树突状细胞功能障碍在无机砷免疫毒性中的可能作用及其机制

Inorganic arsenic are both immunotoxic and carcinogenic to humans. Dendritic cells (DCs), as a type of unique and exclusive antigen presenting cells with property to stimulate the primary immune reactions, is in the central position of initiating, regulating and maintaining a variety of immune responses. We have proved in the just finished research funded by the National Natural Science Foundation of China (NSFC) that arsenic could induce the remarkable and sustained activation of nuclear transcriptional factor Nrf2 in different tissues and organs, especially in the organs of the immune system. The present study will focus on the potential toxic effects of arsenic on DC functions, such as phagocytosis, chemotactic and adhensive activity, as well as antigen presenting ability, in both in vivo and in vitro experiments. We also try to explore whether arsenic-induced DC autophogy could mediate Nrf2 pathway activation, as well as the interactions of Nrf2 upregulation with MAPK and NF-kB signaling pathway, which are strongly linked to the inflammatory and immunological process. We suspect that the dysfunction of DC could subsequently result in the abnormal immunoresponses of T lymphocytes, and therefore be closely linked to the immunotoxicity of inorganic exposure. The current study intends to deepen the understanding of arsenic-related immunotoxicity and carcinogenicity, and provide new theoretical clues and experimental evidences for the prevention and treatment of chronic endemic arsenicosis.

无机砷具有免疫毒性和致癌性。树突状细胞（dendritic cell，DC）作为唯一能够刺激初始免疫应答的抗原提呈细胞，处于启动、调控和维持机体免疫应答的中心环节。在刚结题的国家自然科学基金项目证实无机砷能够显著和持续性激活机体多组织脏器、尤其是免疫器官中核转录因子Nrf2信号通路的整体实验研究基础上，本项目拟采用整体动物和细胞学实验相结合的研究方法，观察无机砷对DC抗原吞噬、趋化粘附、和抗原提呈等功能的影响，并探讨无机砷如何通过DC自噬活化Nrf2通路、进而与MAPK调控的炎症和免疫反应关键转录因子NF-kB等交互作用，导致DC功能障碍、从而进一步影响T淋巴细胞免疫应答反应和无机砷的免疫毒性。本研究试图从更深层次理解砷的免疫毒性作用和长期致癌效应，为慢性砷中毒的防治提供新的理论线索和实验依据。

砷是危害人体健康的毒物之首，砷的免疫毒性是国际砷研究领域的热点问题之一。树突状细胞（DC）是人体功能最强的专职抗原提呈细胞，是机体特异性免疫应答的始动者。本研究采用整体动物和细胞学实验相结合的研究方法，观察无机砷所致DC功能障碍和T淋巴细胞免疫应答失平衡，并探讨其可能的作用机制。研究结果表明，无机砷暴露能够抑制DC的抗原吞噬、趋化粘附、抗原提呈和特定细胞因子分泌等生理功能；无机砷引发mTOR依赖性的的DC自噬和自噬底物蛋白p62的大量积累，诱导核转录因子Nrf2通路、尤其是其下游靶分子HO-1/CO系统的活化，特异性地抑制了DC细胞的靶点CCR7、TNF-α、IL-6和IL-23等，很可能在无机砷诱导的BMDCs免疫耐受性中发挥了重要作用。其次，本研究还从整体动物学实验层面证实了经口无机砷暴露具有免疫毒性，能够诱导机体的免疫器官和非免疫器官的免疫炎性反应、CD4+T细胞的功能分化和免疫相关因子分泌等，同时初步证实了无机砷对DC功能的抑制作用可以间接影响机体T淋巴细胞的免疫应答反应。第三，调控细胞自噬反应的重要转录因子TFEB有可能在无机砷诱导的DC细胞自噬中发挥一定的作用。介于DC作为启动、调控和维持机体免疫应答的中心环节，在调控机体的免疫应答以及肿瘤的免疫逃逸机制中均发挥重要的作用，本项目研究成果为深入理解无机砷的免疫毒性作用和远期致癌效应等提供了一种可能的理论线索和靶点，也为临床中应用砷及其化合物治疗自身性免疫疾病提供一定的理论基础和新的治疗思路。