Sustained NPSLE-like phenotype in the absence of systemic lupus-like disease in TLR7-deficient B6.Nba2 mice.

Objective: To investigate the role of Toll-like Receptor 7 (TLR7) in the development of neuropsychiatric lupus (NPSLE) in the B6.Nba2 murine model of SLE.

Methods: TLR7-deficient B6.Nba2 mice were evaluated for the development of NPSLE symptoms through behavioral testing with comparison groups of wild-type NPSLE-prone B6.Nba2 and B6 controls. Behavioral testing results were evaluated in the context of biomarker data, including flow cytometry for immune cell activation, and enzyme-linked immunosorbent assays (ELISA) to measure serum cytokine and autoantibody levels, including autoantibodies against double stranded DNA (dsDNA) and DWEYS peptide. Brain and spleen tissues waere harvested, and immuno histochemical studies and inflammatory gene activation obtained via qPCR were further analyzed to characterize immune system activation and SLE and NPSLE development in the mice.

Results: TLR7-deficient mice exhibited reduced signs of systemic SLE, including decreased splenomegaly, anti-dsDNA titers, and immune cell activation compared to wild-type mice. However, TLR7-deficient mice displayed a similar behavioral pattern to the NPSLE-prone B6.Nba2 mice, indicating NPSLE development was not influenced by TLR7. Knockout of TLR7 in B6.Nba2 mice also led to increased expression of TLR4 and TLR9, which suggests a possible role for these receptors in NPSLE pathogenesis.

Conclusion: While systemic lupus-like disease in the B6.Nba2 mouse model is dependent on TLR7, NPSLE development is not and may be influenced by TLR4 and TLR9 signaling. Thus, there may be separate mechanisms driving peripheral SLE compared to NPSLE with possible implications for pharmacologic management.