The Role of IL-17RA on Microglial Activation in Alzheimer’s Disease

Abstract

Microglia are brain resident immune cells which play a pivotal role in brain development, maintenance and disease. Previously, we have identified two major microglial phenotypes: the homeostatic microglia (M0) and neurodegenerative (MGnD) microglia. Interleukin-17A (IL-17A) secreted by T helper 17 (Th17) cells and meningeal dgT cells has been recently proved to exacerbate disease pathogenesis in the central nervous system (CNS). IL-17 receptor A (IL-17RA) is highly expressed on microglia, and its expression was significantly reduced in MGnD-microglia associated with amyloid-b Ab plaques in a transgenic Alzheimer’s Disease (AD) mouse model as well as MGnD-like microglia in AD human brains. However, it is unknown how IL-17RA signaling regulates microglia in AD. We hypothesize that adaptive immunity modulates microglia phenotype via IL-17RA signaling to fight against AD pathogenesis. To address this, I used global knockout (IL-17RA-/-) and microglia-specific knockout (Cx3cr1creERT2-IL-17RAfl/fl) mouse models, immunohistochemistry (IHC), and bulk RNA sequencing. I found that global deletion of IL-17RA promoted microglia inflammation in physiological, acute inflammatory (Ab1-42 peptides/dead neurons/synaptosomes injection into cortex and hippocampus) and chronic inflammatory (AD) conditions, which may result from systemic inflammation from fungal/bacterial infection due to the loss of IL-17RA in the barrier. However, the Ab-plaque load and plaque density in the cortex was decreased and the microglia infiltration into single plaques was more in the APP/PS1:IL-17RA-/- mice. Thus, blocking IL-17RA might alleviate AD. On the contrary, deletion of IL-17RA on microglia before clinical onset (1.5 months of age) suppressed microglial inflammation but did not affect microglia phagocytosis, antigen presentation or other immune responses. In acute inflammatory and chronic inflammatory (AD) conditions, microglia in IL-17RA conditionally knockout mice did not show significant difference from the control. In conclusion, deleting IL-17RA globally can induce systemic inflammation, while microglia-specifical deletion of IL-17RA can reduce microglial inflammation but does not influence the other functions. This study has shown that blocking IL-17RA signaling in microglia can prevent microglia being inflammatory and dysfunctional, which is likely to ameliorate AD.