| First Author | Zheng R | Year | 2019 |
| Journal | J Invest Dermatol | Volume | 139 |
| Issue | 9 | Pages | 2029-2038.e3 |
| PubMed ID | 30878678 | Mgi Jnum | J:284272 |
| Mgi Id | MGI:6387319 | Doi | 10.1016/j.jid.2019.02.025 |
| Citation | Zheng R, et al. (2019) Keratinocyte Integrin alpha3beta1 Promotes Secretion of IL-1alpha to Effect Paracrine Regulation of Fibroblast Gene Expression and Differentiation. J Invest Dermatol 139(9):2029-2038.e3 |
| abstractText | 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 alpha3beta1 promotes wound angiogenesis through paracrine stimulation of endothelial cells. We hypothesize here that alpha3beta1-dependent paracrine signaling from keratinocytes regulates the differentiation state of myofibroblasts. We report that epidermal alpha3-knockout mice exhibit more wound myofibroblasts and fewer cyclooxygenase 2 (Cox-2)-positive dermal cells than controls. We also found that conditioned medium from alpha3-expressing mouse keratinocytes (MKalpha3(+)), but not from alpha3-null MK cells (MKalpha3(-)), induces expression of Cox-2 in fibroblasts in a time- and dose-dependent manner and that this induction is mediated by IL-1alpha. Compared with MKalpha3(-) cells, MKalpha3(+) cells secrete more IL-1alpha and less IL-1RA, a natural IL-1 receptor antagonist. Treatment with an IL-1alpha neutralizing antibody, recombinant IL-1RA, or IL-1 receptor-targeting small interfering RNA suppresses MKalpha3(+) conditioned medium-dependent induction of Cox-2 expression in fibroblasts. Finally, active recombinant IL-1alpha is sufficient to induce Cox-2 in fibroblasts and to inhibit transforming growth factor-beta-induced alpha-SMA expression. Our findings support a role for keratinocyte integrin alpha3beta1 in controlling the secretion of IL-1alpha, a paracrine factor that regulates the wound myofibroblast phenotype. |
