Background/Purpose: Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE), including headaches, cognitive dysfunction and psychiatric disorders, appear in up to 75% of SLE patients and may be among the earliest signs of SLE. However, these non-specific symptoms make diagnosis/treatment of NP-SLE problematic. Microglia are the resident innate immune cells in the brain and accumulating evidence points to this population as a source of neurotoxic factors that drive pathology of multiple neurodegenerative diseases. However, relatively little is known about microglia in the context of NP-SLE. We have shown that CD11c-specific deletion of caspase 8, an enzyme in the Fas pathway classically linked to apoptosis initiation and necroptosis suppression, induces a SLE-like disease that originates in part from heightened dendritic cell activation. We find that caspase 8 deletion extends to microglia, as these cells can express CD11c. To this end, we examined the neurological consequences of microglial caspase 8 deletion.

Methods: Mice with caspase 8 flanked by loxP sites (Casp8^fl/fl, WT) were bred to mice expressing Cre under control of the CD11c gene promoter (Cre^CD11c) to generate Cre^CD11cCasp8^flox/flox mice. Mice were subjected to a battery of tasks at Northwestern University’s Behavioral Phenotyping Core. MRI was performed at Northwestern University’s Center for Translational Imaging. Cellular infiltration into the brain was assessed using 10-color flow cytometric analysis. RNAseq analysis was performed on sorted microglia.

Results: With age, Cre^CD11cCasp8^flox/flox mice develop an inflammatory disease reminiscent of both classic murine models of SLE and human SLE. Strikingly, Cre^CD11cCasp8^flox/flox mice also exhibit neurological deficits during the Morris water maze, pre-pulse inhibition, contextual fear conditioning and rotarod tasks that indicate hippocampal and cerebellar abnormalities. Increased vascular permeability in Cre^CD11cCasp8^flox/flox mice, as evidenced by Dynamic Intravascular Contrast Agent MRI, correlates with increased leukocyte infiltration seen by flow cytometric analysis. This infiltration resembles that of an acute model of traumatic brain injury, wherein physical damage to the brain promotes leakage of the blood-brain barrier. However, in our case, this breach is the direct result of CD11c-specific caspase-8 deletion and chronic systemic inflammation. GO analysis of differentially expressed genes reveals that transcriptional profiles of young caspase 8-deficient microglia are enriched for genes involved in amyloid precursor protein metabolic and catabolic processes and Notch receptor processing, while profiles of 10-12 month old caspase 8-deficient microglia are enriched for genes involved in inflammatory and immune responses.

Conclusion: These data substantiate a novel mechanism whereby caspase-8 controls microglial function at both early and late stages of SLE to prevent NP-SLE manifestations and highlight microglial defects as a potential mechanism underlying the pathogenesis of NP-SLE. We intend to leverage our transcriptional data to further interrogate how defective microglial function incites NP-SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/microglial-defects-contribute-to-neuropsychiatric-symptoms-of-systemic-lupus-erythematosus/