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Yet, little is known about the pattern of neutrophil infiltration in inflamed skin in vivo and the mechanisms mediating their recruitment. Here, we provide insight into the dynamics of neutrophil infiltration in skin in response to acute or repeated inflammatory stress, highlighting a novel keratinocyte- and keratin 17 (K17)-dependent mechanism that regulates neutrophil recruitment to inflamed skin. We used the phorbol ester TPA and UVB, alone or in combination, to induce sterile inflammation in mouse skin. A single TPA treatment results in a neutrophil influx in the dermis that peaks at 12 h and resolves within 24 h. A subsequent TPA treatment or a UVB challenge, when applied 24 h but not 48 h later, accelerates, amplifies, and prolongs neutrophil infiltration. This transient amplification response (TAR) is mediated by local signals in inflamed skin, can be recapitulated in\n                    <jats:italic>ex vivo<\/jats:italic>\n                    culture, and involves the K17-dependent sustainment of protein kinase C\u03b1 (PKC\u03b1) activity and release of chemoattractants by stressed keratinocytes. K17 binds RACK1, a scaffold protein essential for PKC\u03b1 activity. The N-terminal head domain of K17 is crucial for its association with RACK1 and regulation of PKC\u03b1 activity. Analysis of RNAseq data reveals a signature consistent with TAR and PKC\u03b1 activation in inflammatory skin diseases. These findings uncover a novel, keratin-dependent mechanism that amplifies neutrophil recruitment in skin under stress, with direct implications for inflammatory skin disorders.\n                  <\/jats:p>","DOI":"10.1371\/journal.pbio.3002779","type":"journal-article","created":{"date-parts":[[2024,8,19]],"date-time":"2024-08-19T14:15:59Z","timestamp":1724076959000},"page":"e3002779","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":16,"title":["Repeated stress to the skin amplifies neutrophil infiltration in a keratin 17- and PKC\u03b1-dependent manner"],"prefix":"10.1371","volume":"22","author":[{"given":"Yang","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erez","family":"Cohen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig N.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1518-1452","authenticated-orcid":true,"given":"Carole A.","family":"Parent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0680-2373","authenticated-orcid":true,"given":"Pierre A.","family":"Coulombe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,8,19]]},"reference":[{"issue":"1","key":"pbio.3002779.ref001","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1111\/joim.13235","article-title":"So close, and yet so far away: The dichotomy of the specific immune response and inflammation in psoriasis and atopic dermatitis","volume":"290","author":"A Schabitz","year":"2021","journal-title":"J Intern Med"},{"key":"pbio.3002779.ref002","doi-asserted-by":"crossref","first-page":"2376","DOI":"10.3389\/fimmu.2019.02376","article-title":"Neutrophils in Psoriasis.","volume":"10","author":"CC Chiang","year":"2019","journal-title":"Front Immunol"},{"issue":"5","key":"pbio.3002779.ref003","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.clindermatol.2004.03.006","article-title":"Acne: inflammation.","volume":"22","author":"MD Farrar","year":"2004","journal-title":"Clin Dermatol"},{"issue":"19","key":"pbio.3002779.ref004","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.139930","article-title":"Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.","volume":"5","author":"JE Gudjonsson","year":"2020","journal-title":"JCI Insight"},{"issue":"1","key":"pbio.3002779.ref005","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.jaci.2021.05.027","article-title":"High inflammation in hidradenitis suppurativa extends to perilesional skin and can be subdivided by lipocalin-2 expression","volume":"149","author":"K Navrazhina","year":"2022","journal-title":"J Allergy Clin Immunol"},{"issue":"7","key":"pbio.3002779.ref006","doi-asserted-by":"crossref","first-page":"1377","DOI":"10.1016\/j.immuni.2021.06.006","volume":"54","author":"GL Burn","year":"2021","journal-title":"The Neutrophil. 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