Arsenic (As) is a prevalent and hazardous environmental toxicant associated with cancer and various health problems, which has been shown suppressive effects on dendritic cells (DCs). Autophagy is essential for the innate and adaptive immune responses of DCs, and the transcription factors TFEB and TFE3 are key regulators of autophagic and lysosomal target genes. However, the detrimental alterations of the autophagy-lysosome pathway in As-exposed DCs and the possible coordinating roles of TFEB and TFE3 in the immune dysfunction of this cell are less understood. In this paper, we found that As exposure significantly impaired lysosomal number, lysosomal acidic environment, and lysosomal membrane permeabilization, which might lead to blocked autophagic flux in cultured DCs. Furthermore, our results confirmed that TFEB or TFE3 knockdown exacerbated the disorders of lysosome and the blockade of autophagic flux in As-exposed DCs, and also enhanced the inhibitory expression of co-stimulatory molecules Cd80 and Cd83; adhesion molecule Icam1; cytokines TNF-α, IL-1β, and IL-6; chemokine receptor Ccr7; and antigen-presenting molecules MHC II and MHC I. By contrast, overexpression of TFEB or TFE3 partially alleviated the above-mentioned impairment of DCs by inorganic As exposure. In conclusion, these findings reveal a previously unappreciated inhibition of lysosome-mediated degradation and damage of lysosomal membrane integrity leading to dysregulated autophagy and impaired immune functions of DCs by arsenicals, and also suggest TFEB and TFE3 as potential therapeutic targets for ameliorating As toxicity.

Graphical abstract

中文翻译：

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TFEB和TFE3协同调节无机砷诱导的原代树突状细胞自噬溶酶体损伤和免疫功能障碍

砷 (As) 是一种与癌症和各种健康问题相关的普遍且危险的环境毒物，已显示出对树突状细胞 (DC) 具有抑制作用。自噬对于 DC 的先天性和适应性免疫反应至关重要，转录因子 TFEB 和 TFE3 是自噬和溶酶体靶基因的关键调节因子。然而，暴露于 As 的 DC 中自噬-溶酶体途径的有害改变以及 TFEB 和 TFE3 在该细胞的免疫功能障碍中可能的协调作用尚不清楚。在本文中，我们发现砷暴露显着损害溶酶体数量、溶酶体酸性环境和溶酶体膜通透性，这可能导致培养 DC 中的自噬通量受阻。此外，我们的结果证实，TFEB或TFE3敲低加剧了暴露于As的DC中溶酶体的紊乱和自噬流的阻断，并且还增强了共刺激分子Cd80和Cd83的抑制表达。粘附分子Icam1 ; 细胞因子 TNF-α、IL-1β 和 IL-6；趋化因子受体Ccr7 ; 相比之下，TFEB 或 TFE3 的过度表达部分减轻了上述无机砷暴露对 DC 的损害。总之，这些发现揭示了砷对溶酶体介导的降解和溶酶体膜完整性损伤的先前未被认识到的抑制，导致自噬失调和 DC 的免疫功能受损，并且还表明 TFEB 和 TFE3 作为改善砷毒性的潜在治疗靶点。

图形概要