Multiphysics and multiscale modeling of erythrophagocytosis

Erythrophagocytosis is an essential human physiological process responsible for daily removal of 16-24 billion damaged and senescent red blood cells (RBCs) from the circulating blood. Biochemical signaling pathways mediated by the ligand-receptor interactions have been considered as the key factors that initiate and drive the phagocytosis of these abnormal RBCs by the tissue-resident macrophages in the spleen and liver. However, increased evidence has underscored the significance of the physical properties of phagocytic targets in modulating the engulfing process. Because of the lack of experimental approaches to quantify the chemical kinetics and cell dynamics during phagocytosis, it is not clear how biological signaling pathways cooperate with biophysical alterations of the phagocytes and their targets to ensure the timely and efficient removal of such an immense number of RBCs. To fill this knowledge gap, we develop a new biochemical signaling model to simulate the initiation of erythrophagocytosis by the interaction between the ligands on the RBCs and their receptors on the macrophages. This model is developed based on system biology-informed neural networks (SBINNs), which can infer the unknown parameters, e.g. reaction rates, and dynamics of species, in the model with a few experimental data as well as enable continuous model refinement using emerging experimental data. Next, we will develop new biophysical models to simulate the macrophage adhering and phagocytosing RBCs. These mechanistic models are used to investigate and quantify the impact of the rigidity of the macrophages as well as the rigidity and morphologies of aged RBCs and RBCs in diseases, such as sickle cell disease (SCD), hereditary spherocytosis and elliptocytosis, on the efficiency of the engulfing processes. The model predictions will be validated against phagocytosis experiments from our collaborators and in the literature. Then, we will integrate the biochemical signaling model with the biophysical phagocytosis model to investigate how biochemical and biophysics are intertwined in dictating the dynamics of phagocytosis.