Sterile Inflammation Enhances ECM Degradation in Integrin ß1 KO Embryonic Skin.

Epidermal knockout of integrin ß1 results in complete disorganization of the basement membrane (BM), resulting in neonatal lethality. Here, we report that this disorganization is exacerbated by an early embryonic inflammatory response involving the recruitment of tissue-resident and monocyte-derived macrophages to the dermal-epidermal junction, associated with increased matrix metalloproteinase activity. Remarkably, the skin barrier in the integrin ß1 knockout animals is intact, suggesting that this inflammatory response is initiated in a sterile environment. We demonstrate that the molecular mechanism involves de novo expression of integrin αvß6 in the basal epidermal cells, which activates a TGF-ß1 driven inflammatory cascade resulting in upregulation of dermal NF-κB in a Tenascin C-dependent manner. Importantly, treatment of ß1 KO embryos in utero with small molecule inhibitors of TGF-ßR1 and NF-κB results in marked rescue of the BM defects and amelioration of immune response, revealing an unconventional immuno-protective role for integrin ß1 during BM remodeling.