Epidermal deletion of Kindlin-1 drives matrix changes in the mouse skin and altered responses to ultraviolet radiation.

BACKGROUND: Kindler syndrome (KS) or Kindler epidermolysis bullosa (KEB) is a rare genetic autosomal skin fragility disorder with photosensitivity and abnormal pigmentation, with patients also having an increased risk of developing cutaneous squamous cell carcinoma (cSCC).

OBJECTIVE: Gain a better understanding of the pathophysiology of KEB and the effects of UV radiation.

METHODS: We generated a K14CreERT2 Kindlin-1-/- SKH1 mouse which provides a valuable model to understand the complex interactions between keratinocytes and the skin environment following epidermal deletion of Kindlin-1 in adult mice.

RESULTS: Proteomic analysis of mouse skin identified significant changes associated with an epithelial-to-mesenchymal transition (EMT) including the upregulation of several extracellular matrix (ECM) proteins comprising fibrillar collagens and matrix remodeling enzymes following deletion of Kindlin-1. Detailed analysis of collagen within the skin showed increased content and fiber alignment consistent with a more fibrotic environment. Mechanistically, we found increased TGFβ signaling and activation of dermal fibroblasts in Kindlin-1 deleted skin, highlighting the importance of paracrine signaling in the control of skin homeostasis by Kindlin-1. Kindlin-1 deletion led to profound suppression of gene expression of the antioxidant enzyme Gstp1 and exacerbated ultraviolet radiation (UVR) induced DNA damage consistent with increased TGFβ signaling and an inability of Kindlin-1 deleted skin to mount an effective protective response to UVR.

CONCLUSION: This work offers insights into how Kindlin-1 loss alters skin homeostasis and induces a tumor-permissive environment.