| First Author | Cherry JD | Year | 2015 |
| Journal | J Neuroinflammation | Volume | 12 |
| Pages | 203 | PubMed ID | 26538310 |
| Mgi Jnum | J:368236 | Mgi Id | MGI:6859228 |
| Doi | 10.1186/s12974-015-0411-8 | Citation | Cherry JD, et al. (2015) Arginase 1+ microglia reduce Abeta plaque deposition during IL-1beta-dependent neuroinflammation. J Neuroinflammation 12:203 |
| abstractText | 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 (Abeta) 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-1beta 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 Abeta 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)-4Ralpha antibody to block the induction of Arg1+ cells in the setting of sustained IL-1beta 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 Abeta 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-4Ralpha 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 Abeta plaque reduction during sustained, IL-1beta-dependent neuroinflammation, opening up possible new avenues for immunomodulatory therapy of AD. |
