Nuclear Calprotectin mediates Epithelial Wound Healing Defects in Crohn’s Disease related Fistula

Wound healing is critical to homeostasis in particular in tissues exposed to environmental insults such as the skin and the intestine. At the intersection of these tissues a particular form of wounding occurs in the form of perianal fistula, i.e. abnormal tracts connecting the intestine with the skin. Importantly, a natural disparity is found in healing efficiency in perianal fistula depending on the underlying medical condition, which is currently not well understood. Using this disparity, we modelled appropriate and defective wound healing by comparing Crohn’s disease related fistula (poor healing) and non-IBD/idiopathic fistula (well healing). We show that during wound healing, cytokines TNFα and IL6 in conjunction with TGF-β induce differentiation of columnar intestinal mucosa into squamous epithelium with high expression of keratins 5 and 13 and WFDC2 . Specifically in poorly healing wounds, cytokines including IL17, IL22 and IFNγ induced expression of S100A8/9 in this intestinal derived tissue. Surprisingly, S100A8/9 was not released but rather functioned as a transcriptional (co)regulator, affecting downstream inflammatory mediators such as C3 and CXCL17. These data identify separate immune pathways contributing to healing in general and deficient healing, allowing for more targeted intervention approaches.