HMGB1, Chlorpyrifos, and Persistent GWI-like Neuropathology

HMGB1、毒死蜱和持续 GWI 样神经病理学

• 批准号: 10237251
• 负责人: Michelle L Block
• 金额: $ 33.31万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237251
• 关键词: Ablation; Affect; Antibodies; Automobile Driving; Biological Assay; Blood; Brain; Cells; Chemical Exposure; Chemicals; Chlorpyrifos; Chronic; Cognitive; Cognitive deficits; Data; Diagnosis; Epidemiology; Exhibits; Fatigue; Genetic; Glycyrrhizic Acid; Gulf War; HMGB1 gene; Headache; Health; Hippocampus (Brain); Human; ITGAM gene; Immune; Immune system; In Vitro; Individual; Inflammatory; Inflammatory Response; Injections; Injury; Intestines; Link; Measures; Memory impairment; Microglia; Modeling; Molecular; Monitor; Mus; Musculoskeletal Pain; Myelogenous; Myeloid Cells; Neuraxis; Neuroimmune; Neurons; Pain; Pathology; Pattern; Peripheral; Persian Gulf Syndrome; Pesticides; Pharmacology; Population; Production; Reporting; Role; Serum; Signal Transduction; Skin Abnormalities; Source; Stimulus; Stomach; Symptoms; Synaptophysin; Tail; Testing; Veins; Veterans; brain endothelial cell; central nervous system injury; cytokine; improved; in vivo; inhibitor/antagonist; insight; mouse model; neurobehavioral; neuroinflammation; neuropathology; new therapeutic target; pesticide exposure; receptor; respiratory; response; targeted treatment; therapeutic target; tool

Approximately 25-30% of U.S. veterans who served in the 1990–1991 Gulf War are affected by Gulf War Illness (GWI). GWI is a devastating and debilitating condition, where GWI symptoms present as both central nervous system (CNS) and peripheral symptoms, including widespread pain, musculoskeletal pain, headache, persistent cognitive deficits, fatigue, stomach and intestinal symptoms, respiratory complaints, and skin abnormalities. Recent studies support abnormal hippocampal pathology in GWI veterans with cognitive deficits, highlighting an important CNS link. One critical and prominent feature of GWI is that symptoms persist and in some cases progress, long after the Gulf War, now over 25 years later. Epidemiology supports that pesticide exposures, such as chlorpyrifos (CPF), may be linked to cognitive effects of GWI, but the underlying mechanisms are unknown. The neuroinflammation hypothesis of GWI cognitive deficits holds that CNS immune perturbation may drive the persistent CNS effects in GWI. Microglia, the resident myeloid (immune origin) cells in the brain, have been implicated as a chronic source of pro-inflammatory factors driving progressive neuron damage in diverse CNS conditions, including GWI. Recent reports indicate that peripheral injury augments the brain's pro-inflammatory response to cause neuronal pathology through circulating factors. Our over-arching hypothesis is that peripheral and CNS injury interact in GWI and in response to the GWI- relevant pesticide, CPF, where circulating damage associated molecular patterns regulate the chronic microglial pro-inflammatory response and consequent neuronal/memory deficits. Preliminary data indicate the chronic CPF GWI mouse model causes persistent neuroinflammation, chronic hippocampal synaptophysin loss, and neurobehavioral deficits 3 months after the last pesticide injection, validating the GWI model. Data also point to a role for HMGB1 in CPF effects, as the CPF GWI mouse model exhibited elevated circulating HMGB1 in bioactive serum, HMGB1 injected by tail vein elicited neuroinflammation/microglial activation, and HMGB1 directly triggered microglial activation in vitro. Mechanistically, microglia depletion was confirmed as neuroprotective against CPF in vitro. Thus, our specific hypothesis is that CPF exposure causes bioactive circulating factors (HMGB1), which then cause persistent microglial activation/neuroinflammation and GWI-like neuropathology. As such, the following AIMS will: 1) Define the neuroprotective efficacy of HMGB1 inhibition in a CPF model of delayed and persistent GWI-like neuropathology; 2) Confirm the role of myeloid cells in GWI- like neuropathology; 3) AIM3: Examine the neuroimmune bioactivity of GWI-like serum. These findings will provide much needed insight into the role of the periphery in the persistent response to GWI-relevant pesticides (CPF), implicate HMGB1 and temporary myeloid cell depletion as novel therapeutic targets, and begin to outline a neuroimmune bioactivity assay as a potential marker for GWI.

参加过 1990-1991 年海湾战争的美国退伍军人中，约有 25-30% 受到海湾战争的影响 疾病 (GWI) 是一种破坏性且使人衰弱的疾病，其中 GWI 症状表现为两种主要症状。 神经系统 (CNS) 和周围症状，包括广泛疼痛、肌肉骨骼疼痛、头痛、 持续的认知缺陷、疲劳、胃肠道症状、呼吸系统疾病和皮肤病 最近的研究支持 GWI 退伍军人的认知异常海马病理学。 缺陷，突出了 GWI 的一个重要且突出的特征是症状持续存在。 在某些情况下，海湾战争发生很久之后，25 年后的今天，流行病学也证明了这一点。 农药暴露，如毒死蜱 (CPF)，可能与 GWI 的认知影响有关，但潜在的影响 GWI 认知缺陷的神经炎症假说认为 CNS 的机制尚不清楚。 免疫扰动可能会驱动 GWI 中小胶质细胞（免疫细胞）的持续中枢神经系统效应。 起源）大脑中的细胞，已被认为是促炎因子驱动的慢性来源 各种中枢神经系统疾病（包括 GWI）中的进行性神经元损伤最近的报告表明，外周神经元损伤。 损伤会增强大脑的促炎反应，通过循环因子引起神经元病理。 我们的首要假设是，GWI 中的外周和中枢神经系统损伤相互作用以及对 GWI 的反应 相关农药，CPF，其中循环损伤相关的分子模式调节慢性 小胶质细胞促炎症反应和随之而来的神经元/记忆缺陷。 慢性 CPF GWI 小鼠模型导致持续性神经炎症、慢性海马突触素 最后一次注射农药后 3 个月的损失和神经行为缺陷，验证了 GWI 模型。 还指出 HMGB1 在 CPF 效应中的作用，因为 CPF GWI 小鼠模型表现出循环升高 生物活性血清中的 HMGB1，通过尾静脉注射的 HMGB1 引发神经炎症/小胶质细胞激活，并且 HMGB1 在体外直接触发小胶质细胞激活，从机制上来说，小胶质细胞耗竭被证实为： 体外对 CPF 具有神经保护作用 因此，我们的具体假设是 CPF 暴露会产生生物活性。 循环因子 (HMGB1)，然后引起持续的小胶质细胞激活/神经炎症和 GWI 样 因此，以下目标将： 1) 定义 HMGB1 抑制的神经保护功效。 延迟性和持续性 GWI 样神经病理学的 CPF 模型 2) 确认骨髓细胞在 GWI 中的作用； 类似神经病理学；3) AIM3：检查 GWI 样血清的神经免疫生物活性。 提供急需的关于外围在 GWI 相关持续响应中的作用的见解 杀虫剂 (CPF)，表明 HMGB1 和暂时性骨髓细胞耗竭是新的治疗靶点，以及 开始概述神经免疫生物活性测定作为 GWI 的潜在标记。