Role of antiviral signaling in psoriatic pathogenesis

项目摘要 近三分之一的牛皮癣患者会患上牛皮癣关节炎；然而，预测哪些患者 会患上关节炎仍然具有挑战性。此外，治疗学在治疗皮肤方面更成功。 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 帮助更早地识别有关节炎风险的患者，并可能揭示新的治疗策略。 TNFAIP3(A20)基因的多态会降低其表达，与罹患高血压的风险增加相关。 牛皮癣和牛皮癣关节炎。此外，与银屑病患者相比，牛皮癣患者的A20水平降低。 给未受影响的人。这些数据表明A20是银屑病炎症的重要限制因子； 然而，A20预防牛皮癣的机制仍不清楚。 在我们之前的工作中，我们产生了一种自发发展的A20基因敲入小鼠突变体 类似牛皮癣皮肤和关节疾病的病理学。这些小鼠最早的组织学炎症 包围了表皮，暗示角质形成细胞的作用。因此，我们培育出了能够 角质形成细胞中A20的可诱导缺失。值得注意的是，这些小鼠患上了牛皮癣和关节疾病。 依赖于肿瘤坏死因子、白介素23、白介素17A和T细胞，反映了介导人类银屑病的已知因素。 为了确定角质形成细胞A20缺失引发的最早的分子事件，我们进行了RNAseq A20缺失后一周的表皮。令人惊讶的是，我们发现了对抗病毒基因的深刻诱导。抗病毒药物 基因在人类银屑病斑块中强烈表达；然而，诱导基因表达的机制 而它们在疾病发病机制中的作用尚不清楚。 在此，我们提出了一些旨在识别激活抗病毒基因的分子机制的研究。 角质形成细胞A20缺失后的治疗方案。我们将利用原代小鼠的体外培养系统 角质形成细胞与抑制特定干扰素受体和病毒核酸受体的策略相结合。 我们还将确定体内观察到的抗病毒基因签名是否取决于是否存在 已知的细胞因子在牛皮癣中起作用。总而言之，这些研究可能会阐明抗病毒基因是如何 在人类牛皮癣中被激活，并导致对其致病意义的理解。作为抗病毒药物 治疗途径与目前靶向治疗的途径不同，这可能导致新的治疗策略。 并揭示了银屑病关节病临床前生物标志物的新机遇。

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.