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

总结 金黄色葡萄球菌引起的感染在同时患有1型糖尿病的人群中更频繁和严重 (T1D)和T2D的发病率。世纪以来，人们一直认为， 糖尿病患者的抗菌功能较差，这就造成了糖尿病导致 免疫抑制然而，高血糖症也会导致炎症介质的过度产生 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的增加是由于不受控制的局部炎症反应 导致皮肤损伤并阻止细菌清除。我们最近发现S.金黄色皮肤感染 糖尿病小鼠伴随着无限制的中性粒细胞迁移到感染部位， 炎症介质的产生，脓肿形成不良（防止扩散到更深组织的结构 和全身感染）和受损的细菌清除。我们还发现， 多效性脂质介质前列腺素E2（PGE2）在感染的糖尿病小鼠皮肤和局部软膏 含有米索前列醇（FDA批准的PGE类似物）的药物可以恢复糖尿病期间的细菌清除。我们 初步数据显示，PGE2产量低可能是由于吞噬细胞摄取能力降低， 清除死细胞（红细胞增多症），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。我们假设在MRSA皮肤感染时， 在糖尿病小鼠中，导致PGE2产生减少，从而增加炎症相关的组织损伤 并阻止伤口愈合，最终增强对不愈合皮肤感染的易感性。我们将利用 产生组成型PGE 2和荧光吞噬细胞的转基因小鼠，沿着最先进的 技术，包括成像质谱（IMS），体内成像（IVIS）和活体显微镜成像 (IVM)揭示PGE2水平、E前列腺素受体和下游效应物在组织修复中的作用 在糖尿病患者和小鼠的皮肤感染过程中（目的1）。接下来，我们假设米索前列醇 通过增加第二信使作用的产生来改善受感染皮肤的伤口愈合 环磷酸腺苷（cAMP）下游效应物参与米索前列醇改善宿主防御 在糖尿病小鼠中（目的2）。在目标3中，我们将研究是否涉及修复机制的失败， 死细胞的消除（红细胞增多症）导致PGE2产生不足和炎性细胞因子的产生。 介质，导致糖尿病小鼠感染皮肤的组织损伤。我们的项目可以迅速转化为 临床上用于改善糖尿病患者皮肤感染的治疗。具有抗菌素耐药性， 随着全球糖尿病患病率的不断增加，迫切需要安全、廉价、非抗生素， 和以宿主为中心的方法来预防和治疗感染。

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.