Autocrine Regulation of Re-Epithelialization After Wounding by Chemokine Receptors CCR1, CCR10, CXCR1, CXCR2, and CXCR3

This study identifies chemokine receptors involved in an autocrine regulation of re-epithelialization after skin tissue damage. We determined which receptors, from a panel of 13, are expressed in healthy human epidermis and which monospecific chemokine ligands, secreted by keratinocytes, were able to stimulate migration and proliferation. A reconstructed epidermis cryo(freeze)-wound model was used to assess chemokine secretion after wounding and the effect of pertussis toxin (chemokine receptor blocker) on re-epithelialization and differentiation. Chemokine receptors CCR1, CCR3, CCR4, CCR6, CCR10, CXCR1, CXCR2, CXCR3, and CXCR4 were expressed in epidermis. No expression of CCR2, CCR5, CCR7, and CCR8 was observed by either immunostaining or flow cytometry. Five chemokine receptors (CCR1, CCR10, CXCR1, CXCR2, and CXCR3) were identified, the corresponding monospecific ligands (CCL14, CCL27, CXCL8, CXCL1, CXCL10, respectively) of which were not only able to stimulate keratinocyte migration and/or proliferation but were also secreted by keratinocytes after introducing cryo-wounds into epidermal equivalents. Blocking of receptor-ligand interactions with pertussis toxin delayed re-epithelialization, but did not influence differentiation (as assessed by formation of basal layer, spinous layer, granular layer, and stratum corneum) after cryo-wounding. Taken together, these results confirm that an autocrine positive-feedback loop of epithelialization exists in order to stimulate wound closure after skin injury.