The role of astrocytes and microglia in interferon-mediated neuroinflammation

Abstract

Chronically elevated levels of interferon (IFN)- in the brain have been linked to neuroinflammatory diseases such as Aicardi-Goutières Syndrome (AGS). A causative role for IFN- in disease pathogenesis has been demonstrated in transgenic mice with chronic production of IFN- in the brain (GIFN39 mice). Reactive astrocytes and microglia are cardinal features of GIFN39 mice and are also implicated in the pathogenesis of AGS. To better understand the responses of these cells to IFN- signalling in neuroinflammation, we used the Cre-loxP system to generate two GIFN39 models with conditional inactivation of the type I interferon receptor (Ifnar1) in either astrocytes or microglia, termed GIFN:Ifnar1fl/fl:GfapCre/+ and GIFN:Ifnar1fl/fl:Cx3cr1Cre/+ mice. Despite efforts to minimise ectopic recombination, we observed a mixed population of mostly cell-type specific Ifnar1 knockout mice and a minor proportion of half-global knockout mice. Due to the minimal impact of these half-global knockout mice, we proceeded to perform a detailed phenotypic analysis of this heterogenous population.

In the GIFN:Ifnar1fl/fl:GfapCre/+ model, astrocyte-targeted ablation of Ifnar1 in GIFN39 mice led to improved survival, without altering neurobehavioral features. These mice exhibited sustained expression of IFN-regulated genes and a partial rescue of blood-brain barrier (BBB) function was conferred, without altering the expression of key endothelial cell markers. In the GIFN:Ifnar1fl/fl:Cx3cr1Cre/+ model, microglia-targeted ablation of Ifnar1 improved survival, but to a lesser extent than in the GIFN:Ifnar1fl/fl:GfapCre/+ model. These mice showed a trend towards reduced expression of IFN-regulated genes compared with GIFN mice, and microglial loss of Ifnar1 did not improve BBB function. Collectively, these findings demonstrate the differential responses of astrocytes and microglia to IFN-α-mediated neuroinflammation, and underscore the challenges associated with the Cre-loxP system.