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.

在1990 - 1991年战争中，约有25-30％的美国退伍军人受到海湾战争的影响 疾病（GWI）。 GWI是一种毁灭性和令人衰弱的状况，GWI症状都作为中央 神经系统（CNS）和周围症状，包括宽度疼痛，肌肉骨骼疼痛，标头， 持续的认知缺陷，疲劳，stallch和肠道症状，呼吸疾病和皮肤 异常。最近的研究支持具有认知性的GWI退伍军人的海马病理异常 缺陷，突出了重要的中枢神经系统链接。 GWI的一个关键而突出的特征是符号持续存在 在某些情况下，在25年后的海湾战争之后很长一段时间，在海湾战争之后很久。流行病学支持这一点 农药暴露，例如毒死rif（CPF），可能与GWI的认知作用有关，但基础 机制是未知的。 GWI认知缺陷的神经炎症假说认为CNS 免疫扰动可能会驱动GWI中的持续性中枢神经系统效应。小胶质细胞，居民髓样（免疫） 脑中的原始细胞已被暗示为促进促炎性因子的慢性来源 潜水中枢神经系统条件（包括GWI）的进行性神经元损害。最近的报告表明外围 损伤增加了大脑的促炎反应，从而通过循环因素引起神经元病理。 我们的架构假设是，周围和中枢神经系统损伤在GWI中相互作用，并响应GWI- 相关农药CPF，其中循环损伤相关的分子模式调节慢性 小胶质促炎反应和随之而来的神经/记忆缺陷。初步数据指示 慢性CPF GWI小鼠模型导致持续的神经炎症，慢性海马突触素 损失和神经行为定义了最后一次农药注射后的3个月，从而验证了GWI模型。数据 同样指出HMGB1在CPF效应中的作用，因为CPF GWI小鼠模型暴露了升高的循环 HMGB1在生物活性血清中，由尾静脉注射的HMGB1引起神经炎症/小胶质细胞激活，并且 HMGB1在体外直接触发小胶质细胞激活。从机械上讲，小胶质细胞的耗竭被证实为 在体外对CPF的神经保护作用。这是我们的具体假设是CPF暴露会导致生物活性 循环因子（HMGB1），然后引起持续的小胶质激活/神经炎症和GWI样 神经病理学。因此，以下目的将：1）定义HMGB1抑制的神经保护效率 延迟和持续性GWI样神经病理学的CPF模型； 2）确认髓样细胞在GWI- 像神经病理学一样； 3）AIM3：检查GWI样血清的神经免疫性生物活性。这些发现会 提供急需的洞察力，了解外围的作用在对GWI与GWI相关的持续反应中的作用 农药（CPF），将HMGB1和临时髓样细胞部署牵涉到新的治疗靶标，而 开始概述神经免疫性生物活性分析作为GWI的潜在标记。