The role of TNFAIP3/A20 in neurolupus

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder characterized by a myriad of clinical presentations, including neurologic and psychiatric manifestations. These neuropsychiatric symptoms, also referred to as NPSLE, contribute significantly to overall morbidity and mortality. However, little is known about the underlying pathogenic mechanisms. Observations in patients indicate that neuropsychiatric symptoms can precede the diagnosis of SLE and that they can appear in the absence of peripheral disease activity. This suggests that NPSLE can be caused by alternative mechanisms that are different from the autoantibody-mediated damage in other organs and tissues. Most of the research has been focused on evaluating how autoantibodies can lead to the development of NPSLE. Given the specific appearance of NPSLE, the objective for my project was to evaluate whether central nervous system (CNS)-intrinsic defects are responsible for the development of NPSLE. This CNS-primary hypothesis was evaluated using two mouse models, A20 heterozygous and A20 microglia-specific knockout mice. A20 is a crucial regulator of inflammation with extensively characterized effects on the NF-kB pathway. The gene, TNFAIP3, encoding A20, is an important susceptibility locus for systemic lupus erythematosus, but little is known about its contribution to neuropsychiatric lupus. The behavior of A20 heterozygous mice was evaluated at the age of 3 and 6 months, corresponding to the age of 20 and 30 years in humans, respectively. SLE is usually diagnosed in females between the age of 30-70 years. Heterozygosity for A20 is associated with cognitive impairment and the development of spontaneous neuroinflammation. The latter was shown to worsen with age. Furthermore, the presence of an environmental trigger, i.e. infection, aggravates behavioral impairments (cognition-related, anxiety-like and sensorimotor gating defects) and the development of spontaneous neuroinflammation in a female predominant way. NPSLE in humans is characterized by several clinical symptoms including psychosis, depression, cognitive dysfunction and anxiety- and mood disorders. Furthermore, the pathogenic mechanisms are incompletely understood, but neuroinflammation has been shown to play a crucial role. A20 heterozygous mice recapitulate several of these key features of human NPSLE, therefore representing an interesting mouse model that can be used for further research. Moreover, the above stated observations were made in the absence of increased white blood cell count and with intact blood brain barrier integrity. This suggests that the behavioral and neuroinflammatory observations were mainly caused by CNS intrinsic defects. In the CNS, A20 is mainly expressed in microglial cells, where it has an important function in controlling microglial reactivity. In the study of microglia-specific A20 knockout mice, the behavior of mice at the age of 3, 6 and 12 months was characterized and cognitive defects were found that become exacerbated with age. To characterize the underlying mechanisms responsible for the behavioral impairments, RNA-sequencing was performed on hippocampal samples from 12 months old mice. We observed an increased activation of immune-related pathways marked by a strong type I IFN response. Furthermore, a number of genes expressed in the choroid plexus were dysregulated. The choroid plexus is located in the ventricles of the CNS. This structure is responsible for the production of cerebrospinal fluid, synthesis of proteins that are essential for the transport of metabolites to the CNS and, lastly, it also forms a barrier protecting the CNS from the periphery. The genes that are downregulated in the choroid plexus can be largely subdivided into these three categories, indicating that the functionality of the choroid plexus might be affected. This work identifies A20 as a predisposing factor for neuropsychiatric lupus. Deregulation of its expression in the CNS is associated with the development of neuroinflammation and behavioral phenotypes that correspond to observations in NPSLE. My work indicates that CNS-primary mechanisms, caused by uncontrolled reactivity of microglia, are responsible for the onset of NPSLE. Type I IFN signature is an important hallmark for microglial reactivity, therefore, interference with this pathway represents an interesting therapeutic target for NPSLE..

Jaar van publicatie:2020

Toegankelijkheid:Closed