Abstract
Microglia contribute to antibody-dependent cell-mediated cytotoxicity (ADCC) in neuromyelitis optica spectrum disorders (NMOSD). This complement-independent process has been implicated in early neuroinflammation following aquaporin-4 immunoglobulin G autoantibodies (AQP4-IgG) binding to astrocytes. We investigated whether pioglitazone, a clinically approved peroxisome proliferator-activated receptor gamma (PPARγ) agonist, could be repurposed to reduce complement-independent neuroinflammation driven by activated microglia and ameliorate disease in mice receiving passive transfers of human AQP4-IgG. Pioglitazone treatment alleviated motor impairments and NMOSD-like pathologies, associating with reduced microglial activation and pro-inflammatory cytokine levels. Antagonizing PPARγ reversed the beneficial effects of pioglitazone, indicating that these effects were PPARγ-dependent. Microglial depletion attenuated AQP4-IgG-induced motor impairments and pathologies, supporting the detrimental role of microglial activation. Serum levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a microglial activation biomarker, were increased in both the mouse model and patients with NMOSD. Pioglitazone reduced sTREM2, which were correlated with attenuated AQP4-IgG-induced microglial activation, neuroinflammation, and pathologies in mice. Elevated sTREM2 levels were associated with cytokines and chemokines related to activated microglia in patients with NMOSD, suggesting the clinical benefits of pioglitazone. Our findings highlight the potential of repurposing PPAR-γ agonists for reducing microglia-mediated neuroinflammation in acute NMOSD attacks. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-025-02182-x.