Activation of Unfolded Protein Response Pathways Promotes Keratinocyte Differentiation and Ameliorates Psoriasis Phenotypes
Description
In this study, we observed significant attenuation of UPR pathways specifically IRE1α-XBP1s and PERK signaling in psoriasis lesions. Administration of ER stress inducers (TM and BFA) alleviated psoriasis-like phenotypes in an imiquimod (IMQ)-induced mouse model. Furthermore, knockdown of Grp78 in KCs activated both IRE1α-XBP1s and PERK pathways, thereby improving KC differentiation in vitro. Notably, combining of Grp78 knockdown with ER stress inducers synergistically enhanced KC differentiation through UPR activation. Together, these findings indicate that the ER stress response promotes epidermal KC differentiation. Targeted activation of UPR pathways may thus represent a novel therapeutic strategy to improve KC differentiation in psoriasis.
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Antibodies and Reagents The following primary antibodies were used for immunoblotting: Grp78 (Santa Cruz, SC-13968), KRT1 (Abclonal, A9776), Involucrin (Abclonal, A8026), Ki67 (Abcam, ab16667), XBP1s (Abclonal, A17007), XBP1u (Proteintech, 25997-1-AP), PERK (Proteintech, 24390-1-AP), p-PERK (Abclonal, AP1501), ATF6 (Proteintech, 24169-1-AP), β-Actin (Santa Cruz, sc-47778). The IRE1α inhibitor 4μ8C (Selleck, S7272) and Kira6 (Selleck, S8658), as well as the PERK inhibitors GSK2606414 (Selleck, S7307) or GSK2656157 (Selleck, S7033), were dissolved in DMSO and used at a final concentration of 4μ8C 1mM, Kira6 5μM, GSK2606414 140μM, GSK2656157 3μM. Primary mouse keratinocytes were treated with these inhibitors for 48 hours prior to subsequent experiments. ER stress inducer Tunicamycin (TM) and Brefeldin (BFA) were obtained from Aladdin (Cat No. T101151; B102375) and dissolved in DMSO. Final working concentration were 0.1μg/mL for TM and 20nM for BFA.
Institutions
- Xiangya Hospital Central South UniversityHunan, Changsha