PDF(Pubmed)
Abstract：
Erythrophagocytosis occurring in the spleen is a critical process for removing senescent and diseased red blood cells (RBCs) from the microcirculation. Although some progress has been made in understanding how the biological signaling pathways mediate the phagocytic processes, the role of the biophysical interaction between RBCs and macrophages, particularly under pathological conditions such as sickle cell disease, has not been adequately studied. Here, we combine computational simulations with microfluidic experiments to quantify RBC-macrophage adhesion dynamics under flow conditions comparable to those in the red pulp of the spleen. We also investigate the RBC-macrophage interaction under normoxic and hypoxic conditions. First, we calibrate key model parameters in the adhesion model using microfluidic experiments for normal and sickle RBCs under normoxia and hypoxia. We then study the adhesion dynamics between the RBC and the macrophage. Our simulation illustrates three typical adhesion states, each characterized by a distinct dynamic motion of the RBCs, namely firm adhesion, flipping adhesion, and no adhesion (either due to no contact with macrophages or detachment from the macrophages). We also track the number of bonds formed when RBCs and macrophages are in contact, as well as the contact area between the two interacting cells, providing mechanistic explanations for the three adhesion states observed in the simulations and microfluidic experiments. Furthermore, we quantify, for the first time to our knowledge, the adhesive forces between RBCs (normal and sickle) and macrophages under different oxygenated conditions. Our results show that the adhesive forces between normal cells and macrophages under normoxia are in the range of 33-58 pN and 53-92 pN for sickle cells under normoxia and 155-170 pN for sickle cells under hypoxia. Taken together, our microfluidic and simulation results improve our understanding of the biophysical interaction between RBCs and macrophages in sickle cell disease and provide a solid foundation for investigating the filtration function of the splenic macrophages under physiological and pathological conditions.
摘要：
脾脏中发生的红细胞吞噬作用是从微循环中去除衰老和患病的红细胞（RBC）的关键过程。尽管在理解生物信号通路如何介导吞噬过程方面取得了一些进展，红细胞和巨噬细胞之间的生物物理相互作用的作用，特别是在镰状细胞病等病理条件下，没有得到充分的研究。这里,我们将计算模拟与微流体实验相结合，以量化在与脾脏红髓相当的流动条件下的红细胞-巨噬细胞粘附动力学。我们还研究了在常氧和低氧条件下RBC-巨噬细胞的相互作用。首先,我们使用微流控实验对正常和镰状红细胞在常氧和缺氧下的粘附模型中的关键模型参数进行校准。然后我们研究红细胞和巨噬细胞之间的粘附动力学。我们的模拟说明了三种典型的粘附状态，每个都以红细胞的不同动态运动为特征，即牢固的附着力，翻转附着力,并且没有粘附（由于不与巨噬细胞接触或与巨噬细胞脱离）。我们还追踪红细胞和巨噬细胞接触时形成的键的数量，以及两个相互作用的细胞之间的接触面积，为模拟和微流体实验中观察到的三种粘附状态提供机械解释。此外，我们量化，据我们所知，这是第一次，在不同的含氧条件下，红细胞(正常和镰刀)和巨噬细胞之间的粘附力。我们的结果表明，常氧下正常细胞与巨噬细胞之间的粘附力在常氧下镰状细胞的范围为33-58pN和53-92pN，在低氧下镰状细胞的范围为155-170pN。一起来看,我们的微流控和模拟结果提高了我们对镰状细胞病中红细胞和巨噬细胞之间生物物理相互作用的理解，并为研究脾巨噬细胞在生理和病理条件下的过滤功能提供了坚实的基础。
