Spontaneous skin erosions and reduced skin and corneal wound healing characterize CLIC4 NULL mice

V. C. Padmakumar, Kelsey Speer, Sonali Pal-Ghosh, Katelyn E. Masiuk, Andrew Ryscavage, Samuel L. Dengler, Shelly Hwang, John C. Edwards, Vincenzo Coppola, Lino Tessarollo, Mary Ann Stepp, Stuart H. Yuspa

Research output: Contribution to journalArticlepeer-review

Abstract

Cutaneous wound healing is a complex process involving blood clotting, inflammation, migration of keratinocytes, angiogenesis, and, ultimately, tissue remodeling and wound closure. Many of these processes involve transforming growth factor-β (TGF-β) signaling, and mice lacking components of the TGF-β signaling pathway are defective in wound healing. We show herein that CLIC4, an integral component of the TGF-β pathway, is highly up-regulated in skin wounds. We genetically deleted murine CLIC4 and generated a colony on a C57Bl/6 background. CLIC4 NULL mice were viable and fertile but had smaller litters than did wild-type mice. After 6 months of age, up to 40% of null mice developed spontaneous skin erosions. Reepithelialization of induced full-thickness skin wounds and superficial corneal wounds was delayed in CLIC4 NULL mice, resolution of inflammation was delayed, and expression of β4 integrin and p21 was reduced in lysates of constitutive and wounded CLIC4 NULL skin. The induced level of phosphorylated Smad2 in response to TGF-β was reduced in cultured CLIC4 NULL keratinocytes relative to in wild-type cells, and CLIC4 NULL keratinocytes migrated slower than did wild-type keratinocytes and did not increase migration in response to TGF-β. CLIC4 NULL keratinocytes were also less adherent on plates coated with matrix secreted by wild-type keratinocytes. These results indicate that CLIC4 participates in skin healing and corneal wound reepithelialization through enhancement of epithelial migration by a mechanism that may involve a compromised TGF-β pathway.

Original languageEnglish (US)
Pages (from-to)74-84
Number of pages11
JournalAmerican Journal of Pathology
Volume181
Issue number1
DOIs
StatePublished - Jul 2012
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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