无机砷调节机体的神经免疫应答及天然抗氧化物姜黄素的神经保护效应研究

Arsenic can cross the blood-brain barrier into the brain tissue, resulting in neurotoxicity. Neuroimmunological studies document that nervous system is not considered to be an immune-privileged site. On the contrary, nervous system contains many immune cells (microglia, astroglia and lymphocyte), consisting of innate immunity system and adaptive immune system, which play an important role in both physiological and pathological processes. Recent reports have indicated that arsenic has been identified as a potent immunomodulatory agent, However, a few studies begin to focus on the possible effects of inorganic arsenic on neuroimmunotoxicity. On the other hand, natural antioxidant curcumin exerts anti-inflammatory, antioxidant and immunomodulation in neurological disease. The role of curcumin on neuroimmunotoxicity has become a hotspot. The present study will focus on the potential effects of toxic arsenic on the innate immunity response and adaptive immune response of the main components (cerebrum, cerebellum, hippocampus and cerebrospinal fluid) in nervous system, especially on immune recognition, antigen presentation, immune factors secretion as well as cellular immunity in vivo; immunological and inflammatory signaling pathway JAK-STAT and SOCS on neuro-immune imbalance, as well as the neuroprotective effect of natural antioxidant curcumin on arsenic-induced neuroimmunotoxicity. The current study intends to provide new theortical clues for the prevention and treatment of arsenicosis-induced immune-related disorders in nervous system.

砷可以通过血脑屏障进入脑实质诱导神经毒性。神经免疫学研究发现神经系统不再是免疫豁免区；相反，神经系统存在由小胶质细胞、星形胶质细胞和淋巴细胞等免疫细胞组成的固有和适应性免疫系统，参与神经系统生理和病理过程。最新的研究提示砷是一种潜在的免疫调节剂，但砷对神经系统免疫调节效应的研究尚不多见。另一方面，天然抗氧化物姜黄素在神经系统疾病中发挥抗炎、抗氧化和免疫调节等效应，其在神经免疫毒性中的作用已成为研究热点。本项目拟采用整体动物学实验，全面系统观察无机砷对神经系统主要成分（大脑、小脑、海马和脑脊液）内固有和适应性免疫应答的影响，尤其是对免疫识别、抗原提呈、免疫分子和细胞免疫功能的调节效应、免疫和炎症信号通路JAK-STAT及其负反馈调节因子SOCS在其的可能作用；以及天然抗氧化物姜黄素对砷神经免疫毒性的保护效应。本研究试图为砷中毒所致神经系统免疫相关疾病的防治提供新的理论依据。

砷是具有明确的免疫毒性和神经毒性。神经免疫学研究发现神经系统不再是免疫豁免区。相反，神经系统内存在小胶质细胞、星型胶质细胞和淋巴细胞等免疫细胞组成的固有免疫系统和适应性免疫系统，也参与神经系统生理和病理过程，但目前关于砷对神经系统免疫损伤的研究报道尚不多见。另一方面，天然抗氧化物姜黄素在神经系统疾病中发挥抗炎、抗氧化和免疫调节等效应，其在神经免疫毒性中的作用已成为研究热点。本研究以亚砷酸钠为暴露因素，全面系统的观察无机砷暴露对小鼠神经系统内固有免疫应答和适应性免疫应答的影响及其可能机制，并初步探讨姜黄素对无机砷暴露所致神经免疫毒性的拮抗效应。结果显示：（1）急性砷暴露通过调控JAK/STAT信号通路影响小鼠海马组织抗原提呈功能相关分子（MHCII、CD40、CD80和CD86）表达和炎症因子（IL-1β、TNF-α和IL-10）分泌以及CD4+T淋巴细胞亚群Th1/Th2/Th17/Treg的分化，诱导神经免疫毒性。（2）饮水砷暴露通过减少神经保护因子(BDNF和VEGF)的表达，以及影响脑组织中固有免疫系统（血脑屏障通透性、神经胶质细胞活化、抗原提呈功能和NLRP3炎症小体）和适应性免疫系统T淋巴细胞亚群CD4和CD8细胞的数目及CD4+T淋巴细胞亚群Th1/Th2/Th17/Treg的分化，最终导致小鼠的学习记忆能力下降和神经免疫失衡，这可能与砷激活神经系统内Nrf2和JAK/STAT信号通路有关。（3）姜黄素通过调控JAK/STAT信号通路拮抗砷诱导的血脑屏障通透性破坏和T淋巴细胞数目和分化异常，进而发挥神经保护效应。本研究试图为砷中毒所致神经系统免疫相关疾病的防治提供新的理论依据。