RT Journal Article
SR Electronic
T1 Keratin 17- and PKCα-dependent transient amplification of neutrophil influx after repeated stress to the skin
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.10.11.561954
DO 10.1101/2023.10.11.561954
A1 Xu, Yang
A1 Cohen, Erez
A1 Johnson, Craig N.
A1 Parent, Carole A.
A1 Coulombe, Pierre A.
YR 2023
UL http://biorxiv.org/content/early/2023/10/14/2023.10.11.561954.abstract
AB Neutrophils contribute to the pathogenesis of chronic inflammatory skin diseases. Little is known about the source and identity of the signals mediating their recruitment in inflamed skin. We used the phorbol ester TPA and UVB, alone or in combination, to induce sterile inflammation in mouse skin and assess whether keratinocyte-derived signals impact neutrophil recruitment. A single TPA treatment results in a neutrophil influx in the dermis that peaks at 12h and resolves within 24h. A second TPA treatment or a UVB challenge, when applied at 24h but not 48h later, accelerates, amplifies, and prolongs neutrophil infiltration. This transient amplification response (TAR) is mediated by local signals in inflamed skin, can be recapitulated in ex vivo culture, and involves the K17-dependent sustainment of protein kinase Cα (PKCα) activity and release of neutrophil chemoattractants by stressed keratinocytes. We show that K17 binds RACK1, a scaffold essential for PKCα activity. Finally, analyses of RNAseq data reveal the presence of a transcriptomic signature consistent with TAR and PKCα activation in chronic inflammatory skin diseases. These findings uncover a novel, transient, and keratin-dependent mechanism that amplifies neutrophil recruitment to the skin under stress, with direct implications for inflammatory skin disorders.Competing Interest StatementThe authors have declared no competing interest.