Dynamic interplay between IL-36 and IL-1 in inflammation and infections

摘要 特应性皮炎(AD)是一种炎症性皮肤疾病，自相矛盾地增加了皮肤感染的风险。 最具临床意义的细菌感染是金黄色葡萄球菌，而疱疹 单纯疱疹病毒(HSV)和水痘带状疱疹病毒(VZV)极大地影响生活质量，并可导致 严重感染需要住院治疗。虽然众所周知，AD失调了对脑屏障功能的调节 皮肤，这是如何影响对微生物病原体的免疫力的，人们知之甚少。更深入地了解如何 皮肤中免疫机制的启动和解决可能为未来预防和治疗的发展奠定基础 治疗策略。 白介素36(IL-36)代表IL-36a、IL-36b和IL-36g，与IL-1a和IL-1b相关。升高的IL- 36个水平与金黄色葡萄球菌定植和严重AD有关。以HSV1为模型疱疹病毒，我们 已发表的关于IL-1和IL-36在启动保护性免疫反应中所起作用的研究。其他数据 从我们的实验室中确定了有助于炎症和消除金黄色葡萄球菌的关键活动。这些 这些发现提高了我们对IL-36和IL-1共同功能的理解。新的未出版的 数据显示了这两个细胞因子组也具有不同功能的机制，以及它们如何 当调节失调时，会导致AD。为了阐明这些机制，我们将在这里使用in的小鼠模型。 体内皮肤感染HSV1和金黄色葡萄球菌以鉴定IL-1和IL-36敏感细胞类型 促进炎症和限制病原体的免疫反应。这些研究将涉及一种新的 我们开发了与现有的IL-1受体株相结合的IL-36受体株。 还将在人和鼠的原代细胞中进行互补性和机械性研究。一个 要成功地抑制免疫，需要对这些系统进行全面深入的了解 治疗上的反应，同时保持功能性保护性免疫 病原体，如单纯疱疹病毒和金黄色葡萄球菌。

SUMMARY Atopic dermatitis (AD) is an inflammatory skin condition that paradoxically increases the risk of skin infections. The most common bacterial infection of clinical significance is Staphylococcus aureus, while the herpes viruses herpes simplex virus (HSV) and varicella zoster virus (VZV) greatly affect quality of life and can lead to severe infections requiring hospitalization. While it is known that AD dysregulates the barrier function of the skin, how this impacts immunity against microbial pathogens is poorly understood. Improved insight into how immune mechanisms in the skin are initiated and resolved may underpin future development of preventive and therapeutic strategies. Interleukin-36 (IL-36) represents IL-36a, IL-36b and IL-36g, which are related to IL-1a and IL-1b. Elevated IL- 36 levels are associated with S. aureus colonization and severe AD. Using HSV1 as a model herpes virus, we published studies on the roles IL-1 and IL-36 play in initiating protective immune responses. Additional data from our lab identified critical activities that contribute to inflammation and the elimination of S. aureus. These findings improved our understanding of functions that are common for both IL-36 and IL-1. New unpublished data indicate mechanisms whereby the two cytokine groups also have distinct functions and how they may contribute to AD when dysregulated. To elucidate these mechanisms, we will here use mouse models of in vivo skin infections with HSV1 and S. aureus to identify the IL-1 and IL-36 sensing cell types essential for immune responses that promote inflammation and restrict the pathogens. These studies will involve a new floxed IL-36 receptor mouse strain we developed, in conjunction with an existing floxed IL-1 receptor strain. Complementary and mechanistic studies will also be conducted in human and mouse primary cells. A comprehensive in-depth understanding of these systems is needed to successfully suppress immune responses therapeutically, while at the same time maintaining functional protective immunity against pathogens such as HSV and S. aureus.