TFE3-mediated lysosomal biogenesis and homeostasis alleviates arsenic-induced lysosomal and immune dysfunction in macrophages

Abstract

Arsenic is a prevalent environmental toxin associated with cancer that disrupts the immune surveillance and defense functions of macrophages. The MiT/TFE family plays a crucial role in maintaining lysosomal biogenesis and homeostasis, with TFE3 being ubiquitously expressed across most immune cell types, however, its specific role in immune function remains largely unexplored and controversial. In this study, arsenic decreased the cellular phagocytic and adhesion abilities and co-stimulatory molecules CD80, CD86 and pro-inflammatory cytokines TNF-α, IL-6 and IL-1β of cultured J774A.1 macrophages. We also observed that arsenic exposure decreased mRNA expression of LYSET and lysosomal hydrolases Ctsd and Ctss, impaired OVA degradation, reduced Lyso-Tracker Red and Lyso-Sensor Green fluorescence intensity, caused abnormal lysosomal pH, as well as blocked the autophagic flux process in macrophages. Co-treatment with arsenic and CQ further enhanced these arsenic-induced immune responses. More importantly, TFE3 knockdown significantly reduced lysosomal cathepsins levels of CTSB and CTSD, decreased lysosomal abundance, disrupted the lysosomal acidic environment and membrane permeabilization. Further TFE3 knockdown enhanced the decrease in phagocytosis, cellular adhesion, and Icam-1 mRNA expression in macrophages. In addition, the co-stimulatory molecules and pro-inflammatory cytokines were further reduced. By contrast, TFE3 overexpression partially alleviated the above lysosomal impairment and macrophage dysfunction induced by arsenic exposure. Collectively, arsenic exposure impairs macrophages immune function and lysosomal homeostasis. TFE3 regulates lysosomal biogenesis and homeostasis, alleviates arsenic-induced lysosomal and immune dysfunction in macrophages. Targeting the MiT/TFE family may provide new strategies for modulating lysosomal homeostasis and immune function.

Keywords: Immunotoxicity; Inorganic arsenic; Lysosome; Macrophage; TFE3.