IRE1 and PERK signaling regulates inflammatory responses in a murine model of contact hypersensitivity
IRE1 and PERK signaling regulates inflammatory responses in a murine model of contact hypersensitivity
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DOI：
10.1111/all.15024
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发表时间：
2021-08-07
期刊：
影响因子：
12.4
通讯作者：
Esser, Philipp R.
中科院分区：
文献类型：
--
作者：
Gendrisch, Fabian;Voelkel, Lukas;Esser, Philipp R.
背景接触致敏剂可能会干扰蛋白质的正确折叠。未折叠/错误折叠蛋白质的产生可以激活IRE-1或PERK信号传导途径，引发未折叠蛋白质应答（UPR），从而确定炎性免疫应答。我们已经分析了具有不同效力的致敏剂对诱导UPR激活/抑制和随后在体外产生促炎微环境的影响，以及UPR调节对小鼠接触性超敏反应（CHS）体内炎症反应的影响。方法采用半定量和定量PCR、荧光显微镜、ELISA、NF-κ B活化和易位试验、DC/角质形成细胞共培养试验、流式细胞术和体内CHS试验。结果致敏剂和刺激剂激活小鼠和人角质形成细胞中的IRE-1和PERK。不同弱致敏剂组合/添加刺激物后出现协同效应。此外，致耐受性二硝基硫氰基苯可通过预活化的UPR转化为强致敏剂。阻断UPR信号传导导致角质形成细胞中NF-κ B活化和细胞因子产生减少，并导致HaCaT/THP-1共培养物中活化标志物下调。有趣的是，不仅全身，而且局部应用UPR抑制剂消除CHS反应在体内。结论UPR在体内外炎症反应中的重要作用进一步强调了组织应激和损伤反应在ACD发展中的重要性，并为开发治疗变应性接触性皮炎的新方法提供了机制基础。
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-kappa B 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-kappa B activation and cytokine production in keratinocytes and in activation marker downregulation in a HaCaT/THP-1 co-culture. Interestingly, not only systemic 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.