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

Abstract

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.

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

“…This extract was able to stimulate migration of healthy dermal fibroblasts and bioactive molecule secretion from cellular skin substitutes suggesting that senescent cells also show aberrant responses to chemokines. 101 Interestingly, there was little variation in chemokine concentration between donors in this study, despite differing wound etiologies, size, and duration. 101 Finally, it is not just inflammatory processes that are deranged in chronic wounds.…”

“…40,100 Chemokine receptors CCR1, CCR10, CXCR1, CXCR2, and CXCR3 are expressed on the surface of mouse keratinocytes and since the same keratinocytes are able to secrete their corresponding monospecific ligands a model of autocrine regulation of re-epithelialization has been postulated. 101 Chemokines may also play a role during nonhematopoietic cell recruitment in wound healing. Bone-marrow derived stem cells (BMDSCs) possess the ability to self-renew and differentiate into multiple cell lines.…”

CXCL1 Inhibits Airway Smooth Muscle Cell Migration through the Decoy Receptor Duffy Antigen Receptor for Chemokines

“…Although primarily known as a potent inducer of neutrophil chemotaxis (16), CXCL1 was shown to induce cancer cell invasion (17) and endothelial (18) and epithelial cell migration (19). CXCL1 facilitates its signaling by binding to its putative receptor, the chemokine receptor CXCR2, although it also was found to bind to CXCR1, albeit with lower affinity (20).…”

Comparison of advanced therapy medicinal product gingiva and skin substitutes and their in vitro wound healing potentials

“…For CXCL8 and IL‐6, literature is conflicting. There is evidence that elevated levels of CXCL8 stimulate keratinocyte proliferation in vitro (Kroeze et al, 2012a; Rennekampff et al, 2000), but the opposite, inhibition of keratinocyte proliferation, has also been described (Iocono et al, 2000). Furthermore, elevated levels of CXCL8 have been described to contribute to delayed wound healing, as CXCL8 was increased in non‐healing human thermal wounds compared with healing wounds.…”