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Polystyrene-nanoplastics-induced unfolded protein response in monocyte-derived macrophages mediates pulmonary fibrosis via oxidative-stress-dependent IL-6 secretion
Summary
Researchers found that inhaled polystyrene nanoplastics promote pulmonary fibrosis by activating macrophages through a PERK/oxidative stress/IL-6 signaling cascade — in which nanoplastics trigger an unfolded protein response (a cellular stress reaction) that drives IL-6 secretion and transforms fibroblasts into scar-forming cells — identifying IL-6 as a potential therapeutic target.
Micro- and nano-plastics have emerged as widespread environmental pollutants, with growing concerns regarding their impact on human health. Polystyrene nanoplastics (PS-NPs) accumulate in the alveolar region and have been implicated in the development of pulmonary fibrosis. However, the underlying mechanisms by through which PS-NPs promote fibrotic lung disease remain poorly understood. Macrophages are closely associated with both inflammation and fibrosis progression, which are central players in the pulmonary response to environmental insults. This study aimed to determine whether PS-NPs activated pulmonary macrophages to induce lung fibrosis. We demonstrated that bronchial exposure to PS-NPs induced pulmonary fibrosis, accompanied by robust inflammatory responses and pro-inflammatory activation of monocyte-derived macrophages (MoMs) in vivo. The pro-resolving mediator resolvin D1 effectively ameliorated PS-NP-induced fibrosis by attenuating inflammation and inhibiting the secretion of pro-inflammatory cytokines from MoMs. PS-NPs activated MoMs to promote fibroblast-to-myofibroblast differentiation via an oxidative-stress-dependent mechanism involving IL-6 secretion in vitro. Mechanistically, PS-NPs triggered the unfolded protein response (UPR) activation in MoMs, which drove oxidative-stress-dependent IL-6 secretion and promoted fibroblast-to-myofibroblast differentiation. The PERK arm was identified as the predominant UPR pathway and it initiated a critical PERK/oxidative-stress/IL-6 signaling axis in the MoMs. Importantly, IL-6 deficiency (IL-6 mice) and IL-6 neutralization significantly suppressed PS-NP-induced lung inflammation and fibrosis, highlighting the essential role of macrophage-derived IL-6 in this process. In conclusion, PS-NPs drive pulmonary fibrosis by activating the UPR/oxidative-stress/IL-6 signaling axis in MoMs. These findings highlight IL-6 as a potential therapeutic target for the prevention of environmental-insult-related fibrotic lung disease.