Epithelial Hedgehog (Hh) ligands regulate several aspects of fetal intestinal organogenesis, and emerging data implicate the Hh pathway in inflammatory signaling in the adult colon. Here, we investigated the effects of chronic Hh inhibition in vivo and profiled molecular pathways acutely modulated by Hh signaling in the intestinal mesenchyme.

The progression of inflammatory disease was characterized in a bi-transgenic mouse model of chronic Hh inhibition (VFHhip). In parallel, microarray and bioinformatic analyses (Gene Ontology terms overrepresentation analysis, hierarchical clustering, and MeSH term filtration) were performed on isolated cultured intestinal mesenchyme acutely exposed to Hh ligand.

Six- to 10-month-old VFHhip animals exhibited villus smooth muscle loss and subsequent villus atrophy. Areas of villus loss became complicated by spontaneous inflammation and VFHhip animals succumbed to wasting and death. Phenotypic similarities were noted between the VFHhip phenotype and human inflammatory disorders, especially human celiac disease. Microarray analysis revealed that inflammatory pathways were acutely activated in intestinal mesenchyme cultured in the absence of epithelium, and the addition of Hh ligand alone was sufficient to largely reverse this inflammatory response within 24 hours.

Hh ligand is a previously unrecognized anti-inflammatory epithelial modulator of the mesenchymal inflammatory milieu. Acute modulation of Hh signals results in changes in inflammatory pathways in intestinal mesenchyme, while chronic inhibition of Hh signaling in adult animals leads to spontaneous intestinal inflammation and death. Regulation of epithelial Hh signaling may be an important mechanism to modulate tolerogenic versus proinflammatory signaling in the small intestine.