Keratinocyte Integrin ?3?1 Promotes Secretion of IL-1? to Effect Paracrine Regulation of Fibroblast Gene Expression and Differentiation.

ABSTRACT: After cutaneous injury, keratinocytes secrete paracrine factors that regulate wound cell functions; dysregulation of this signaling can lead to wound pathologies. Previously, we established that keratinocyte integrin ?3?1 promotes wound angiogenesis through paracrine stimulation of endothelial cells. We hypothesize here that ?3?1-dependent paracrine signaling from keratinocytes regulates the differentiation state of myofibroblasts. We report that epidermal ?3-knockout mice exhibit more wound myofibroblasts and fewer cyclooxygenase 2 (Cox-2)-positive dermal cells than controls. We also found that conditioned medium from ?3-expressing mouse keratinocytes (MK?3+), but not from ?3-null MK cells (MK?3-), induces expression of Cox-2 in fibroblasts in a time- and dose-dependent manner and that this induction is mediated by IL-1?. Compared with MK?3- cells, MK?3+ cells secrete more IL-1? and less IL-1RA, a natural IL-1 receptor antagonist. Treatment with an IL-1? neutralizing antibody, recombinant IL-1RA, or IL-1 receptor-targeting small interfering RNA suppresses MK?3+ conditioned medium-dependent induction of Cox-2 expression in fibroblasts. Finally, active recombinant IL-1? is sufficient to induce Cox-2 in fibroblasts and to inhibit transforming growth factor-?-induced ?-SMA expression. Our findings support a role for keratinocyte integrin ?3?1 in controlling the secretion of IL-1?, a paracrine factor that regulates the wound myofibroblast phenotype.

SUBMITTER: Zheng R 

PROVIDER: S-EPMC7171922 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature