The Nanomaterial-Induced Bystander Effects Reprogrammed Macrophage Immune Function

Abstract Background: In the case of most popularly engineered nanomaterials (e.g., transition-metal dichalcogenide (TMDCs) nanosheets), direct exposure toxicities are investigated extensively to understand the effect on specific cells and organs; however, there has been limited focus on their potential bystander effects. Bystander effects in biological systems are the responses shown by nontargeted neighboring cells or tissues, and critical to the bio-nano interface interactions. In addition to direct effects, bystander effects also determine the design, applications and safety of nanomaterials, although the related information of bystander effects remain largely unknown.Results: A coculture system of A549 and THP-1 was established to mimic the lung microenvironment to study the bystander effects of WS2 nanosheets (representative TMDCs nanosheets) on microenvironment macrophages during the inhalation exposure or the nanomaterial biomedical application in the lung. Lung cells exposed to WS2 nanosheet resulted in an increase in reactive oxygen species and the depolarization of mitochondrial membrane potential in neighboring macrophages. Bystander exposure also induced macrophage polarization toward the anti-inflammatory M2 phenotype, which is adverse to disease therapy. Metabolomics showed that WS2 nanosheets disturbed the energy metabolism and amino acid metabolism of macrophages, consistent with the metabolic characteristics of M2 macrophages. Nitric oxide-transforming growth factor-β1 played an important mediator in the bystander effects. Importantly, WS2 nanosheet bystander exposure affected macrophage phagocytosis and migration and altered the macrophage immune response to environmental endotoxin.Conclusion: This study demonstrated that WS2 exposed lung cells would elicit bystander effects on surrounding macrophage cells, which weaken the immune response of surrounding macrophage cells. This study improves the current understanding of bio-nano interactions and highlights the importance of bystander effects and neighboring cell responses, allowing us to use the maximum benefits of nanomaterials while limiting their adverse bystander effects.