Indian Hedgehog Suppresses Intestinal Inflammation

edgehog signaling is an evolutionarily conserved Hpathway that is important for tissue patterning and repair and has been implicated in inflammatory responses for several tissues. However, the gene and cellular targets of the Hedgehog signaling pathway that orchestrate the inflammatory responses are not clearly defined. Hedgehog signaling is mediated by 3 different ligands (sonic hedgehog [Shh], Indian hedgehog [Ihh], and Desert hedgehog [Dhh]), multiple co-receptors (patched, smoothened, growth arrestspecific 1, cell adhesion molecule-related/down-regulated by oncogenes, and brother of cell adhesion moleculerelated/down-regulated by oncogenes), 3 transcriptional effectors (glioma [Gli]-associated oncogene homologs 1, 2, 3), and additional regulatory factors. In the gastrointestinal tract, Shh and Ihh are the major ligands expressed by the epithelium. These ligands activate receptors on several stromal cell types, including myofibroblasts, smooth muscle, immune, neural, lymphatic, and vascular cells. Such complexity in the cellular targets has confounded the precise determination of which cell population mediates the response to a specific environmental challenge. Several studies have reported that Hedgehog signaling in the intestine suppresses inflammation. In particular, recent studies from Lee et al have shown that Hedgehog signaling induces expression of the anti-inflammatory cytokine interleukin (IL)10 in stromal cells, which in turn activates regulatory T cells through induction of the transcription factor Foxp3. In the current study, Westendorp et al identified a gp38-, smooth muscle actin–, and desmin-positive fibroblast that is critical for mediating the recruitment of inflammatory cells. They showed that the hedgehog ligand Ihh normally suppresses the release of immune chemoattractants such as the chemokine C-X-C motif chemokine ligand 12 (CXCL12) from these fibroblasts. By using immune cell–specific Cre recombinase drivers that delete smoothened from macrophage or dendritic cells, Westendorp et al ruled out the notion that direct Hh signaling in these immune cell populations controls the mucosal inflammatory response. Because they showed that conditional deletion of Ihh in the intestine exacerbates colitis, there is the possibility that dextran sulfate sodium induces inflammation in wild-type mice by suppressing mucosal expression of the Hh ligand during mucosal damage. However, the level of Ihh ligand was not assessed by enzyme-linked immunosorbent assay or Western blot to definitively establish this point. Collectively, the 2 intestinal studies complement each other by showing that loss of hedgehog signaling leads to increased inflammation by 2 different mechanisms. In the Westendorp et al study, hedgehog ligands suppress CXCL12 expression specifically in fibroblasts, whereas Beachy et al described a pro-reparative pathway mediated