Protein phosphatase 2A/Hedgehog pathway governs efferocytosis of pulmonary macrophages and participates in nanoplastics-induced mouse lung injury.

Although inhalation of nanoplastics (NPs) is widely recognized as a trigger of pulmonary injury, the mechanisms underlying lung damage induced by orally ingested NPs remain largely uncharacterized. Computational toxicology profiling predicted the involvement of efferocytosis in nanoplastic toxicity. Protein phosphatase 2A (PP2A) is an important regulator of macrophage function, and PP2A Aα deficiency impaired efferocytosis. To delineate the contribution of efferocytosis to nanoplastics-induced pulmonary toxicity, myeloid-specific PP2A Aα-deficient (HO) mice model (Ppp2r1a gene deletion) and matched wild-type (WT) littermates were administrated with polystyrene nanoplastics (PS-NPs) by gavage at dose of 10 mg/kg·bw for 4 successive weeks. PS-NPs treatment led to sex-dependent lung inflammation, oxidative damage, and apoptosis in WT mice, which were further aggravated in HO mice. Proteomics analysis revealed impaired efferocytosis in HO mice was associated with perturbations in protein kinase A, ERK/MAPK, Hedgehog signaling pathway etc. In vitro studies confirmed that PP2A Aα deficiency dysregulated Hedgehog signaling, thereby suppressing macrophage efferocytosis and exacerbating pulmonary injury following PS-NPs exposure. Notably, we identified biochanin A as a compound capable of attenuating PS-NPs-induced pulmonary inflammation by enhancing efferocytosis. Together, these findings uncover a novel PP2A-Hedgehog-efferocytosis axis in NPs-induced pulmonary injury and highlight biochanin A as a potential intervention candidate for particulate pollutants-associated respiratory diseases.