title: Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology.
abstract: The impact of inflammation suppressor pathways on Alzheimer's disease (AD) evolution remains poorly understood. Human genetic evidence suggests involvement of the cardinal anti-inflammatory cytokine, interleukin-10 (IL10). We crossed the APP/PS1 mouse model of cerebral amyloidosis with a mouse deficient in Il10 (APP/PS1(+)Il10(-/-)). Quantitative in silico 3D modeling revealed activated Aβ phagocytic microglia in APP/PS1(+)Il10(-/-) mice that restricted cerebral amyloidosis. Genome-wide RNA sequencing of APP/PS1(+)Il10(-/-) brains showed selective modulation of innate immune genes that drive neuroinflammation. Il10 deficiency preserved synaptic integrity and mitigated cognitive disturbance in APP/PS1 mice. In vitro knockdown of microglial Il10-Stat3 signaling endorsed Aβ phagocytosis, while exogenous IL-10 had the converse effect. Il10 deficiency also partially overcame inhibition of microglial Aβ uptake by human Apolipoprotein E. Finally, the IL-10 signaling pathway was abnormally elevated in AD patient brains. Our results suggest that "rebalancing" innate immunity by blocking the IL-10 anti-inflammatory response may be therapeutically relevant for AD.
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90089-2821, USA.
authors.forename: Marie-Victoire
authors.initials: MV
authors.lastname: Guillot-Sestier
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90089-2821, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Doty
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90089-2821, USA.
authors.forename: David
authors.initials: D
authors.lastname: Gate
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90089-2821, USA.
authors.forename: Javier
authors.initials: J
authors.lastname: Rodriguez
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90089-2821, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Leung
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
authors.forename: Kavon
authors.initials: K
authors.lastname: Rezai-Zadeh
authors.affiliation: Zilkha Neurogenetic Institute, Department of Physiology & Biophysics, Keck School of Medicine of the University of Southern California, 1501 San Pablo Street, Los Angeles, CA 90089-2821, USA. Electronic address: ttown@usc.edu.
authors.forename: Terrence
authors.initials: T
authors.lastname: Town
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D005260:Female; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D016753:Interleukin-10 / Q000172:deficiency*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: C508609:IL10 protein, human; D016753:Interleukin-10