Université catholique de Louvain, de Duve Institute, Brussels, Belgium.
Clarivate Analytics, Carlsbad, California, United States of America.
PLoS Comput Biol. 2021 Apr 5;17(4):e1008854. doi: 10.1371/journal.pcbi.1008854. eCollection 2021 Apr.
Colony Stimulating Factor 1 Receptor (CSF1R) is a potential target for anti-epileptic drugs. However, inhibition of CSF1R is not well tolerated by patients, thereby prompting the need for alternative targets. To develop a framework for identification of such alternatives, we here develop a mathematical model of a pro-inflammatory gene regulatory network (GRN) involved in epilepsy and centered around CSF1R. This GRN comprises validated transcriptional and post-transcriptional regulations involving STAT1, STAT3, NFκB, IL6R, CSF3R, IRF8, PU1, C/EBPα, TNFR1, CSF1 and CSF1R. The model was calibrated on mRNA levels of all GRN components in lipopolysaccharide (LPS)-treated mouse microglial BV-2 cells, and allowed to predict that STAT1 and STAT3 have the strongest impact on the expression of the other GRN components. Microglial BV-2 cells were selected because, the modules from which the GRN was deduced are enriched for microglial marker genes. The function of STAT1 and STAT3 in the GRN was experimentally validated in BV-2 cells. Further, in silico analysis of the GRN dynamics predicted that a pro-inflammatory stimulus can induce irreversible bistability whereby the expression level of GRN components occurs as two distinct states. The irreversibility of the switch may enforce the need for chronic inhibition of the CSF1R GRN in order to achieve therapeutic benefit. The cell-to-cell heterogeneity driven by the bistability may cause variable therapeutic response. In conclusion, our modeling approach uncovered a GRN controlling CSF1R that is predominantly regulated by STAT1 and STAT3. Irreversible inflammation-induced bistability and cell-to-cell heterogeneity of the GRN provide a theoretical foundation to the need for chronic GRN control and the limited potential for disease modification via inhibition of CSF1R.
集落刺激因子 1 受体（CSF1R）是抗癫痫药物的潜在靶点。然而，CSF1R 的抑制作用不能被患者很好地耐受，因此需要寻找替代靶点。为了开发鉴定替代靶点的框架，我们在此开发了一个涉及癫痫的炎症基因调控网络（GRN）的数学模型，该模型以 CSF1R 为中心。该 GRN 包括涉及 STAT1、STAT3、NFκB、IL6R、CSF3R、IRF8、PU1、C/EBPα、TNFR1、CSF1 和 CSF1R 的经过验证的转录和转录后调控。该模型基于 LPS 处理的小鼠小胶质细胞 BV-2 细胞中所有 GRN 成分的 mRNA 水平进行了校准，并预测 STAT1 和 STAT3 对其他 GRN 成分的表达具有最强的影响。选择小胶质细胞 BV-2 细胞是因为，推导 GRN 的模块富含小胶质细胞标记基因。STAT1 和 STAT3 在 GRN 中的功能在 BV-2 细胞中进行了实验验证。此外，GRN 动力学的计算分析预测，炎症刺激可以诱导不可逆的双稳态，其中 GRN 成分的表达水平表现为两种不同的状态。开关的不可逆性可能强制需要慢性抑制 CSF1R GRN 以实现治疗效果。双稳态驱动的细胞间异质性可能导致治疗反应的可变性。总之，我们的建模方法揭示了一个主要由 STAT1 和 STAT3 调控的 CSF1R 调控的 GRN。炎症诱导的不可逆双稳态和 GRN 的细胞间异质性为慢性 GRN 控制的必要性以及通过抑制 CSF1R 改变疾病的潜力有限提供了理论基础。
