Background/Purpose: Previous studies implicate dendritic cells (DCs) in the initiation and persistence of systemic lupus erythematosus (SLE), and although DCs from SLE patients exhibit elevated activation, the factors responsible remain largely unknown. Neuropsychiatric symptoms of SLE (NP-SLE), which affect roughly 40-70% of SLE patients, include headaches, cognitive dysfunction and psychiatric disorders, and may be among the earliest symptoms of SLE. Mice with an underlying defect in Fas (MRL/lpr) display cognitive and affective dysfunction characteristic of NP-SLE. We have shown that DC-specific loss of caspase 8, an enzyme in the Fas pathway classically linked to apoptosis initiation and necroptosis suppression, induces a SLE-like disease that originates from heightened DC activation. However, whether there exists a link between caspase 8 signaling, heightened DC activation and NP-SLE is a mystery. To this end, we examined the neurological consequences of DC-specific 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/floxmice. Neurological deficiency was assessed via 8 tests (exit circle, startle reflex, seeking behavior, beam balancing, round stick balancing, beam walk: 3 cm, beam walk: 2 cm, beam walk:1 cm) with each test providing 0, 0.5 or 1 points depending on the severity of the behavioral deficit and, when combined, provide a neurological severity score (NSS). Cellular infiltration into the brain was assessed using 10-color flow cytometric analysis.

Results: With age, Cre^CD11cCasp8^flox/flox mice develop an inflammatory disease reminiscent of both classic murine models of SLE and human SLE that is characterized by splenomegaly, lymphadenopathy, autoantibodies, elevated serum cytokines, glomerulonephritis, immune complex deposition in the kidney and proteinuria. Strikingly, Cre^CD11cCasp8^flox/floxmice develop neurological deficiencies, with a 4-fold higher NSS than WT mice. These observed behavioral consequences correlate with increased numbers of microglia, as well as cellular infiltration of not only DCs, but also macrophages, lymphocytes and neutrophils. The cellular infiltration is reminiscent 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 of the blood-brain barrier is the direct result of DC-specific caspase 8 deletion and chronic systemic inflammation.

Conclusion: Our previous studies showed that DC-specific loss of caspase 8 induced a SLE-like disease that originated from heightened DC activation. We now reveal that deletion of caspase 8 in DCs is sufficient to incite symptoms of NP-SLE that correspond with a breach in the blood-brain barrier and leukocyte infiltration. These data substantiate a novel DC-specific mechanism whereby caspase 8 controls DC activation to prevent not only end-organ failure and peripheral pathology associated with SLE-like disease, but also NP-SLE manifestations, thereby highlighting a potentially useful target for therapy.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/dendritic-cell-specific-loss-of-caspase-8-incites-symptoms-of-neuropsychiatric-systemic-lupus-erythematosus/