Scratch wound-induced CXCL8 upregulation is EGFR-dependent in keratinocytes

Abstract

Wound healing is a sophisticated defense mechanism involving cell activation, migration, and proliferation, which are orchestrated by the coordinated production of various cytokines/chemokines such as chemokine (C-X-C motif) ligand 8 (CXCL8) [ [1] Rennekampff H.O. Hansbrough J.F. Kiessig V. Doré C. Sticherling M. Schröder J.M. Bioactive interleukin-8 is expressed in wounds and enhances wound healing. J. Surg. Res. 2000; 93: 41-54 Abstract Full Text PDF PubMed Scopus (216) Google Scholar ] and chemokine (C-C motif) ligand 20 (CCL20) [ [2] Vongsa R.A. Zimmerman N.P. Dwinell M.B. CCR6 regulation of the actin cytoskeleton orchestrates human beta defensin-2- and CCL20-mediated restitution of colonic epithelial cells. J. Biol. Chem. 2009; 284: 10034-10045 Crossref PubMed Scopus (64) Google Scholar ]. CXCL8 and CCL20 are potent chemoattractants for neutrophils and IL-17A–producing immune cells, respectively [ [1] Rennekampff H.O. Hansbrough J.F. Kiessig V. Doré C. Sticherling M. Schröder J.M. Bioactive interleukin-8 is expressed in wounds and enhances wound healing. J. Surg. Res. 2000; 93: 41-54 Abstract Full Text PDF PubMed Scopus (216) Google Scholar , [3] Furue K. Ito T. Tsuji G. Nakahara T. Furue M. The CCL20 and CCR6 axis in psoriasis. Scand. J. Immunol. 2020; 91e12846 Crossref PubMed Scopus (29) Google Scholar ]. Notably, CXCL8, CCL20, and IL-17A accelerate epithelial wound healing [ [1] Rennekampff H.O. Hansbrough J.F. Kiessig V. Doré C. Sticherling M. Schröder J.M. Bioactive interleukin-8 is expressed in wounds and enhances wound healing. J. Surg. Res. 2000; 93: 41-54 Abstract Full Text PDF PubMed Scopus (216) Google Scholar , [2] Vongsa R.A. Zimmerman N.P. Dwinell M.B. CCR6 regulation of the actin cytoskeleton orchestrates human beta defensin-2- and CCL20-mediated restitution of colonic epithelial cells. J. Biol. Chem. 2009; 284: 10034-10045 Crossref PubMed Scopus (64) Google Scholar , [4] Chen X. Cai G. Liu C. Zhao J. Gu C. Wu L. et al. IL-17R-EGFR axis links wound healing to tumorigenesis in Lrig1+ stem cells. J. Exp. Med. 2019; 216: 195-214 Crossref PubMed Scopus (45) Google Scholar ]. In addition, neutrophils are the first immune cells to infiltrate wounded sites, and appropriate neutrophilic recruitment is critical for efficient wound healing [ [5] Brazil J.C. Quiros M. Nusrat A. Parkos C.A. Innate immune cell-epithelial crosstalk during wound repair. J. Clin. Invest. 2019; 129: 2983-2993 Crossref PubMed Scopus (58) Google Scholar , [6] Devalaraja R.M. Nanney L.B. Du J. Qian Q. Yu Y. Devalaraja M.N. et al. Delayed wound healing in CXCR2 knockout mice. J. Invest. Dermatol. 2000; 115: 234-244 Abstract Full Text Full Text PDF PubMed Scopus (304) Google Scholar ]. Keratinocytes represent rich sources of CXCL8 and CCL20, and scratch wounds stimulate keratinocytes to release CXCL8 and CCL20 in a scratch line number-dependent manner [ [7] Furue K. Ito T. Tanaka Y. Yumine A. Hashimoto-Hachiya A. Takemura M. et al. Cyto/chemokine profile of in vitro scratched keratinocyte model: implications of significant upregulation of CCL20, CXCL8 and IL36G in Koebner phenomenon. J. Dermatol. Sci. 2019; 94: 244-251 Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar ]. In addition, we previously demonstrated that scratch wounding induces epidermal growth factor receptor (EGFR) phosphorylation and that specific inhibition of EGFR by PD153035 abrogates the scratch wound-induced upregulation of CCL20 [ [8] Furue K. Ito T. Tanaka Y. Hashimoto-Hachiya A. Takemura M. Murata M. et al. The EGFR-ERK/JNK-CCL20 pathway in scratched keratinocytes may underpin koebnerization in psoriasis patients. Int. J. Mol. Sci. 2020; 21: 434 Crossref Scopus (8) Google Scholar ]. However, it remains elusive whether scratch wound-induced CXCL8 production is EGFR-dependent.