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.
Highlights
Tyro3, Axl and Mertk belong to a structurally and functionally closely-related TAM family of receptor tyrosine kinases
Our results showed that antibody deposition and autoreactive T cells accumulation occurred in triply knockout (TKO) brains; and the brain blood vessel permeability was dramatically increased in the mutants
Given that the mice lacking TAM receptors develop systemic autoimmunity spontaneously [1] and neuropsychiatric lupus (NPSLE) patients are frequently accompanied by increased levels of serum autoantibodies reacting with brain specific antigens [29], we examined whether antibody deposition occurred in TAM TKO brains by immunohistochemistry with anti-mouse IgG antibody
Summary
Axl and Mertk belong to a structurally and functionally closely-related TAM family of receptor tyrosine kinases. Both Gas and Protein S serve as ligands for this family of receptors. Tyro is expressed by microvessel endothelial and vascular smooth muscle cells, and functions as trophic factor to support cell proliferation, migration and survival. Loss of this receptor, impaired brain microvessel integrity, endothelial cell adhesion, eventually leading to brain-blood barrier (BBB) disrupt and leakage [11]. Axl and its ligand Gas expressed in vascular smooth muscle and endothelial cells were upregulated during vascular injury, likely to support cell migration and suppress apoptosis [14,15,16]
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