IL-1β-driven amyloid plaque clearance is associated with an expansion of transcriptionally reprogrammed microglia

Journal of Neuroinflammation

Jonathan J. Pinney¹  Michael R. Elliott¹  Juilee Thakar²  Laura Owlett³  John A. Olschowka³  M. Kerry O’Banion³  Fátima Rivera-Escalera³  Hoda Ahmed³ 

[1] David H. Smith Center for Vaccine Biology and Immunology, University of Rochester School of Medicine and Dentistry;Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry;Department of Neuroscience, University of Rochester School of Medicine and Dentistry;

关键词: Alzheimer’s disease;    Interleukin-1β;    Neuroinflammation;    Microglia;    Phagocytosis;    Amyloid plaque;   

DOI  :  10.1186/s12974-019-1645-7

来源: DOAJ

【 摘 要 】

Abstract Background Neuroinflammation is thought to contribute to the pathogenesis of Alzheimer’s disease (AD), yet numerous studies have demonstrated a beneficial role for neuroinflammation in amyloid plaque clearance. We have previously shown that sustained expression of IL-1β in the hippocampus of APP/PS1 mice decreases amyloid plaque burden independent of recruited CCR2+ myeloid cells, suggesting resident microglia as the main phagocytic effectors of IL-1β-induced plaque clearance. To date, however, the mechanisms of IL-1β-induced plaque clearance remain poorly understood. Methods To determine whether microglia are involved in IL-1β-induced plaque clearance, APP/PS1 mice induced to express mature human IL-1β in the hippocampus via adenoviral transduction were treated with the Aβ fluorescent probe methoxy-X04 (MX04) and microglial internalization of fibrillar Aβ (fAβ) was analyzed by flow cytometry and immunohistochemistry. To assess microglial proliferation, APP/PS1 mice transduced with IL-1β or control were injected intraperitoneally with BrdU and hippocampal tissue was analyzed by flow cytometry. RNAseq analysis was conducted on microglia FACS sorted from the hippocampus of control or IL-1β-treated APP/PS1 mice. These microglia were also sorted based on MX04 labeling (MX04+ and MX04− microglia). Results Resident microglia (CD45loCD11b+) constituted > 70% of the MX04+ cells in both Phe- and IL-1β-treated conditions, and < 15% of MX04+ cells were recruited myeloid cells (CD45hiCD11b+). However, IL-1β treatment did not augment the percentage of MX04+ microglia nor the quantity of fAβ internalized by individual microglia. Instead, IL-1β increased the total number of MX04+ microglia in the hippocampus due to IL-1β-induced proliferation. In addition, transcriptomic analyses revealed that IL-1β treatment was associated with large-scale changes in the expression of genes related to immune responses, proliferation, and cytokine signaling. Conclusions These studies show that IL-1β overexpression early in amyloid pathogenesis induces a change in the microglial gene expression profile and an expansion of microglial cells that facilitates Aβ plaque clearance.

【 授权许可】

Unknown