The Role Of Endoplasmic Reticulum Stress In Impeding Pathogenesis Of Psoriasis By Promoting Keratinocyte Differentiation

Backgrounds: Psoriasis is a chronic inflammatory disease of the skin,affecting up to 125 million people worldwide.The pathological manifestations of psoriasis include excessive proliferation and abnormal differentiation of keratinocytes,infiltration of inflammatory cells in both epidermis and dermis,and dilatation of vessels in dermal layer.The pathogenesis of psoriasis is complex and has not been fully elucidated.Although the overactivation of immune system factor is the core of the pathogenesis of psoriasis,the asymmetry and local characteristics of psoriasis manifestations drives researchers to pay more and more attentions to the importance of local signals from the psoriasis local lesions.The changes of keratinocytes are the main manifestation of psoriasis pathology,and the state of keratinocytes is also an important factor for the local signals in psoriasis.Therefore,it is important to elucidate the role of keratinocyte proliferation and differentiation in initiating local inflammation.Endoplasmic reticulum(ER)is an important organelle for storing calcium ions and protein folding modification.After ER stress response is activated,ER homeostasis is ensured through the synergistic activation of IRE1α/XBP1 s,PERK/EIF2 A,and ATF6 signaling pathways caused by the departure of GRP78.ER stress is involved in many normal physiological processes,for example,in secreting cells such as pancreatic β cells and B cells,in muscle cells that require large amounts of calcium ions,and in liver cells that synthesize large amounts of lipids,ER expands to meet the compensation function.Weakened or overactivated ER stress leads to many diseases,such as atherosclerosis,diabetes,obesity,and tumors.Objective: 1)The state of ER stress of keratinocytes in psoriatic lesions.2)Effects of ER stress inducers on psoriasis manifestations in IMQ inducing psoriasis mouse model.3)Effects of ER stress on keratinocyte differentiation and the corresponding activated ER signaling pathways.4)Expressions of Prdx4 in psoriasis.5)The effects of Prdx4 on keratinocyte differentiation and the ER stress pathways influenced by Prdx4.Methods: Immunohistochemistry,western blot,cell proliferation assay,ROS detection,mouse model of psoriasis induced by IMQ,primary keratinocyte culture,gene knockdown or overexpression,etc.Results: 1)Compared with normal healthy skin,ER stress was inactivated in psoriasis lesions.ER stress response was also reduced in tissues derived from IMQ-inducing psoriasis mice model.2)In mouse models,ER stress inducers BFA(Brefeldin A)and TM(Tunicamycin)can effectively improve IMQ-inducing psoriasis-like manifestations.3)In vitro experiments,we confirmed that BFA and TM promoted keratinocyte differentiation and inhibited keratinocyte proliferation.BFA and TM activated IRE1α-XBP1 s and PERK signaling pathways.In keratinocytes,deletion or overexpression of GRP78 can also affect keratinocyte differentiation.4)We also found that Prdx4,an oxidative stress molecule located in ER,was highly expressed in psoriatic lesions.5)In vitro,Prdx4 inhibited keratinocyte differentiation and promoted cell proliferation under ER stress.The expressions of Prdx4 attenuated the activation of IRE1α-XBP1 s signaling pathway stimulated by BFA and TM.The elevated levels of Prdx4 in Ha Ca T cells induced the expressions of LCN2(lipocalin Lipocalin 2)considered as an important proinflammation factor in psoriasis.Conclusions: In conclusion,our study,for the first time,elucidated the effects of ER stress on keratinocyte differentiation and proliferation in psoriasis,and confirmed the effectiveness of ER stress inducing drugs in the treatment of psoriasis in mice model.We also found the effects of Prdx4,an oxidative stress molecule located in ER,on keratinocyte differentiation and proliferation.This study investigated the mechanism of ER stress and oxidative stress molecule Prdx4 in the pathogenesis of psoriasis,and supplemented the mechanism of signals from keratinocyte cells promoting psoriasis progression.