title: Arginase 1+ microglia reduce Aβ plaque deposition during IL-1β-dependent neuroinflammation.
abstract: 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)-4Rα 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-4Rα 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA. jdcherry@bu.edu.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Cherry
authors.affiliation: Department of Neurobiology & Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA. John_Olschowka@urmc.rochester.edu.
authors.forename: John A
authors.initials: JA
authors.lastname: Olschowka
authors.affiliation: Department of Neurobiology & Anatomy, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA. kerry_obanion@urmc.rochester.edu.|Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, NY, 14642, USA. kerry_obanion@urmc.rochester.edu.
authors.forename: M Kerry
authors.initials: MK
authors.lastname: O'Banion
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001119:Arginase / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D006624:Hippocampus / Q000378:metabolism; D007249:Inflammation / Q000473:pathology*; D007375:Interleukin-1 / Q000235:genetics; D053583:Interleukin-1beta / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit / Q000276:immunology; D008262:Macrophage Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000201:enzymology* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D058225:Plaque, Amyloid / Q000473:pathology*; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D018076:DNA, Complementary; D007375:Interleukin-1; D053583:Interleukin-1beta; D053662:Interleukin-4 Receptor alpha Subunit; D018696:Neuroprotective Agents; D053764:Presenilin-1; D052247:Nitric Oxide Synthase Type II; C544448:Arg1 protein, mouse; D001119:Arginase