Razani Bahram, Chandran Vinod, de Vlam Kurt, Liao Wilson, Malynn Barbara A, Ma Averil
B. Razani, MD, PhD, Department of Dermatology, University of California, and San Francisco VA Medical Center, San Francisco, California, USA.
V. Chandran, MD, PhD, Division of Rheumatology, Department of Medicine, Department of Laboratory Medicine and Pathobiology, Institute of Medical Science, University of Toronto, and Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
J Rheumatol. 2025 Aug 15. doi: 10.3899/jrheum.2025-0528.
Polymorphisms in the locus encoding the A20 protein are strongly associated with psoriatic skin and joint disease. Reduced A20 expression, driven by both genetic and epigenetic factors, underscores its critical role as a negative regulator of psoriatic disease (PsD). Our recent study using a germline knockin mouse model harboring a mutation in A20's seventh zinc finger, which impairs A20 binding to linear (M1) ubiquitin, revealed a spontaneous phenotype resembling psoriatic arthritis. These mice demonstrated sustained nuclear factor-κB signaling in response to transient tumor necrosis factor stimulation, leading to inappropriate transcription of mid- and late-response inflammatory genes. These findings highlight the role of dysregulated innate immune-signaling kinetics as a potential driver of PsD pathogenesis. These findings, together with distinct inflammatory mouse models resulting from temporally extended inflammatory gene activation, highlight the role of dysregulated innate immune-signaling kinetics as a potential driver of tissue inflammation with relevance to psoriatic skin and joint disease. This newly developed mouse model of PsD was presented at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2024 annual meeting.
编码A20蛋白的基因座中的多态性与银屑病皮肤和关节疾病密切相关。由遗传和表观遗传因素驱动的A20表达降低，突显了其作为银屑病疾病（PsD）负调节因子的关键作用。我们最近使用一种种系敲入小鼠模型进行的研究发现，该模型中A20的第七个锌指发生突变，损害了A20与线性（M1）泛素的结合，表现出一种类似银屑病关节炎的自发表型。这些小鼠在受到短暂的肿瘤坏死因子刺激后，显示出持续的核因子-κB信号传导，导致中期和晚期反应性炎症基因的不适当转录。这些发现突出了先天免疫信号动力学失调作为PsD发病机制潜在驱动因素的作用。这些发现，连同因炎症基因激活时间延长而产生的不同炎症小鼠模型，突出了先天免疫信号动力学失调作为与银屑病皮肤和关节疾病相关的组织炎症潜在驱动因素的作用。这种新开发的PsD小鼠模型在银屑病和银屑病关节炎研究与评估小组（GRAPPA）2024年年会上进行了展示。
