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HSPA2 is a heat shock-non-inducible member of the human HSPA\/HSP70 family, which includes several highly homologous chaperone proteins. HSPA2 exhibits a cell type-specific expression pattern in the testis, brain, and multilayered epithelia. It is a crucial male fertility-related factor, but its role in somatic cells is poorly understood. Previously, we found that HSPA2 deficiency can impair epidermal keratinocyte differentiation. In this study, we confirmed the crucial role of HSPA2 in keratinocyte differentiation by investigating immortalized keratinocytes cultured in a reconstructed human epidermis model. Moreover, we uncovered the influence of HSPA2 on immunomodulation. Transcriptomic analysis revealed that the total loss of HSPA2 affected the expression of genes related to keratinocyte differentiation and interleukin- and interferon-mediated signaling. The functional analysis confirmed bidirectional changes associated with the loss of HSPA2. The HSPA2 knockout in HaCaT and Ker-CT keratinocytes, but not HSPA2 overproduction, impaired granular layer development as evidenced by reduced levels of late keratinocyte differentiation markers, filaggrin and involucrin, along with structural abnormalities in the upper epidermal layer. Differentiation defects were accompanied by increased mRNA expression and extracellular secretion of keratinocyte-derived pro-inflammatory IL-6 cytokine and CCL2, CCL8, CXCL1, CXCL6, and CXCL10 chemokines. The loss of HSPA2 also led to increased expression of extracellular HSPA1 and interferon-stimulated genes and secretion of immune cell modulator SLAMF7. Knocking down HSPA1 expression in keratinocytes decreased the secretion of IL-6 and CCL5 release, suggesting extracellular HSPA1\u2019s role in the HSPA2-regulated molecular network. To summarize, we uncovered the complex homeostatic role of HSPA2 in epidermal keratinocytes. Our results suggest that dysfunction in HSPA2 activity could be an important pathogenicity factor and potential therapeutic target for inflammatory cutaneous diseases.<\/jats:p>","DOI":"10.1038\/s41419-025-07565-5","type":"journal-article","created":{"date-parts":[[2025,4,26]],"date-time":"2025-04-26T07:32:28Z","timestamp":1745652748000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["HSPA2 influences the differentiation and production of immunomodulatory mediators in human immortalized epidermal keratinocyte lines"],"prefix":"10.1038","volume":"16","author":[{"given":"Agnieszka","family":"Gogler","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7554-1803","authenticated-orcid":false,"given":"Agata Ma\u0142gorzata","family":"Wilk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Damian Robert","family":"Sojka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ma\u0142gorzata","family":"Adamiec-Organi\u015bciok","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalia","family":"Matysiak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daria","family":"Kania","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klaudia","family":"Wiecha","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ewa","family":"Ma\u0142usecka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander Jorge","family":"Cortez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-2427-2680","authenticated-orcid":false,"given":"Dawid","family":"Zamojski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2508-5736","authenticated-orcid":false,"given":"Micha\u0142","family":"Marczyk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agnieszka Maria","family":"Mazurek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sylwia","family":"Ozi\u0119b\u0142o","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3489-8464","authenticated-orcid":false,"given":"Dorota","family":"Scieglinska","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,4,26]]},"reference":[{"key":"7565_CR1","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/s12192-008-0068-7","volume":"14","author":"HH Kampinga","year":"2009","unstructured":"Kampinga HH, Hageman J, Vos MJ, Kubota H, Tanguay RM, Bruford EA, et al. 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