Systemic Autoimmunity in TAM Triple Knockout Mice Causes Inflammatory Brain Damage and Cell Death
Open Access
- 20 June 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (6), e64812
- https://doi.org/10.1371/journal.pone.0064812
Abstract
The Tyro3, Axl and Mertk (TAM) triply knockout (TKO) mice exhibit systemic autoimmune diseases, with characteristics of increased proinflammatory cytokine production, autoantibody deposition and autoreactive lymphocyte infiltration into a variety of tissues. Here we show that TKO mice produce high level of serum TNF-α and specific autoantibodies deposited onto brain blood vessels. The brain-blood barrier (BBB) in mutant brains exhibited increased permeability for Evans blue and fluorescent-dextran, suggesting a breakdown of the BBB in the mutant brains. Impaired BBB integrity facilitated autoreactive T cells infiltrating into all regions of the mutant brains. Brain autoimmune disorder caused accumulation of the ubiquitin-reactive aggregates in the mutant hippocampus, and early formation of autofluorescent lipofuscins in the neurons throughout the entire brains. Chronic neuroinflammation caused damage of the hippocampal mossy fibers and neuronal apoptotic death. This study shows that chronic systemic inflammation and autoimmune disorders in the TKO mice cause neuronal damage and death.Keywords
This publication has 61 references indexed in Scilit:
- TAMReceptor Knockout Mice Are Susceptible to Retinal Autoimmune InductionInvestigative Opthalmology & Visual Science, 2011
- C5a alters blood‐brain barrier integrity in experimental lupusThe FASEB Journal, 2010
- Purkinje cell loss in experimental autoimmune encephalomyelitisNeuroImage, 2009
- Lack of Protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesisJCI Insight, 2009
- Deletion of both ICAM-1 and C3 enhances severity of experimental autoimmune encephalomyelitis compared to C3-deficient miceNeuroscience Letters, 2008
- MerTK is required for apoptotic cell–induced T cell toleranceThe Journal of Experimental Medicine, 2008
- Localization and signaling of the receptor protein tyrosine kinase Tyro3 in cortical and hippocampal neuronsNeuroscience, 2007
- Stereological analysis of GluR2-immunoreactive hilar neurons in the pilocarpine model of temporal lobe epilepsy: Correlation of cell loss with mossy fiber sproutingExperimental Neurology, 2007
- Twist mediates suppression of inflammation by type I IFNs and AxlThe Journal of Experimental Medicine, 2006
- Cerebral leucocyte infiltration in lupus-prone MRL/MpJ-faslpr mice − roles of intercellular adhesion molecule-1 and P-selectinClinical and Experimental Immunology, 2006