Intracerebral Hemorrhage Induces Monocyte <scp>TNF</scp> Signaling in Patients That Is Suppressed by <scp>BAF</scp> 312

OBJECTIVE: Intracerebral hemorrhage (ICH) causes high morbidity and mortality, with neurotoxic inflammation driven by infiltrating monocytes. This study is an in-depth longitudinal examination of the immune response during the first week of ICH in the presence and absence of the immunomodulatory drug BAF312 (Siponimod). METHODS: We performed single-cell RNA sequencing on peripheral blood samples taken 1, 3, and 7 days post-ICH in patients treated with BAF312 (5 patients) or placebo (2 patients). The correlation of gene expression with time, drug treatment, measures of ICH severity, and clinical outcome was examined. Results were validated by comparison with previous studies and measurement of plasma cytokine concentration. RESULTS: A broad peripheral inflammatory response involving both lymphoid and myeloid cells peaked at day 3 post ICH. BAF312 markedly reduced peripheral blood T and B lymphocyte numbers by day 3. BAF312 also impacted the myeloid response, suppressing TNF signaling in classical and nonclassical monocytes. Multiple cytokine signaling pathways were decreased, though BAF312 did not impact plasma cytokine or chemokine concentrations. Surprisingly, increased monocyte TNF signaling was associated with better 90-day clinical outcome. INTERPRETATION: These findings demonstrate broad peripheral leukocyte activation after ICH and suggest that during ICH, BAF312 suppresses both lymphoid and myeloid responses. The positive association of monocyte TNF signaling with better outcome points to the positive role of monocytes during the subacute stage of ICH and supports a complex role of monocytes in this disease. Larger studies will determine the extent to which these findings apply beyond the small cohort examined here.