Prostaglandin E2 Actions and Enhanced Susceptibility to Skin Infection in Diabetic Mice

前列腺素 E2 的作用和糖尿病小鼠皮肤感染的易感性增强

• 批准号: 9980677
• 负责人: C. Henrique Serezani
• 金额: $ 62.03万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980677
• 关键词: Abscess; Address; Adenosine Monophosphate; Antibiotics; Antimicrobial Resistance; Biological Response Modifiers; Cells; Chronic; Clinical; Containment; Cyclic AMP; Data; Diabetes Mellitus; Diabetic mouse; Dinoprostone; Disease; Event; Extravasation; FDA approved; Failure; Generations; Glucose; Homeostasis; Host Defense; Human; Hyperglycemia; Image; Immune; Immune response; Immunosuppression; Impairment; Individual; Infection; Infectious Skin Diseases; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Ingestion; Insulin-Dependent Diabetes Mellitus; Integration Host Factors; Knowledge; Lesion; Mass Spectrum Analysis; Misoprostol; Modeling; Molecular; Mus; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Ointments; Outcome; PTPNS1 gene; Patients; Periodicity; Phagocytes; Predisposition; Prevalence; Production; Prostaglandins; Reporter; Resolution; Role; Scientist; Second Messenger Systems; Secondary to; Site; Skin; Staphylococcus aureus; Structure; Systemic infection; Techniques; Testing; Tissues; Transgenic Mice; Transgenic Organisms; Translating; Vulnerable Populations; analog; antimicrobial; base; improved; in vivo; in vivo imaging; inhibitor/antagonist; intravital microscopy; lipid mediator; macrophage; methicillin resistant Staphylococcus aureus; microbial; microscopic imaging; migration; neutrophil; non-diabetic; novel therapeutics; pathogen; phenome; prevent; receptor; repaired; response; theories; tissue injury; tissue repair; wound healing

Summary Infections caused by Staphylococcus aureus are more frequent and severe in people with both type 1 diabetes (T1D) and T2D than in healthy individuals. For over a century, it has been suggested that phagocytes from people with diabetes show poor antimicrobial functions, which created the paradigm that diabetes leads to immunosuppression. However, hyperglycemia also drives an excessive production of inflammatory mediators by immune cells. Here, we will take our current knowledge in host defense and diabetes in a different direction. We speculated that increased susceptibility to infection is due to an uncontrolled localized inflammatory response that causes skin damage and prevents bacterial elimination. We recently showed that S. aureus skin infection in diabetic mice was accompanied by unrestrained neutrophil migration to the site of infection, increased the production of inflammatory mediators, poor abscess formation (a structure that prevents spread to deeper tissues and systemic infection) and impaired bacterial clearance. We also showed inadequate production of the pleiotropic lipid mediator prostaglandin E2 (PGE2) in the skin of infected diabetic mice and a topical ointment containing misoprostol (an FDA-approved PGE analog) restored bacterial clearance during diabetes. Our preliminary data reveal low PGE2 production could be due to a reduced capacity to phagocytes to ingest and clear dead cells (efferocytosis), leading to secondary necrosis, leakage of endogenous inflammatory mediators, tissue injury and poor host defense. We are hypothesizing that deficient efferocytosis during MRSA skin infection in diabetic mice is responsible for low PGE2 production, which increases inflammation-associated tissue damage and prevents wound healing to ultimately enhance susceptibility to non-healing skin infections. We will utilize transgenic mice producing constitutively PGE2 and fluorescent phagocytes, along with state-of-the-art techniques, including imaging mass spectrometry (IMS), in vivo imaging (IVIS) and intravital microscopy imaging (IVM) to unveil the role of PGE2 levels, the E prostanoid receptors and downstream effectors in tissue repair during skin infection in people and mice with diabetes (Aim 1). Next, we are postulating that misoprostol improves wound healing in the infected skin by increasing the production of actions of the second messenger cyclic adenosine monophosphate (cAMP) downstream effectors involved in misoprostol-improved host defense in diabetic mice (Aim 2). In the Aim 3, we will study whether the failure of a repair mechanism involved in the elimination of dead cells (efferocytosis) leads to deficient PGE2 production and generation of inflammatory mediators, causing tissue injury in the infected skin of diabetic mice. Our project could rapidly translate into clinical use to improve the treatment of skin infection in patients with diabetes. With antimicrobial resistance and increasing prevalence of diabetes worldwide, there is a compelling need for safe, inexpensive, non-antibiotic, and host-centered approaches to prevent and treat infections.

摘要 金黄色葡萄球菌引起的感染在两种1型糖尿病患者中更频繁和更严重 (T1D)和T2D。一个多世纪以来，人们一直认为吞噬细胞来自 糖尿病患者表现出较差的抗菌功能，这创造了糖尿病导致的范式 免疫抑制。然而，高血糖也会导致炎症介质的过度产生。 通过免疫细胞。在这里，我们将把我们目前在宿主防御和糖尿病方面的知识带到一个不同的方向。 我们推测，感染易感性增加是由于局部炎症反应失控所致。 这会对皮肤造成损害，并阻止细菌清除。我们最近发现，金黄色葡萄球菌的皮肤感染 糖尿病小鼠伴有中性粒细胞向感染部位的不受限制的迁移，增加了 产生炎症介质，不易形成脓肿(一种防止扩散到深层组织的结构 和全身性感染)和细菌清除受损。我们还显示出产量不足的情况。 多效性脂质介质前列腺素E_2(PGE_2)在糖尿病感染小鼠皮肤和局部软膏中的作用 含有米索前列醇(一种FDA批准的PGE类似物)可以恢复糖尿病期间的细菌清除。我们的 初步数据显示，PGE2产量低可能是由于吞噬细胞吞噬和 清除死亡细胞(泡沫化)，导致继发性坏死，内源性炎症介质渗漏， 组织损伤和宿主防御能力差。我们推测在耐甲氧西林金黄色葡萄球菌皮肤感染过程中泡出细胞缺乏。 在糖尿病小鼠中，PGE2的低产生是导致炎症相关组织损伤的原因 并阻止伤口愈合，最终增加对无法愈合的皮肤感染的敏感性。我们将利用 产生PGE2和荧光吞噬细胞的转基因小鼠，以及最新技术 技术，包括成像质谱仪(IMS)、活体成像(IVIS)和活体显微成像 (IVM)揭示PGE2水平、E前列腺素受体及其下游效应因子在组织修复中的作用 在糖尿病患者和小鼠的皮肤感染期间(目标1)。接下来，我们假设米索前列醇 通过增加第二信使活动的产生来促进感染皮肤的伤口愈合 环磷酸腺苷(CAMP)下游效应参与米索前列醇增强宿主防御 糖尿病小鼠(目标2)。在目标3中，我们将研究修复机制的故障是否涉及 清除死亡细胞(泡沫化)会导致前列腺素E_2分泌不足和炎症的产生 介体，造成糖尿病小鼠受感染皮肤的组织损伤。我们的项目可以迅速转化为 临床用于提高糖尿病患者皮肤感染的治疗水平。具有抗菌素耐药性和 糖尿病在世界范围内日益流行，迫切需要安全、廉价、非抗生素、 以及以宿主为中心的预防和治疗感染的方法。