RESUMO
Intestinal barrier function requires intricate cooperation between intestinal epithelial cells and immune cells. Enteropathogens are able to invade the intestinal lymphoid tissue known as Peyer's patches (PPs) and disrupt the integrity of the intestinal barrier. However, the underlying molecular mechanisms of this process are poorly understood. In mice infected with Yersinia pseudotuberculosis, we found that PP barrier dysfunction is dependent on the Yersinia virulence plasmid and the expression of TLR-2 by hematopoietic cells, but not by intestinal epithelial cells. Upon TLR-2 stimulation, Y. pseudotuberculosis-infected monocytes activated caspase-1 and produced IL-1ß. In turn, IL-1ß increased NF-κB and myosin light chain kinase activation in intestinal epithelial cells, thus disrupting the intestinal barrier by opening the tight junctions. Therefore, Y. pseudotuberculosis subverts intestinal barrier function by altering the interplay between immune and epithelial cells during infection.
Assuntos
Células-Tronco Hematopoéticas/imunologia , Mucosa Intestinal/imunologia , Nódulos Linfáticos Agregados/imunologia , Transdução de Sinais/imunologia , Receptor 2 Toll-Like/imunologia , Infecções por Yersinia pseudotuberculosis/imunologia , Yersinia pseudotuberculosis/imunologia , Animais , Células CACO-2 , Caspase 1/genética , Caspase 1/imunologia , Ativação Enzimática/genética , Ativação Enzimática/imunologia , Células-Tronco Hematopoéticas/microbiologia , Células-Tronco Hematopoéticas/patologia , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/microbiologia , Monócitos/patologia , Quinase de Cadeia Leve de Miosina/genética , Quinase de Cadeia Leve de Miosina/imunologia , NF-kappa B/genética , NF-kappa B/imunologia , Nódulos Linfáticos Agregados/microbiologia , Nódulos Linfáticos Agregados/patologia , Transdução de Sinais/genética , Receptor 2 Toll-Like/genética , Yersinia pseudotuberculosis/genética , Infecções por Yersinia pseudotuberculosis/genética , Infecções por Yersinia pseudotuberculosis/patologiaRESUMO
Autophagy-related 16 like-1 (ATG16L-1), immunity-related GTPase-M (IRGM), and nucleotide-binding oligomerization domain-containing 2 (NOD2) regulate autophagy, and variants in these genes have been associated with predisposition to Crohn's disease (CD). However, little is known about the role of autophagy in CD. Intestinal biopsies from untreated pediatric patients with CD, celiac disease, or ulcerative colitis were analyzed by immunohistochemistry and electron microscopy. We observed that autophagy was specifically activated in Paneth cells from patients with CD, independently of mucosal inflammation or disease-associated variants of ATG16L1 or IRGM. In these cells, activation of autophagy was associated with a significant decrease in number of secretory granules and features of crinophagy. These observations might account for the disorganization of secretory granules previously reported in Paneth cells from patients with CD.
