Activation of the unfolded protein response in resident lamina propria cells during the initiation of intestinal inflammation.

Mucosal lamina propria cells of IBD patients are highly activated in contrast to the hyporesponsive phenotype of these cells under homeostatic conditions. Given, that human studies are based on patient biopsies taken years after disease onset, the molecular events initially causing this inflammation are still largely unknown. In this study, we aimed to characterize early activation mechanisms of resident lamina propria cells by utilizing an ex vivo human intestinal organ culture model which was recently described by us.

In this model, healthy human colonic mucosa was depleted of epithelial cells by EDTA treatment, which resulted in the activation of lamina propria immune cells and their emigration out of the tissue. Bioinformatic analysis of in situ gene expression profiles revealed the induction of signalling pathways not yet associated with the activation of lamina propria cells under inflammatory conditions, e.g. the response to unfolded protein. The upregulation of known target genes of this pathway such as GADD153, C/EBPβ, and HSPA5 in the latter cell population was subsequently confirmed in situ by qRT-PCR and/ or immunofluorescence.

These findings provide insight into molecular events underlying the change from a hyporesponsive to a highly activated phenotype in lamina propria cells at the very onset of inflammation.