Role of antiviral signaling in psoriatic pathogenesis

项目摘要 近三分之一的银屑病患者发展为银屑病关节炎;然而，预测哪些患者 关节炎仍然是一个挑战。此外，治疗方法在治疗皮肤 与关节疾病相比。阐明银屑病中皮肤和关节疾病的联系机制可能 有助于早期识别有关节炎风险的患者，并可能揭示新的治疗策略。 Tnfaip 3（A20）的多态性降低了其表达，与糖尿病风险增加相关。 银屑病和银屑病关节炎。此外，银屑病患者显示A20水平降低， 不受影响的个人。这些数据表明，A20是银屑病炎症的重要限制因子; 然而，A20预防银屑病疾病的机制仍不清楚。 在我们之前的工作中，我们产生了A20的敲入小鼠突变体， 病理学类似于银屑病皮肤和关节疾病。这些小鼠最早的组织学炎症 包围表皮，表明角质形成细胞的作用。因此，我们培育了能够 角质形成细胞中A20的可诱导缺失。值得注意的是，这些老鼠患上了银屑病皮肤和关节疾病 依赖于TNF、IL 23、IL 17 A和T细胞，反映了介导人银屑病疾病的已知因子。 为了鉴定由角质形成细胞A20丢失引发的最早的分子事件，我们进行了RNASeq， A20基因缺失后1周，表皮脱落。令人惊讶的是，我们发现了抗病毒基因的深刻诱导。抗病毒 基因在人类银屑病斑块中强烈表达;然而，它们被诱导的机制 并且它们在疾病发病机制中的作用是未知的。 在这里，我们提出的研究，旨在确定激活抗病毒基因的分子机制， 角质形成细胞A20丢失后的程序。我们将利用体外培养系统， 角质形成细胞与抑制特异性干扰素受体和病毒核酸受体的策略相结合。 我们还将确定在体内观察到的抗病毒基因签名是否依赖于 已知在银屑病中起作用的细胞因子。总之，这些研究可能会揭示抗病毒基因是如何 激活人类银屑病，并导致其致病意义的理解。作为抗病 途径与目前治疗靶向的途径不同，这可能导致新的治疗策略 并揭示银屑病关节疾病临床前生物标志物的新机会。

PROJECT ABSTRACT Nearly a third of patients with psoriasis develop psoriatic arthritis; however, predicting which patients will develop arthritis remains challenging. Additionally, therapeutics are more successful in treating skin compared to joint disease. Clarifying the mechanisms which connect skin and joint disease in psoriasis may help identify patients at risk for arthritis earlier and may reveal novel therapeutic strategies. Polymorphisms in Tnfaip3 (A20), which reduce its expression, are associated with increased risk of both psoriasis and psoriatic arthritis. Furthermore, patients with psoriasis display reduced A20 levels compared to unaffected individuals. These data suggest that A20 is an important restrictor of psoriatic inflammation; however, the mechanisms by which A20 prevents psoriatic disease remain unknown. In our prior work, we generated a knock-in mouse mutant of A20 that developed spontaneous pathology analogous to psoriatic skin and joint disease. The earliest histological inflammation in these mice surrounded the epidermis, suggesting a role for keratinocytes. Therefore, we generated mice capable of inducible deletion of A20 in keratinocytes. Remarkably, these mice developed psoriatic skin and joint disease dependent on TNF, IL23, IL17A, and T-cells, reflecting known factors that mediate human psoriatic disease. To identify the earliest molecular events initiated by keratinocyte A20 loss, we performed RNASeq of epidermis one week after A20 deletion. Surprisingly, we found profound induction of antiviral genes. Antiviral genes are strongly expressed in human psoriatic plaques; however, the mechanism by which they are induced and their role in disease pathogenesis is unknown. Here we propose studies aimed at identifying the molecular mechanisms which activate antiviral gene programs following loss of keratinocyte A20. We will utilize in vitro culture systems of primary murine keratinocytes combined with strategies to inhibit specific interferon receptors and viral nucleic acid receptors. We will also determine whether the antiviral gene signature observed in vivo depends on the presence of cytokines known to play a role in psoriasis. Together, these studies may shed light on how antiviral genes are activated in human psoriasis and lead to an understanding of their pathogenic significance. As antiviral pathways are distinct from those currently targeted therapeutically, this may lead to novel treatment strategies and reveal new opportunities for pre-clinical biomarkers of psoriatic joint disease.