{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:04:22Z","timestamp":1790053462082,"version":"4.0.1"},"reference-count":47,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2021,8,7]],"date-time":"2021-08-07T00:00:00Z","timestamp":1628294400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Allergy"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Contact sensitizers may interfere with correct protein folding. Generation of un\u2010\/misfolded proteins can activate the IRE\u20101 or PERK signaling pathways initiating the unfolded protein response (UPR) and thereby determine inflammatory immune responses. We have analyzed the effect of sensitizers with different potencies on the induction of UPR activation\/inhibition and the subsequent generation of a pro\u2010inflammatory micromilieu in vitro as well as the effect of UPR modulation on the inflammatory response in the murine contact hypersensitivity (CHS) in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Semi\u2010quantitative and quantitative PCR, fluorescence microscopy, ELISA, NF\u2010\u03baB activation and translocation assays, DC\/keratinocyte co\u2010culture assay, FACS, and in vivo CHS experiments were performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Sensitizers and irritants activate IRE\u20101 and PERK in murine and human keratinocytes. Synergistic effects occur after combination of different weak sensitizers \/ addition of irritants. Moreover, tolerogenic dinitrothiocyanobenzene can be converted into a strong sensitizer by pre\u2010activation of the UPR. Blocking UPR signaling results in decreased NF\u2010\u03baB activation and cytokine production in keratinocytes and in activation marker downregulation in a HaCaT\/THP\u20101 co\u2010culture. Interestingly, not only\n                      <jats:italic>s<\/jats:italic>\n                      ystemic but also topical application of UPR inhibitors abrogates CHS responses in vivo.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These observations highlight an important role of the UPR in determination of the inflammatory response in vitro and in vivo further underlining the importance of tissue stress and damage responses in the development of ACD and provide mechanistically based concepts as a basis for the development of new therapeutic approaches to treat allergic contact dermatitis.<\/jats:p>\n                  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