IRE1 and PERK signaling regulates inflammatory responses in a murine model of contact hypersensitivity. Issue 3 (7th August 2021)

• Record Type: Journal Article
• Authors: Gendrisch, Fabian; Völkel, Lukas; Fluck, Melanie; Apostolova, Petya; Zeiser, Robert; Jakob, Thilo; Martin, Stefan F.; Esser, Philipp R.
• Is Part Of: Allergy. Volume 77:Issue 3(2022)
• Page Start: 966
• Page End: 978
• Publication Date: 2021-08-07
• Subjects: allergic contact dermatitis -- contact hypersensitivity -- inflammation -- unfolded protein response; Allergy -- Periodicals; 616.97
• DOI: 10.1111/all.15024
• Languages: English
• ISSNs: 0105-4538

Abstract

Abstract: Background: Contact sensitizers may interfere with correct protein folding. Generation of un‐/misfolded proteins can activate the IRE‐1 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‐inflammatory micromilieu in vitro as well as the effect of UPR modulation on the inflammatory response in the murine contact hypersensitivity (CHS) in vivo. Methods: Semi‐quantitative and quantitative PCR, fluorescence microscopy, ELISA, NF‐κB activation and translocation assays, DC/keratinocyte co‐culture assay, FACS, and in vivo CHS experiments were performed. Results: Sensitizers and irritants activate IRE‐1 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‐activation of the UPR. Blocking UPR signaling results in decreased NF‐κB activation and cytokine production in keratinocytes and in activation marker downregulation in a HaCaT/THP‐1 co‐culture. Interestingly, not only s ystemic but also topical application of UPR inhibitors abrogates CHS responses in vivo. Conclusion: 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. Abstract : UPR in murine and human keratinocytes is activated by contact sensitizers and irritants; combining weak sensitizers results in synergistic effects. UPR inhibition reduces NF‐kB activation and pro‐inflammatory cytokine production thereby preventing ER stress–mediated DC activation in a keratinocyte/DC co‐culture assay in vitro. Systemic or topical inhibitor application prevents CHS; UPR pre‐activation enhances CHS to the weak allergen/tolerogen DNTB. Abbreviations: ATF‐4 /‐6, activating transcritption factor 4/ ‐6; CHS, contact hypersensitivity; DC, dendritic cell; DNTB, 2, 4‐dinitrothiocyanobenzene; eIF2, elongation initiation factor 2; ER, endoplasmic reticulum; i.p., intraperitoneal; IRE, inositol‐requiring transmembrane kinase/endonuclease; PERK, protein kinase RNA‐like ER kinase; UPR, unfolded protein response; XBP‐1, X‐box binding protein 1