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是一种毁灭性的和衰弱的情况，其中GWI的症状表现为 神经系统和外周症状，包括广泛性疼痛、肌肉骨骼疼痛、头痛、 持续性认知障碍、疲劳、胃肠症状、呼吸不适和皮肤 异常现象。最近的研究支持患有认知障碍的GWI退伍军人的海马区异常病理 赤字，突出了中枢神经系统的一个重要联系。GWI的一个关键和突出的特征是症状持续存在 在某些情况下，在海湾战争之后很久，现在已经超过25年了。流行病学支持这一观点 接触杀虫剂，如毒死蜱(CPF)，可能与GWI的认知影响有关，但潜在的 机制尚不清楚。GWI认知缺陷的神经炎症假说认为，中枢神经系统 免疫紊乱可能是GWI持续的中枢神经系统效应的驱动因素。小胶质细胞，常驻的髓样细胞(免疫 起源)细胞，一直被认为是推动促炎因子的慢性来源 不同中枢神经系统条件下的进行性神经元损伤，包括GWI。最近的报告表明，外围设备 损伤通过循环因子增强大脑的促炎反应，导致神经元病理。 我们的最重要的假设是，外周和中枢神经系统损伤在GWI中相互作用，并对GWI- 相关农药，CPF，其中循环损伤相关的分子模式调节慢性 小胶质细胞促炎反应和随之而来的神经元/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、慢性海马区突触素 最后一次注射杀虫剂3个月后的丢失和神经行为缺陷，验证了GWI模型。数据 也指出了HMGB1在CPF效应中的作用，因为CPF GWI小鼠模型显示出循环增加 在生物活性血清中，尾静脉注射HMGB1可引起神经炎症/小胶质细胞活化，并 HMGB1在体外直接激活小胶质细胞。从机制上讲，小胶质细胞的耗竭被确认为 体外抗CPF的神经保护作用。因此，我们的特定假设是，接触CPF会导致生物活性 循环因子(HMGB1)，然后导致持续的小胶质细胞激活/神经炎症和GWI样 神经病理学。因此，以下目的将：1)确定抑制HMGB1在脑内的神经保护作用 延迟性和持续性GW I样神经病理的CPF模型；2)证实髓系细胞在GW I中的作用。 3)AIM3：检测GWI样血清的神经免疫生物活性。这些发现将 提供亟需的洞察，了解外围设备在持续响应与GWI相关的问题中所扮演的角色 杀虫剂(CPF)，涉及HMGB1和暂时性髓系细胞衰竭作为新的治疗靶点，以及 开始概述神经免疫生物活性分析作为GWI的潜在标记物。

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.