RESUMO
Ulcerative colitis (UC) is a chronic inflammatory bowel disease affecting the rectum which progressively extents. Its etiology remains unknown and the number of treatments available is limited. Studies of UC patients have identified an unbalanced endoplasmic reticulum (ER) stress in the non-inflamed colonic mucosa. Animal models with impaired ER stress are sensitive to intestinal inflammation, suggesting that an unbalanced ER stress could cause inflammation. However, there are no ER stress-regulating strategies proposed in the management of UC partly because of the lack of relevant preclinical model mimicking the disease. Here we generated the IL10/Nox1dKO mouse model which combines immune dysfunction (IL-10 deficiency) and abnormal epithelium (NADPH oxidase 1 (Nox1) deficiency) and spontaneously develops a UC-like phenotype with similar complications (colorectal cancer) than UC. Our data identified an unanticipated combined role of IL10 and Nox1 in the fine-tuning of ER stress responses in goblet cells. As in humans, the ER stress was unbalanced in mice with decreased eIF2α phosphorylation preceding inflammation. In IL10/Nox1dKO mice, salubrinal preserved eIF2α phosphorylation through inhibition of the regulatory subunit of the protein phosphatase 1 PP1R15A/GADD34 and prevented colitis. Thus, this new experimental model highlighted the central role of epithelial ER stress abnormalities in the development of colitis and defined the defective eIF2α pathway as a key pathophysiological target for UC. Therefore, specific regulators able to restore the defective eIF2α pathway could lead to the molecular remission needed to treat UC.
Assuntos
Colite Ulcerativa/etiologia , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático , Inflamação/etiologia , Interleucina-10/fisiologia , NADH NADPH Oxirredutases/fisiologia , Animais , Western Blotting , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Colite Ulcerativa/metabolismo , Colite Ulcerativa/patologia , Colo/imunologia , Colo/metabolismo , Colo/patologia , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/patologia , Feminino , Citometria de Fluxo , Imunofluorescência , Humanos , Técnicas Imunoenzimáticas , Inflamação/metabolismo , Inflamação/patologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NADPH Oxidase 1 , Fosforilação , Proteína Fosfatase 1/genética , Proteína Fosfatase 1/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Resposta a Proteínas não DobradasRESUMO
Accumulating evidence suggests that CD4 help is needed at the memory stage to mount effective secondary CD8 T cell responses. In this paper, we report that memory CD4 T cells can provide efficient help to memory CD8 T cells after interaction of the two lymphocytes with distinct dendritic cells. Provision of help to CD8 T cells required direct cell-cell contact and involved both IL-2 and CD40 ligation, within a CD4-CD8 T cell synapse. Thus, following antigenic interaction with APCs, activated memory CD4 and CD8 T cells appear to separate from their respective APCs before meeting each other for help provision, regardless of their Ag specificity. CD4 help for memory CD8 T cells therefore appears to be conditioned primarily not by Ag specificity but by activation status.
