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，反而会增加皮肤感染的风险。 最常见的具有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，并可导致 严重感染需要住院治疗。虽然众所周知，AD 会失调免疫系统的屏障功能 皮肤，这如何影响对微生物病原体的免疫力，人们知之甚少。更好地了解如何 皮肤免疫机制的启动和解决可能会巩固未来预防和治疗的发展 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。 IL-升高 36 水平与金黄色葡萄球菌定植和严重 AD 相关。使用 HSV1 作为模型疱疹病毒，我们 发表了关于 IL-1 和 IL-36 在启动保护性免疫反应中的作用的研究。附加数据 我们实验室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 研究结果提高了我们对 IL-36 和 IL-1 共同功能的理解。新未发表 数据表明两种细胞因子组也具有不同功能的机制以及它们如何发挥作用 失调时会导致AD。为了阐明这些机制，我们将在这里使用小鼠模型 HSV1 和金黄色葡萄球菌的体内皮肤感染，以鉴定对感染至关重要的 IL-1 和 IL-36 传感细胞类型 促进炎症并限制病原体的免疫反应。这些研究将涉及新的 我们开发了 floxed IL-36 受体小鼠品系，与现有的 floxed IL-1 受体品系相结合。 还将在人类和小鼠原代细胞中进行补充和机制研究。一个 需要对这些系统进行全面深入的了解才能成功抑制免疫 治疗反应，同时保持功能性保护性免疫 病原体，例如 HSV 和金黄色葡萄球菌。