Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition.
Navarro Negredo P., You J., Hauptschein M., Schroer AB., Richard DJ., Abhiraman GC., Tsai AP., Sun ED., Notarangelo G., Ramirez-Matias J., Zhou OY., Buckley MT., Malacon KE., Xu L., Sucharov J., Ramirez Lopez E., Picton L., Wyss-Coray T., Saxton RA., Fernandes RA., Villeda SA., Garcia KC., Brunet A.
The immune system could play an important role in the age-related decline in brain function, yet specific immune-based strategies to enhance brain resilience in older individuals are lacking. Here, we combined engineered proteins and direct brain delivery to target immune cell populations within the old brain. We detected T cells with an exhaustion signature in the old brain and targeted them with a potent engineered checkpoint inhibitor (RIPR-PD1). This led to T cell expansion and strong pro-inflammatory responses in many brain cell types, notably microglia. To rescue age-related inflammatory imbalances in microglia, we used the anti-inflammatory cytokine interleukin (IL)-10. IL-10 boosted anti-inflammatory responses in old microglia, but it also triggered pro-inflammatory signaling. An engineered IL-10 variant that uncouples pro- and anti-inflammatory responses positively impacted the transcriptome of multiple cell types, enhanced neurogenesis, and improved cognition in aged mice. Our findings pave the way for immunotherapies for the aged brain.