Background/Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects many end organs including the brain. Despite a prevalence of over 50% in SLE patients, neuropsychiatric symptoms of SLE (NPSLE) are among the least understood complications. Similar to SLE patients, the lupus-prone NZB/W strain develops NPSLE-like disease that manifests in mood-related disorders and learning impairment. Despite the paucity of data examining underlying mechanisms, accumulating evidence points to microglia, the resident innate immune cells in the brain, as a driver of disease. The cross-talk between infiltrating monocyte-derived macrophages and microglia plays a critical role in directing microglial responses. Evidence shows that IFNα exacerbates systemic disease and induces early lethality in the NZB/W strain in a T cell-mediated manner. In contrast, blocking the CD28/cytotoxic T lymphocyte antigen (CTLA)-4/B7 interaction (using CTLA4Ig) induces disease remission in NZB/W mice in combination with anti-CD40L antibodies and cyclophosphamide. Here, we elucidate the role of IFNα administration and costimulatory blockade on the infiltration of monocyte-derived macrophages and the corresponding microglial responses in NPSLE-like disease.

Methods: One cohort of female NZB/W mice (n= 5) was given a single intravenous injection of adenovirus-IFNα (AD-IFNα) at 12-14 wks of age and tissues were harvested at 18 wks. An additional cohort (n=5) was intraperitoneally injected 3 times/wk for 2 wks with CTLA4Ig/anti-CD40L (costimulatory blockade) at 18-20 wks prior to overt disease and tissues were harvested at 32 wks. Treated animals and age-matched NZB/W control mice were examined for proteinuria and splenic alterations as an indicator of systemic disease. Brain monocytic infiltration was evaluated via flow cytometry as a measure of blood-brain barrier breach. Neurocognitive testing and RNA-seq analysis of sorted microglia are pending.

Results: Mice immunized with AD-IFNα developed proteinuria and splenomegaly, corresponding to an increase in total splenocyte numbers, compared to age-matched control NZB/W mice. In contrast, costimulatory blockade prevented development of proteinuria and splenomegaly compared to their age-matched counterparts. Similar to SLE patients with NPSLE, AD-IFNα-immunized mice showed reduced brain volume compared to age-matched control mice. However, animals placed on the costimulatory blockade treatment showed a trend towards prevention of this brain volume loss compared to age-matched control mice. Furthermore, the increased macrophage infiltration into brains of 18-wk-old AD-IFNα-immunized mice mirrored that found in brains of 32-wk-old NZB/W control mice. Strikingly, costimulatory blockade prevented this infiltration at 32 wks.

Conclusion: These data indicate that IFNα accelerates brain macrophage infiltration, potentially impacting repair and regeneration responses of microglia within the injured brain, while costimulatory blockade prevents this insult. Future studies will examine neurocognitive decline and microglial-specific responses to these treatments.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/effect-of-ifn%ce%b1-and-costimulatory-blockade-on-brain-infiltration-in-a-model-of-neuropsychiatric-symptoms-of-systemic-lupus-erythematosus/