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TWEAK/Fn14信号通路参与自发性狼疮MRL/lpr模型中皮肤病的发病机制。

TWEAK/Fn14 Signaling Involvement in the Pathogenesis of Cutaneous Disease in the MRL/lpr Model of Spontaneous Lupus.

作者信息

Doerner Jessica L, Wen Jing, Xia Yumin, Paz Karin Blecher, Schairer David, Wu Lan, Chalmers Samantha A, Izmirly Peter, Michaelson Jennifer S, Burkly Linda C, Friedman Adam J, Putterman Chaim

机构信息

The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.

The Division of Dermatology, Albert Einstein College of Medicine, Bronx, New York, USA.

出版信息

J Invest Dermatol. 2015 Aug;135(8):1986-1995. doi: 10.1038/jid.2015.124. Epub 2015 Mar 31.

DOI:10.1038/jid.2015.124
PMID:25826425
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4504782/
Abstract

Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK, TNFSF12) and its sole receptor Fn14, belonging to the TNF ligand and receptor superfamilies respectively, are involved in cell survival and cytokine production. The role of TWEAK/Fn14 interactions in the pathogenesis of cutaneous lupus has not been explored. TWEAK treatment of murine PAM212 keratinocytes stimulated the secretion of RANTES via Fn14 and promoted apoptosis. Parthenolide, but not wortmanin or the MAPK inhibitor PD98059, significantly decreased production of RANTES, indicating that this effect of TWEAK is mediated via NF-κB signaling. UVB irradiation significantly upregulated the expression of Fn14 on keratinocytes in vitro and in vivo and increased RANTES production. MRL/lpr Fn14 knockout (KO) lupus mice were compared with MRL/lpr Fn14 wild-type (WT) mice to evaluate for any possible differences in the severity of cutaneous lesions and the presence of infiltrating immune cells. MRL/lpr Fn14 KO mice had markedly attenuated cutaneous disease as compared with their Fn14 WT littermates, as evidenced by the well-maintained architecture of the skin and significantly decreased skin infiltration of T cells and macrophages. Our data strongly implicate TWEAK/Fn14 signaling in the pathogenesis of the cutaneous manifestations in the MRL/lpr model of spontaneous lupus and suggest a possible target for therapeutic intervention.

摘要

肿瘤坏死因子（TNF）样凋亡微弱诱导因子（TWEAK，TNFSF12）及其唯一受体Fn14，分别属于TNF配体和受体超家族，参与细胞存活和细胞因子产生。TWEAK/Fn14相互作用在皮肤狼疮发病机制中的作用尚未得到探索。用TWEAK处理小鼠PAM212角质形成细胞可通过Fn14刺激RANTES的分泌并促进细胞凋亡。小白菊内酯，而非渥曼青霉素或MAPK抑制剂PD98059，可显著降低RANTES的产生，表明TWEAK的这种作用是通过NF-κB信号传导介导的。紫外线B（UVB）照射在体外和体内均显著上调角质形成细胞上Fn14的表达并增加RANTES的产生。将MRL/lpr Fn14基因敲除（KO）狼疮小鼠与MRL/lpr Fn14野生型（WT）小鼠进行比较，以评估皮肤病变严重程度和浸润免疫细胞存在情况的任何可能差异。与它们的Fn14 WT同窝小鼠相比，MRL/lpr Fn14 KO小鼠的皮肤疾病明显减轻，皮肤结构保持良好以及T细胞和巨噬细胞的皮肤浸润显著减少证明了这一点。我们的数据强烈表明TWEAK/Fn14信号传导参与自发性狼疮MRL/lpr模型皮肤表现的发病机制，并提示了一个可能的治疗干预靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d48/4504782/34dda2d4c6f0/nihms675320f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d48/4504782/7ffac83c0181/nihms675320f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d48/4504782/34dda2d4c6f0/nihms675320f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d48/4504782/7ffac83c0181/nihms675320f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d48/4504782/a7ae66eb3f55/nihms675320f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8d48/4504782/499879a164fe/nihms675320f3.jpg
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