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

TY - JOUR

T1 - Epidermal deletion of Kindlin-1 drives matrix changes in the mouse skin and altered responses to ultraviolet radiation

AU - Carrasco, Giovana

AU - Webb, Emily R

AU - Danks, Molly R

AU - Muir, Morwenna

AU - Hardman, David

AU - Pednekar, Chinmayi

AU - Masalmeh, Roza H A

AU - Lee, Martin

AU - Krishna, Rashi

AU - von Kriegsheim, Alex

AU - Bernabeu, Miguel O

AU - Dinkova-Kostova, Albena T

AU - Brunton, Valerie G

N1 - Publisher Copyright: © 2026 The Authors

PY - 2026/4/27

Y1 - 2026/4/27

N2 - 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 K14CreER T2 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.

AB - 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 K14CreER T2 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.

KW - Antioxidant

KW - Epithelial-to-mesenchymal transition

KW - Kindler epidermolysis bullosa

KW - Kindler syndrome

KW - UV radiation

U2 - 10.1016/j.jdermsci.2026.04.007

DO - 10.1016/j.jdermsci.2026.04.007

M3 - Article

C2 - 42091340

SN - 0923-1811

JO - Journal of Dermatological Science

JF - Journal of Dermatological Science

ER -