Arsenic Induces M2 Macrophage Polarization and Shifts M1/M2 Cytokine Production via Mitophagy

• Published in: International journal of molecular sciences 2022-11, Vol.23 (22), p.13879
• Main Authors: Hung, Chih-Hsing, Hsu, Hua-Yu, Chiou, Hsin-Ying Clair, Tsai, Mei-Lan, You, Huey-Ling, Lin, Yu-Chih, Liao, Wei-Ting, Lin, Yi-Ching
• Format: Article
• Language: English
• Subjects: Animals; Arginase; Arsenic; Arsenic - metabolism; Arsenic - toxicity; Autophagy; Carcinogens; Cell adhesion & migration; Cell culture; Cell viability; Chemokines; Chloroquine; Cytokines; Cytokines - metabolism; Epithelial cells; Epithelium; Gene Expression; Genotype & phenotype; Growth factors; Kinases; Ligands; Lung cancer; Lung diseases; Lungs; Macrophages; Macrophages - metabolism; Mesenchyme; Mice; Microscopy; Microtubule-associated protein 1; Mitochondria; Mitophagy; Nitric oxide; Nitric-oxide synthase; Parkin protein; Phenotypes; Phosphors; Polarization; Proteins; Pulmonary fibrosis; Surface markers; Transforming growth factor-b1; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms232213879

Arsenic is an environmental factor associated with epithelial-mesenchymal transition (EMT). Since macrophages play a crucial role in regulating EMT, we studied the effects of arsenic on macrophage polarization. We first determined the arsenic concentrations to be used by cell viability assays in conjunction with previous studies. In our results, arsenic treatment increased the alternatively activated (M2) macrophage markers, including arginase 1 ( ) gene expression, chemokine (C-C motif) ligand 16 (CCL16), transforming growth factor-β1 (TGF-β1), and the cluster of differentiation 206 (CD206) surface marker. Arsenic-treated macrophages promoted A549 lung epithelial cell invasion and migration in a cell co-culture model and a 3D gel cell co-culture model, confirming that arsenic treatment promoted EMT in lung epithelial cells. We confirmed that arsenic induced autophagy/mitophagy by microtubule-associated protein 1 light-chain 3-II (LC3 II) and phosphor-Parkin (p-Parkin) protein markers. The autophagy inhibitor chloroquine (CQ) recovered the expression of the inducible nitric oxide synthase ( ) gene in arsenic-treated M1 macrophages, which represents a confirmation that arsenic indeed induced the repolarization of classically activated (M1) macrophage to M2 macrophages through the autophagy/mitophagy pathway. Next, we verified that arsenic increased M2 cell markers in mouse blood and lungs. This study suggests that mitophagy is involved in the arsenic-induced M1 macrophage switch to an M2-like phenotype.