Work

Inorganic arsenic and its methylated metabolites induce pulmonary immunosuppression via the p62-Keap1-Nrf2 positive feedback loop-mediated M2 macrophage polarization

Year: 2026

Type: article

Abstract: Trivalent inorganic arsenic (iAs III ) is a widespread environmental contaminant associated with adverse health outcomes, including immune dysregulation. However, the mechanisms underlying pulmonary immunotoxicity induced by iAs III and its methylated metabolites remain unclear. In this study, acute oral exposure to iAs III in C57BL/6 mice elicited an early immunosuppressive shift in the pulmonary microenvironment, characterized by upregulated expression of M2 macrophage phenotypic markers and reduced inflammatory cytokines. In vitro , iAs III and its methylated metabolites, monomethylarsonous acid (MMA III ) and dimethylarsinous acid (DMA III ), promoted a phenotypic transition of murine alveolar macrophages from an M1- to an M2-like state. This shift was evidenced by decreased expression of the M1 marker iNOS and pro-inflammatory cytokines (IL-6 and IL-1β), along with enhanced expression of the M2 marker ARG1 and the anti-inflammatory cytokine IL-10, with MMA III exhibiting the strongest immunosuppressive potency. Mechanistically, iAs III and MMA III robustly activated the Nrf2-HO-1 pathway, whereas DMA III elicited relatively weaker activation. Silencing of Nrf2 abolished iAs III - and MMA III -driven M2 polarization, indicating an essential role for Nrf2. Furthermore, iAs III and MMA III induced aberrant accumulation of the autophagy adaptor p62, accompanied by impaired autophagic flux, lysosomal alkalinization, and increased lysosomal membrane permeability. Knockdown of p62 attenuated Nrf2 activation and reversed the M2-like polarization phenotype. Moreover, the reduction of p62 following Nrf2 silencing further suggests a bidirectional regulatory interaction between p62 and Nrf2. Collectively, these findings demonstrate that iAs III and MMA III drive alveolar macrophage polarization toward an immunosuppressive M2 phenotype via a p62-Keap1-Nrf2 positive feedback loop, providing mechanistic insight into iAs III -induced pulmonary immunosuppression.

Source: Ecotoxicology and Environmental Safety

DOI: 10.1016/j.ecoenv.2026.120214