Background/Purpose: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with diverse clinical presentations, including neuropsychiatric symptoms (NPSLE). Despite being a major cause of morbidity and mortality among SLE patients, mechanisms driving NPSLE remain poorly understood. Prior work implicates uncontrolled MyD88-dependent toll-like receptor (TLR) activation, increased interferon regulatory factor 5 (IRF5) activity and elevated type I interferon (IFN) levels in peripheral SLE and SLE-like disease. Immune complexes containing self-nucleic acids can aberrantly activate endosomal TLRs 7/8/9, which require signaling adaptor MyD88 to modulate downstream gene expression through transcription factor 1) IRF7 to upregulate IFN, which can subsequently act on the IFN-alpha/beta receptor (IFNAR) or 2) IRF5 to upregulate proinflammatory genes. These cascades result in an inflammatory state throughout the body that is characteristic of SLE. However, it has not yet been shown whether these same pathways are driving inflammation in the brain.

Methods: SLE-and NPSLE-prone CReCOM mice were used, where a conditional deletion of caspase8 in dendritic cells and tissue resident-macrophages leads to development of disease. Conditional deletion of signaling mediators MyD88, IRF5, and IFNAR was introduced into the CReCOM strain. At 3-4 months of age, behavioral phenotypes were assessed by the Rotarod test of coordination and the Morris Water Maze test of memory. At 8-10 months of age, spleens, kidneys, and cervical lymph nodes were collected to assess peripheral disease. Perfused brains were extracted following intravenous labelling for CD45 to exclude remaining circulating immune cells, dural meninges were removed, and cells were analyzed by flow cytometric methods to quantify immune cell populations in the brain.

Results: Conditional deletion of MyD88 and IRF5 ameliorated peripheral disease phenotypes including splenomegaly, lymphadenopathy, and glomerulonephritis, but NPSLE-associated phenotypes in the brain, including expansion of extravascular T and B cells, macrophages, and microglia persisted. In contrast, IFNAR deletion worsened peripheral disease, yet reversed several NPSLE-associated phenotypes. Notably, an important subpopulation of microglia associated with neurodegenerative disease called disease-associated microglia (DAM), characteristically expanded in NPSLE models, remained elevated with MyD88 deletion, but was reduced to near healthy levels with IRF5 and IFNAR deletion. Correspondingly, conditional deletion of IRF5 and IFNAR improved behavior from CReCOM levels, while deletion of MyD88 increased severity of behavioral deficits.

Conclusion: These discoveries suggest an uncoupling of mechanisms driving peripheral and neurological disease. Namely, neurophysiological phenotypes manifest independently from the TLR-dependent pathway that drives peripheral disease and appear to be heavily impacted by the activity of DAM via mechanisms yet unexplored.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/neurophysiological-phenotypes-are-uncoupled-from-toll-like-receptor-mediated-peripheral-disease-in-a-mouse-model-of-neuropsychiatric-symptoms-of-systemic-lupus-erythematosus/