Arginase 1+ microglia reduce Aβ plaque deposition during IL-1β-dependent neuroinflammation

35Citations
Citations of this article
77Readers
Mendeley users who have this article in their library.

Abstract

© 2015 Cherry et al. Background: Neuroinflammation has long been considered a driver of Alzheimer's disease progression. However, experiments developed to explore the interaction between neuroinflammation and Alzheimer's disease (AD) pathology showed a surprising reduction in amyloid beta (Aβ) plaque deposition. We sought to understand this unexpected outcome by examining microglia phenotypes during chronic neuroinflammation. Methods: Using an adeno-associated virus vector carrying hIL-1β cDNA, inflammation was induced in one hippocampus of 8-month-old amyloid precursor protein (APP)/PS1 mice for 4 weeks, while the other hemisphere received control injections. Bone marrow chimeras and staining analysis were used to identify the origins and types of immune cells present during sustained inflammation. Arginase 1 (Arg1) and inducible nitric oxide synthase (iNOS) immunoreactivity were used as markers of alternatively activated and classically activated cells, respectively, and changes in cellular uptake of Aβ by Arg1+ or iNOS+ microglia was demonstrated by confocal microscopy. To determine if an anti-inflammatory phenotype was present during neuroinflammation, RNA was extracted on flow-sorted microglia and rt-PCR was performed. Interleukin-4 injection was used to induce alternatively activated cells, whereas a minipump and intrahippocampal cannula was used to deliver an interleukin (IL)-4Raα antibody to block the induction of Arg1+ cells in the setting of sustained IL-1β expression. Results: We observed a robust upregulation of centrally derived Arg1+ microglia present only in the inflamed hemisphere. Furthermore, in the inflamed hemisphere, greater numbers of Arg1+ microglia contained Aβ when compared to iNOS+ microglia. RNA isolated from flow-sorted microglia from the inflamed hemisphere demonstrated elevation of mRNA species consistent with alternative activation as well as neuroprotective genes such as BDNF and IGF1. To explore if Arg1+ microglia mediated plaque reduction, we induced Arg1+ microglia with IL-4 and observed significant plaque clearance. Moreover, when we reduced Arg1+ microglia induction in the context of neuroinflammation using an anti-IL-4Raα antibody delivered via intrahippocampal cannula, we observed a clear correlation between numbers of Arg1+ microglia and plaque reduction. Conclusions: Together, these findings suggest that Arg1+ microglia are involved in Aβ plaque reduction during sustained, IL-1β-dependent neuroinflammation, opening up possible new avenues for immunomodulatory therapy of AD.

Cite

CITATION STYLE

APA

Cherry, J. D., Olschowka, J. A., & O’Banion, M. K. (2015). Arginase 1+ microglia reduce Aβ plaque deposition during IL-1β-dependent neuroinflammation. Journal of Neuroinflammation, 12(1). https://doi.org/10.1186/s12974-015-0411-8

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free