Temporal dynamics of a CSF1R signaling gene regulatory network involved in epilepsy.

Claude Gérard,Jonathan Van Eyll,Sabine Cordi,Frédéric P Lemaigre,Laurane De Mot,Jonathan Rubin

doi:10.1371/journal.pcbi.1008854

Abstract

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.

Highlights

Epilepsy is a heterogeneous disease characterized by recurrent unprovoked seizures, cognitive and behavioral impairments, and increased risk of death [1]
We identified a gene regulatory network (GRN) involved in epilepsy that is controlled by inflammation and which regulates the expression and function of Colony
We and others identified and modeled GRNs based on a set of stringent functional criteria where GRN members are connected by direct functional links characterized by protein-protein and protein-DNA interactions, or epistatic relationships identified in lossand gain- of function analyses

Summary

Introduction

Epilepsy is a heterogeneous disease characterized by recurrent unprovoked seizures, cognitive and behavioral impairments, and increased risk of death [1]. Chronic neuroinflammation is a common biological feature of epilepsies and inhibition of the inflammatory response has demonstrated therapeutic efficacy in preclinical contexts [4,5,6]. In this context, our previous study identified Colony Stimulating Factor 1 receptor (CSF1R) as a new therapeutic target, as its inhibition induced anti-inflammatory effects associated with a decrease in epileptic seizures in a pilocarpine mouse model of epilepsy [6]. The clinical side effects of long-term inhibition of CSF1R are not acceptable for epileptic patients [7]. Identifying a therapeutic target that shares the beneficial consequences of CSF1R inhibition on neuro-inflammation, but devoid of side effects, would be of significant interest

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Results

Discussion

Conclusion