Brain ischemia induces an INF-mediated response in microglia of mice and humans.

Trabajo presentado en el 19th National Meeting of the Spanish Society of Neuroscience, celebrado en Lleida (España), del 3 al 5 de noviembre de 2021Brain ischemia causes necrotic cell death, microglia reactivity and blood-brain barrier breakdown. Danger signals ¿ including nuclear proteins, nucleic acids and heat-shock proteins ¿ are released from injured cells and trigger immune responses by activating pattern recognition receptors (PRRs). Microglial cells are equipped with PRRs, can sense danger signals in the environment and induce inflammation. Our aim was to investigate the inflammatory response of microglia to ischemia in mice and humans. We induced cerebral ischemia in mice by 45-min middle cerebral artery occlusion followed by reperfusion. We compared the transcriptomic profile of microglia isolated from brain tissue of control and ischemic mice using fluorescence activated cell sorting followed by RNA-Seq. Enrichment analysis showed a strong anti-viral response induced by ischemia in microglia, highlighted by upregulation of type-I interferons (IFNs) including Ifnb and many IFN-stimulated genes (ISG). Accordingly, in whole brain tissue, ischemia increased Ifnb, Ifna7 and Ifna9 mRNA expression, as well as many ISG, including Dhx58, Cxcl10, Irf7, and Irg15. A time-course study in brain tissue samples obtained between 1h and 7 days post-ischemia showed ISG expression increase from about 16h post-ischemia, reaching a plateau at 4-7 days. We also detected enhanced expression of ISG in post-mortem human brain tissue of ischemic stroke patients. To find out the contribution of microglia to gene expression in whole brain tissue, we depleted microglia in mice with a CSF1R inhibitor (PLX5622). Ischemia-induced expression of Ifnb, Ifna7, or Ifna9 mRNA was not reduced after microglia depletion. This implies that cells other than microglia are the main source of IFNs in the injured brain. In contrast, we found that microglia depletion reduced cerebral ISG expression. The results show that type I IFNs generated after ischemia in cells other than microglia activate type I IFN receptors in microglia, inducing ISG expression and triggering a specific transcriptional program.Peer reviewe