Department of Mathematical Sciences, Worcester Polytechnic Institute, Worcester, MA, USA.
Bull Math Biol. 2021 May 12;83(6):72. doi: 10.1007/s11538-021-00905-4.
Neural inflammation immediately follows the onset of ischemic stroke. During this process, microglial cells can be activated into two different phenotypes: the M1 phenotype, which can worsen brain injury by producing pro-inflammatory cytokines; or the M2 phenotype, which can aid in long term recovery by producing anti-inflammatory cytokines. In this study, we formulate a nonlinear system of differential equations to model the activation of microglia post-ischemic stroke, which includes bidirectional switching between the microglia phenotypes, as well as the interactions between these cells and the cytokines that they produce. Further, we explore neuroprotectant-based modeling strategies to suppress the activation of the detrimental M1 phenotype, while promoting activation of the beneficial M2 phenotype. Through use of global sensitivity techniques, we analyze the effects of the model parameters on the ratio of M1 to M2 microglia and the total number of activated microglial cells in the system over time. Results demonstrate the significance of bidirectional microglia phenotype switching on the ratio of M1 to M2 microglia, in both the absence and presence of neuroprotectant terms. Simulations further suggest that early inhibition of M1 activation and support of M2 activation leads to a decreased minimum ratio of M1 to M2 microglia and allows for a larger number of M2 than M1 cells for a longer time period.
神经炎症紧随缺血性中风而发生。在此过程中，小胶质细胞可被激活为两种不同的表型：M1 表型，通过产生促炎细胞因子加重脑损伤；或 M2 表型，通过产生抗炎细胞因子有助于长期恢复。在这项研究中，我们构建了一个非线性微分方程系统来模拟缺血性中风后小胶质细胞的激活，其中包括小胶质细胞表型之间的双向转换，以及这些细胞与它们产生的细胞因子之间的相互作用。此外，我们还探索了基于神经保护剂的建模策略，以抑制有害的 M1 表型的激活，同时促进有益的 M2 表型的激活。通过使用全局敏感性技术，我们分析了模型参数对系统中小胶质细胞 M1 与 M2 比例以及激活的小胶质细胞总数随时间的变化的影响。结果表明，双向小胶质细胞表型转换对 M1 与 M2 小胶质细胞比例的重要性，无论是否存在神经保护剂。模拟进一步表明，早期抑制 M1 激活并支持 M2 激活可降低 M1 与 M2 小胶质细胞的最小比例，并允许更长时间内产生更多的 M2 细胞而不是 M1 细胞。
