Interferon regulatory factor 5 modulates microglia response to tau by interfering with phagocytosis

AbstractBackgroundThe role of the immune system in responding to neurodegenerative pathology is well established. Microglia are at the center of such response, conveying on one end a positive protective effect, but on the other end, as with senescence, contributing to the hyperinflammation that is a core feature of neurodegeneration. We have identified the transcription factor interferon regulatory factor 5 (IRF5) as a mediator of microglia activation in response to pathological tau, described its specific activation by human‐derived PHF tau and its over‐representation in AD brains. We are now proposing that IRF5 can control the phagocytic activity of microglia, hence modulating their tau‐directed activity.MethodWe utilized age‐ and sex‐matched Irf5+/+ (WT) and Irf5− / − littermate mice for the analysis of ex vivo phagocytic activity of primary microglia, at steady‐state and triggered by tau. We examined microglia morphology and numbers under these conditions and with ageing. Last, we injected PHF tau intracranially to WT and Irf5− / − mice, monitoring tau accumulation and IRF5 response.Result1) Irf5− / − microglia have higher baseline phagocytic activity compared to WT microglia, which may be modulated by tau. 2) Microglia numbers are reduced in ageing Irf5− / − 3) PHF tau‐injected Irf5− / − mice show significant soluble tau accumulation, but a different pattern of oligomeric and insoluble tau accumulation with age. 4) In WT mice, the PHF tau‐injected hemisphere showed significantly higher levels of IRF5 compared to the contralateral, confirming a specific response of IRF5 to tau.ConclusionTau is a specific activator of microglia and of the IRF5 pathway, which can modulate microglia response to pathology. Ageing is an active variable in the process, affecting the pattern of microglia response to tau, differentially in WT and Irf5− / − mice. Modulating the IRF5 pathway may be a viable therapeutic approach in tauopathies.