HMGB1, Chlorpyrifos, and Persistent GWI-like Neuropathology

在1990-1991年海湾战争中服役的美国退伍军人中，约有25-30%受到海湾战争的影响。 疾病（GWI）。GWI是一种破坏性和衰弱的条件，其中GWI症状表现为两个中心 神经系统（CNS）和外周症状，包括广泛疼痛，肌肉骨骼疼痛，头痛， 持续性认知缺陷、疲劳、胃和肠道症状、呼吸系统疾病和皮肤 异常最近的研究支持GWI退伍军人认知功能障碍的海马病理学异常 缺乏，突出了一个重要的中枢神经系统联系。GWI的一个关键和突出的特点是症状持续存在 在某些情况下，在海湾战争之后很久，现在已经过去了25年。流行病学支持这一观点 农药暴露，如毒死蜱（CPF），可能与GWI的认知影响有关，但潜在的 机制不明。GWI认知缺陷的神经炎症假说认为， 免疫干扰可能会驱动GWI中持续的CNS效应。小胶质细胞，常驻骨髓（免疫 起源）细胞，已经被认为是促炎因子的慢性来源， 包括GWI在内的各种CNS疾病中的进行性神经元损伤。最近的报告显示， 损伤增强了脑的促炎反应，通过循环因子引起神经元病变。 我们的过度假设是外周和中枢神经系统损伤在GWI中相互作用，并对GWI作出反应。 相关农药CPF，其中循环损伤相关的分子模式调节慢性 小胶质细胞促炎反应和随后的神经元/记忆缺陷。初步数据显示， 慢性CPF GWI小鼠模型引起持续性神经炎症，慢性海马突触素 最后一次农药注射后3个月的损失和神经行为缺陷，验证GWI模型。数据 还指出HMGB 1在CPF效应中的作用，因为CPF GWI小鼠模型显示出升高的循环 生物活性血清中的HMGB 1，尾静脉注射的HMGB 1引起神经炎症/小胶质细胞活化， HMGB 1在体外直接触发小胶质细胞活化。从机制上讲，小胶质细胞耗竭被证实为 体外对CPF的神经保护作用。因此，我们的具体假设是，CPF暴露导致生物活性 循环因子（HMGB 1），然后引起持续的小胶质细胞活化/神经炎症和GWI样 神经病理学因此，以下AIMS将：1）定义HMGB 1抑制在脑缺血中的神经保护功效。 延迟和持续性GWI样神经病理学的CPF模型; 2）证实骨髓细胞在GWI中的作用。 AIM 3：检测GWI样血清的神经免疫活性。这些发现将 提供了急需的洞察力的作用，周边地区的持续反应，全球变暖相关的 农药（CPF），涉及HMGB 1和暂时性骨髓细胞耗竭作为新的治疗靶点， 开始概述神经免疫生物活性测定作为GWI的潜在标志物。

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.