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

IL-36 和 IL-1 在炎症和感染中的动态相互作用

• 批准号: 10728994
• 负责人: LISELOTTE E JENSEN
• 金额: $ 39.63万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728994
• 关键词: Acute; Affect; Anti-Inflammatory Agents; Atopic Dermatitis; Bacterial Infections; Cell Culture Techniques; Cells; Chronic; Conflict (Psychology); Data; Dendritic Cells; Dermis; Development; Disease; Epidermis; Fibroblasts; Future; Genes; Health; Herpes Simplex Infections; Herpesviridae; Herpesvirus 1; Herpesvirus Type 3; Hospitalization; Human; ICAM1 gene; IL17 gene; Immune; Immune System Diseases; Immune response; Immunity; Immunohistochemistry; In Vitro; Infection; Infectious Skin Diseases; Infiltration; Inflammation; Inflammatory; Interferons; Interleukin-1; Interleukin-1 Receptors; Interleukins; Knockout Mice; Knowledge; Langerhans cell; Lesion; LoxP-flanked allele; Macrophage; Modeling; Mouse Strains; Mus; Pathway interactions; Patients; Physiological; Play; Population; Positioning Attribute; Preventive; Publishing; Quality of life; Reporter; Reporter Genes; Research; Risk; Role; Signal Transduction; Simplexvirus; Skin; Skin colonization; Staphylococcus aureus; System; T-Lymphocyte; Therapeutic; Time; Up-Regulation; Viral Load result; Virus; Virus Diseases; antagonist; antimicrobial; cell type; chronic inflammatory skin; clinically significant; conditional knockout; cytokine; draining lymph node; experimental study; improved; in vivo; in vivo Model; insight; keratinocyte; monocyte; mouse model; pathogen; pathogenic microbe; polarized cell; promoter; receptor; receptor expression; response; skin disorder; transcriptome sequencing; treatment response

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.

概括 特应性皮炎（AD）是一种炎症性皮肤病，矛盾地增加了皮肤感染的风险。 最常见的临床意义的细菌感染是金黄色葡萄球菌，而疱疹 病毒单纯疱疹病毒（HSV）和水痘带状疱疹病毒（VZV）极大地影响生活质量，并可能导致 需要住院的严重感染。虽然已知AD失调的屏障功能 皮肤，这如何影响对微生物病原体的免疫力的了解很少。改善了对如何的见解 启动皮肤中的免疫机制并解决，可能是预防和预防性发展的基础 治疗策略。 白介素-36（IL-36）代表与IL-1A和IL-1B有关的IL-36A，IL-36B和IL-36G。升高的IL- 36个水平与金黄色葡萄球菌定植和严重的AD有关。使用HSV1作为模型疱疹病毒，我们 发表了关于IL-1和IL-36在发起保护性免疫反应中发挥作用的研究。其他数据 从我们的实验室确定了导致炎症和消除金黄色葡萄球菌的关键活动。这些 研究结果提高了我们对IL-36和IL-1常见功能的理解。新的未出版 数据表明两个细胞因子组也具有不同功能以及它们如何可能的机制 失调时会导致AD。为了阐明这些机制，我们将在这里使用In的鼠标模型 用HSV1和金黄色链球菌感染体内皮肤，以识别IL-1和IL-36感应细胞类型必不可少的 促进炎症并限制病原体的免疫反应。这些研究将涉及一个新的 我们开发的Floxed IL-36受体小鼠菌株与现有的Floxed IL-1受体菌株结合使用。 互补和机械研究也将在人和小鼠原代细胞中进行。一个 需要全面了解这些系统以成功抑制免疫 治疗反应，同时保持功能性保护免疫 病原体，例如HSV和金黄色葡萄球菌。