State Key Laboratory for Chemo/Bio-Sensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University, Changsha 410082, China.
State Key Laboratory of Research and Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang 712083, China.
Proc Natl Acad Sci U S A. 2024 Aug 13;121(33):e2403740121. doi: 10.1073/pnas.2403740121. Epub 2024 Aug 5.
The formation of macrophage-derived foam cells has been recognized as the pathological hallmark of atherosclerotic diseases. However, the pathological evolution dynamics and underlying regulatory mechanisms remain largely unknown. Herein, we introduce a single-particle rotational microrheology method for pathological staging of macrophage foaming and antiatherosclerotic explorations by probing the dynamic changes of lysosomal viscous feature over the pathological evolution progression. The principle of this method involves continuous monitoring of out-of-plane rotation-caused scattering brightness fluctuations of the gold nanorod (AuNR) probe-based microrheometer and subsequent determination of rotational relaxation time to analyze the viscous feature in macrophage lysosomes. With this method, we demonstrated the lysosomal viscous feature as a robust pathological reporter and uncovered three distinct pathological stages underlying the evolution dynamics, which are highly correlated with a pathological stage-dependent activation of the NLRP3 inflammasome-involved positive feedback loop. We also validated the potential of this positive feedback loop as a promising therapeutic target and revealed the time window-dependent efficacy of NLRP3 inflammasome-targeted drugs against atherosclerotic diseases. To our knowledge, the pathological staging of macrophage foaming and the pathological stage-dependent activation of the NLRP3 inflammasome-involved positive feedback mechanism have not yet been reported. These findings provide insights into in-depth understanding of evolutionary features and regulatory mechanisms of macrophage foaming, which can benefit the analysis of effective therapeutical drugs as well as the time window of drug treatment against atherosclerotic diseases in preclinical studies.
巨噬细胞源性泡沫细胞的形成已被认为是动脉粥样硬化疾病的病理标志。然而，其病理演变动力学和潜在的调控机制在很大程度上仍不清楚。在此，我们通过探测溶酶体粘性特征在病理演变过程中的动态变化，引入了一种用于巨噬细胞泡沫化病理分期和抗动脉粥样硬化探索的单颗粒旋转微流变学方法。该方法的原理涉及基于金纳米棒（AuNR）探针的微流变仪对平面外旋转引起的散射亮度波动的连续监测，以及随后对旋转松弛时间的分析，以分析巨噬细胞溶酶体中的粘性特征。利用该方法，我们证明了溶酶体粘性特征作为一种强大的病理报告器，并揭示了三个不同的病理阶段，这些阶段与 NLRP3 炎性体相关的正反馈环的病理阶段依赖性激活密切相关。我们还验证了该正反馈环作为一种有前途的治疗靶点的潜力，并揭示了 NLRP3 炎性体靶向药物对动脉粥样硬化疾病的时间依赖性疗效。据我们所知，巨噬细胞泡沫化的病理分期和 NLRP3 炎性体相关的正反馈机制的病理阶段依赖性激活尚未被报道。这些发现为深入了解巨噬细胞泡沫化的进化特征和调控机制提供了思路，这将有助于分析有效的治疗药物以及临床前研究中针对动脉粥样硬化疾病的药物治疗时间窗。
