at a late stage inhibited the Th1 response but had an enhancing effect on the Th17 response. We also showed that the effects of NECA on Th1 and Th17 responses were completely dissociated, that the enhancing effect of NECA on Th17 responses was modulated by γδ T cells, and that the response of γδ T cells to NECA was determined by their activation status. We conclude that the inflammatory environment has a strong impact on converting the effect of AR agonist on the Th17 autoimmune response from anti-inflammatory to proinflammatory. Our observation should help in the designing of better AR-targeted therapies.
Asunto(s)
Adenosina-5'-(N-etilcarboxamida)/administración & dosificación , Antiinflamatorios/administración & dosificación , Enfermedades Autoinmunes/inmunología , Mediadores de Inflamación/administración & dosificación , Agonistas del Receptor Purinérgico P1/administración & dosificación , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Células TH1/inmunología , Células Th17/inmunología , Uveítis/inmunología , Animales , Autoantígenos/inmunología , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/terapia , Células Cultivadas , Proteínas del Ojo/inmunología , Femenino , Humanos , Inmunomodulación/efectos de los fármacos , Inmunomodulación/genética , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Fragmentos de Péptidos/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Proteínas de Unión al Retinol/inmunología , Células TH1/efectos de los fármacos , Células Th17/efectos de los fármacos , Uveítis/inducido químicamente , Uveítis/terapiaRESUMEN
BACKGROUND: It is not clear how invading autoreactive T cells initiate the pathogenic process inside the diseased organ in T cell-mediated organ-specific autoimmune disease. In experimental autoimmune uveitis (EAU) induced by adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells in mice, we have previously reported that intraocular inflammation was initiated by infiltrating IRBP-specific T cells that directly interacted with retinal cells and resulted in the active release of high mobility group box 1 (HMGB1), an important member of damage associate molecular patterns (DAMPs). Furthermore, blockade of HMGB1 in our murine model reduced intraocular inflammation via suppression of IRBP-specific T cell functions. These results have demonstrated that HMGB1 is an early and critical mediator of induction of intraocular inflammation. The present study identified the cell surface molecule that triggers HMGB1 secretion. METHODS: Retinal explants from Fas-deficient (Fas(lpr)) and wild-type (Wt) C57BL/6 (B6) mice were cultured with activated IRBP 1-20 peptide-specific T cells or with a Fas-activating antibody (Jo2), and then the level of HMGB1 in culture supernatants were detected by ELISA. In addition, released HMGB1 was examined in the eye of Fas(lpr) and Wt mice after IRBP-specific T cell transfer. Uveitis was evaluated in the IRBP-specific T cell transferred Fas(lpr) mice after recombinant HMGB1 was restored within the eye and in the IRBP-specific T cell transferred Wt mice after they were treated with a Fas antagonist (Met12). RESULTS: In contrast to retinal explants from Wt mice, those from Fas(lpr) mice did not release HMGB1 after exposure to IRBP-specific T cells or to Jo2. The release of HMGB1 by Wt retinal explants was suppressed by Met 12. Moreover, after IRBP-specific T cell injection, Fas(lpr) mice did not release HMGB1 in the eye or develop EAU, but intravitreous injection of HMGB1 resulted in intraocular inflammation. Finally, tEAU in Wt mice was attenuated by local treatment with Met 12. Unlike HMGB1, Fas-induced IL-1 and IL-18 were not essential for tEAU induction. CONCLUSION: Our results show that interaction of retinal cells with infiltrating uveitogenic T cells leads to rapid release of HMGB1 via the Fas/FasL inflammatory signaling pathway.
Asunto(s)
Comunicación Celular/inmunología , Proteína Ligando Fas/metabolismo , Proteína HMGB1/biosíntesis , Células Ganglionares de la Retina/metabolismo , Linfocitos T/inmunología , Uveítis/metabolismo , Traslado Adoptivo , Animales , Enfermedades Autoinmunes/inmunología , Técnicas de Cocultivo , Modelos Animales de Enfermedad , Proteína Ligando Fas/inmunología , Citometría de Flujo , Proteína HMGB1/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Células Ganglionares de la Retina/inmunología , Uveítis/inmunología , Receptor fas/inmunología , Receptor fas/metabolismoRESUMEN
The proinflammatory and pathogenic function of Th17 cells in autoimmune diseases have been established but the mechanism by which such cells cause disease remains to be determined. Inflammatory cytokines produced by Th17 cells may either promote or inhibit disease development. The major cytokines produced by the uveitogenic T cells, such as IL-17 and IL-22, are not always pathogenic, and the disease-inducing ability of pathogenic T cells is not immediately correlated to the amount of cytokine they produce. Future studies identifying factors causing increased Th17 responses and determining the types of cells that regulating Th17 autoreactive T cells should facilitate our effort of understanding Th17-mediated disease pathogenesis.