RESUMEN
The cationic polysaccharide chitosan is an attractive candidate adjuvant capable of driving potent cell-mediated immunity, but the mechanism by which it acts is not clear. We show that chitosan promotes dendritic cell maturation by inducing type I interferons (IFNs) and enhances antigen-specific T helper 1 (Th1) responses in a type I IFN receptor-dependent manner. The induction of type I IFNs, IFN-stimulated genes and dendritic cell maturation by chitosan required the cytoplasmic DNA sensor cGAS and STING, implicating this pathway in dendritic cell activation. Additionally, this process was dependent on mitochondrial reactive oxygen species and the presence of cytoplasmic DNA. Chitosan-mediated enhancement of antigen specific Th1 and immunoglobulin G2c responses following vaccination was dependent on both cGAS and STING. These findings demonstrate that a cationic polymer can engage the STING-cGAS pathway to trigger innate and adaptive immune responses.
Asunto(s)
Adyuvantes Inmunológicos/administración & dosificación , Quitosano/administración & dosificación , Células Dendríticas/fisiología , Proteínas de la Membrana/metabolismo , Mitocondrias/metabolismo , Nucleotidiltransferasas/metabolismo , Células TH1/inmunología , Animales , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Movimiento Celular , Células Cultivadas , ADN/metabolismo , Células Dendríticas/efectos de los fármacos , Femenino , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/genética , Inmunoglobulina G/metabolismo , Interferón Tipo I/metabolismo , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Nucleotidiltransferasas/genética , Especies Reactivas de Oxígeno/metabolismo , Vacunas/administración & dosificaciónRESUMEN
Autophagy is a key regulator of cellular homeostasis that can be activated by pathogen-associated molecules and recently has been shown to influence IL-1ß secretion by macrophages. However, the mechanisms behind this are unclear. Here, we describe a novel role for autophagy in regulating the production of IL-1ß in antigen-presenting cells. After treatment of macrophages with Toll-like receptor ligands, pro-IL-1ß was specifically sequestered into autophagosomes, whereas further activation of autophagy with rapamycin induced the degradation of pro-IL-1ß and blocked secretion of the mature cytokine. Inhibition of autophagy promoted the processing and secretion of IL-1ß by antigen-presenting cells in an NLRP3- and TRIF-dependent manner. This effect was reduced by inhibition of reactive oxygen species but was independent of NOX2. Induction of autophagy in mice in vivo with rapamycin reduced serum levels of IL-1ß in response to challenge with LPS. These data demonstrate that autophagy controls the production of IL-1ß through at least two separate mechanisms: by targeting pro-IL-1ß for lysosomal degradation and by regulating activation of the NLRP3 inflammasome.