Red Blood Cell Damage Induced by Polystyrene Nanoparticles Drives Inflammatory Responses in Macrophages = 폴리스티렌 나노입자에 의해 유도된 적혈구 손상이 대식세포의 염증 반응에 미치는 영향

다국어 초록 (Multilingual Abstract)

Polystyrene nanoparticles （PS-NPs） are emerging environmental contaminants whose potential hematological and immunological risks remain fully elucidated. In this study, we investigated a novel secondary immunotoxic mechanism wherein polystyrene nanoparticles-damaged red blood cells （PS-NPs-damaged RBCs） trigger inflammatory activation in bone marrow-derived macrophages （BMDMs）. We preferentially screened multiple dimensions of polystyrene nanoparticles and identified that 50 nm particles induced the most prominent structural damage to RBCs. Co-culture of 50 nm PS-NPs- damaged RBCs with BMDMs induced excessive erythrophagocytosis by macrophages, subsequently leading to excessive intracellular iron accumulation within BMDMs. This deregulated and accumulated intracellular iron pool catalyzed the generation of reactive oxygen species （ROS） via the Fenton reaction, inducing cellular oxidative stress characterized by the concomitant depletion of reduced glutathione （GSH） and the concentration-dependent accumulation of oxidized glutathione （GSSG）. Consequently, PS-NPs-damaged RBCs stimulated a robust upregulation of pro-inflammatory cytokines, including TNF-α and IL-1β. Crucially, this pro-inflammatory immune response induced by these events, highlighted by the substantial upregulation of TNF-α secretion, was effectively suppressed by a signaling pathway block utilizing the specific TLR4 inhibitor TAK-242, demonstrating that this activation process is mediated through the TLR4 signaling pathway. In conclusion, our studies demonstrate that the hematological exposure to nanoparticles can trigger secondary immunotoxic pathways via compromised erythrocytes, providing a critical academic framework for evaluating human-predictive immunotoxicity using translational human samples in the future.

목차 (Table of Contents)

• I. Introduction 1
• II. Materials and Methods 11
• III. Results 18
• 1. PS-NPs-damaged RBCs induced cytokine expression in bone marrow-derived macrophages 18
• 2. Phagocytosis of PS-NPs-damaged RBC by bone marrow-derived macrophages 22
• 3. PS-NPs-damaged RBCs induced oxidative stress in activated bone marrow-derived macrophages 24
• 4. TAK-242 inhibits TNF-α release induced by PS-NPs-damaged RBCs 26
• IⅤ. Discussion 28
• V. Conclusion 32
• ⅤI. References 33
• ⅤII. 국문 초록 40