Activation of the human keratinocyte B1 bradykinin receptor induces expression and secretion of metalloproteases 2 and 9 by transactivation of epidermal growth factor receptor

The B1 bradykinin receptor ( BDKRB 1) is a component of the kinin cascade localized in the human skin. Some of the effects produced by stimulation of BDKRB 1 depend on transactivation of epidermal growth factor receptor ( EGFR ), but the mechanisms involved in this process have not been clarified yet. The primary purpose of this study was to determine the effect of a BDKRB 1 agonist on wound healing in a mouse model and the migration and secretion of metalloproteases 2 and 9 from human HaCaT keratinocytes and delineate the signalling pathways that triggered their secretion. Although stimulation of BDKRB 1 induces weak chemotactic migration of keratinocytes and wound closure in an in vitro scratch‐wound assay, the BDKRB 1 agonist improved wound closure in a mouse model. BDKRB 1 stimulation triggers synthesis and secretion of both metalloproteases, effects that depend on the activity of EGFR and subsequent phosphorylation of ERK 1/2 and p38 mitogen‐activated protein kinases and PI3K/Akt. In the mouse model, immunoreactivity for both gelatinases was concentrated around wound borders. EGFR transactivation by BDKRB 1 agonist involves Src kinases family and ADAM 17. In addition to extracellular matrix degradation, metalloproteases 2 and 9 regulate cell migration and differentiation, cell functions that are associated with the role of BDKRB 1 in keratinocyte differentiation. Considering that BDKRB 1 is up‐regulated by inflammation and/or by cytokines that are abundant in the inflammatory milieu, more stable BDKRB 1 agonists may be of therapeutic value to modulate wound healing.