Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

Abstract

Type I interferons (IFN-I) are crucial for effective antimicrobial defense in the central nervous system (CNS) but also can cause severe neurological disease (termed cerebral interferonopathy) as exemplified by Aicardi-Goutières Syndrome. In the CNS, microglia and astrocytes have essential roles in host responses to infection and injury, with both cell types responding to IFN-I. While the IFN-I signaling pathways are the same in astrocytes and microglia, the extent to which the IFN-I responses of these cells differ, if at all, is unknown. Here we determined the global transcriptional responses of astrocytes and microglia to the IFN-I, IFN-α. We found that under basal conditions, each cell type has a unique gene expression pattern reflective of its developmental origin and biological function. Following stimulation with IFN-α, astrocytes and microglia also displayed a common core response that was characterized by the increased expression of genes required for pathogen detection and elimination. Compared with astrocytes, microglia had a more extensive and diverse response to IFN-α with significantly more genes with expression upregulated (282 vs. 141) and downregulated (81 vs. 3). Further validation was documented for selected IFN-I-regulated genes in a murine model of cerebral interferonopathy. In all, the findings highlight not only overlapping but importantly divergent responses to IFN-I by astrocytes versus microglia. This suggests specialized roles for these cells in host defense and in the development of cerebral interferonopathy.

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

“…Additionally, the transcriptome of microglia from 564Igi mice is largely defined by a response to IFN‐I, with a significant portion of IFN‐I‐dependent genes enriched in processes such as IFN‐I production, environmental sensing, and phagocytosis (Bialas et al, ). Of note, these functional properties are similar to those recently identified in IFN‐α‐treated microglia (Li et al, ). It has also recently been demonstrated that microglia mediate pathologic dendritic pruning of hippocampal neurons in an anti‐DNA antibody‐mediated mouse model of CNS lupus (Nestor et al, ).…”

“…Similarly, the expression of the IFN‐I receptor genes IFNAR1 and IFNAR2 is also widespread (Zhang et al, , ), enabling all cell types in the CNS of humans and mice to respond to IFN‐I. Interestingly, in vitro studies have shown that microglia have a more pronounced response compared with astrocytes and neurons, suggesting that microglia are the major IFN‐I responder cell population in the CNS (Li et al, ; Wang & Campbell, ).…”

“…On the other hand, microglia in the CNS of GFAP‐IFN mice appear hypertrophied (Akwa et al, ; Campbell, ) compared with the smaller, less ramified microglia in the brain of GFAP‐IL6 and WT mice (Figure ; Campbell et al, ; Quintana et al, ; Vallieres et al, ). Furthermore, the CNS of GFAP‐IFN mice also shows increased expression of microglia‐related IRGs, including the antigen presentation molecule MHC‐I (Akwa et al, ), as well as IRGs that are specifically regulated in IFN‐α‐treated microglia but not astrocytes, including Ifi203 , Slfn5 , and Ccl5 (Li et al, ). In addition, levels of the transcription factor IRF1 are increased in the nucleus of GFAP‐IFN microglia and these cells also show increased surface levels of the T lymphocyte communication molecule CD86 (Li et al, ), which together with other molecular sensors, such as MHC‐I, may prime GFAP‐IFN microglia to adopt an immune vigilant state and may be deleterious to the steady‐state function of the CNS.…”

“…Furthermore, the CNS of GFAP‐IFN mice also shows increased expression of microglia‐related IRGs, including the antigen presentation molecule MHC‐I (Akwa et al, ), as well as IRGs that are specifically regulated in IFN‐α‐treated microglia but not astrocytes, including Ifi203 , Slfn5 , and Ccl5 (Li et al, ). In addition, levels of the transcription factor IRF1 are increased in the nucleus of GFAP‐IFN microglia and these cells also show increased surface levels of the T lymphocyte communication molecule CD86 (Li et al, ), which together with other molecular sensors, such as MHC‐I, may prime GFAP‐IFN microglia to adopt an immune vigilant state and may be deleterious to the steady‐state function of the CNS. Given that microglia respond to IFN‐α more strongly than other cells in the CNS (Li et al, ; Wang & Campbell, ), their response likely contributes significantly to the pathology observed in GFAP‐IFN mice.…”

“…In addition, levels of the transcription factor IRF1 are increased in the nucleus of GFAP‐IFN microglia and these cells also show increased surface levels of the T lymphocyte communication molecule CD86 (Li et al, ), which together with other molecular sensors, such as MHC‐I, may prime GFAP‐IFN microglia to adopt an immune vigilant state and may be deleterious to the steady‐state function of the CNS. Given that microglia respond to IFN‐α more strongly than other cells in the CNS (Li et al, ; Wang & Campbell, ), their response likely contributes significantly to the pathology observed in GFAP‐IFN mice. However, this remains to be determined.…”