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.
Keyphrases
- cell adhesion
- cell death
- dendritic cells
- immune response
- oxidative stress
- endoplasmic reticulum stress
- fluorescent probe
- transcription factor
- living cells
- signaling pathway
- regulatory t cells
- diabetic rats
- mental health
- single cell
- healthcare
- magnetic resonance
- poor prognosis
- drinking water
- human health
- toll like receptor
- rheumatoid arthritis
- endothelial cells
- stem cells
- high glucose
- mesenchymal stem cells
- dna methylation
- escherichia coli
- squamous cell carcinoma
- climate change
- cell proliferation
- binding protein
- contrast enhanced
- young adults
- case report
- biofilm formation
- candida albicans