Keratinocyte Integrin α3β1 Promotes Secretion of IL-1α to Effect Paracrine Regulation of Fibroblast Gene Expression and Differentiation

J Invest Dermatol. 2019 Sep;139(9):2029-2038.e3. doi: 10.1016/j.jid.2019.02.025. Epub 2019 Mar 13.

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 α3β1 promotes wound angiogenesis through paracrine stimulation of endothelial cells. We hypothesize here that α3β1-dependent paracrine signaling from keratinocytes regulates the differentiation state of myofibroblasts. We report that epidermal α3-knockout mice exhibit more wound myofibroblasts and fewer cyclooxygenase 2 (Cox-2)-positive dermal cells than controls. We also found that conditioned medium from α3-expressing mouse keratinocytes (MKα3+), but not from α3-null MK cells (MKα3-), induces expression of Cox-2 in fibroblasts in a time- and dose-dependent manner and that this induction is mediated by IL-1α. Compared with MKα3- cells, MKα3+ cells secrete more IL-1α and less IL-1RA, a natural IL-1 receptor antagonist. Treatment with an IL-1α neutralizing antibody, recombinant IL-1RA, or IL-1 receptor-targeting small interfering RNA suppresses MKα3+ conditioned medium-dependent induction of Cox-2 expression in fibroblasts. Finally, active recombinant IL-1α is sufficient to induce Cox-2 in fibroblasts and to inhibit transforming growth factor-β-induced α-SMA expression. Our findings support a role for keratinocyte integrin α3β1 in controlling the secretion of IL-1α, a paracrine factor that regulates the wound myofibroblast phenotype.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Actins / metabolism
  • Animals
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cell Line
  • Culture Media, Conditioned / metabolism
  • Cyclooxygenase 2 / metabolism
  • Epidermis / immunology
  • Epidermis / metabolism
  • Humans
  • Integrin alpha3 / genetics
  • Integrin alpha3 / metabolism
  • Integrin alpha3beta1 / immunology
  • Integrin alpha3beta1 / metabolism*
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Interleukin-1alpha / antagonists & inhibitors
  • Interleukin-1alpha / immunology
  • Interleukin-1alpha / metabolism*
  • Keratinocytes / immunology
  • Keratinocytes / metabolism*
  • Mice
  • Mice, Knockout
  • Myofibroblasts / physiology*
  • Paracrine Communication / drug effects
  • Paracrine Communication / physiology*
  • Re-Epithelialization / immunology
  • Receptors, Interleukin-1 / antagonists & inhibitors
  • Receptors, Interleukin-1 / genetics
  • Receptors, Interleukin-1 / metabolism
  • Recombinant Proteins / metabolism
  • Skin / cytology
  • Skin / immunology
  • Skin / injuries

Substances

  • Acta2 protein, mouse
  • Actins
  • Culture Media, Conditioned
  • IL1RN protein, human
  • Il1a protein, mouse
  • Il1rn protein, mouse
  • Integrin alpha3
  • Integrin alpha3beta1
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1alpha
  • Itga3 protein, mouse
  • Receptors, Interleukin-1
  • Recombinant Proteins
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2