Inflammatory, metabolic, and sex-dependent gene-regulatory dynamics of microglia and macrophages in neonatal hippocampus after hypoxia-ischemia
Elena Di Martino, Anoop T. Ambikan, Daniel Ramsköld, Takashi Umekawa, Sarantis Giatrellis, Davide Vacondio, Alejandro Lastra Romero, Marta Gómez-Galán, Rickard Sandberg, Ulrika Ådén, Volker M. Lauschke, Ujjwal Neogi, Klas Blomgren, Julianna Kele
Abstract
Neonatal hypoxia-ischemia (HI) is a major cause of perinatal death and long-term disabilities worldwide. Post-ischemic neuroinflammation plays a pivotal role in HI pathophysiology. In the present study, we investigated the temporal dynamics of microglia (CX3CR1 GFP/+ ) and infiltrating macrophages (CCR2 RFP/+ ) in the hippocampi of mice subjected to HI at postnatal day 9. Using inflammatory pathway and transcription factor (TF) analyses, we identified a distinct post-ischemic response in CCR2 RFP/+ cells characterized by differential gene expression in sensome, homeostatic, matrisome, lipid metabolic, and inflammatory molecular signatures. Three days after injury, transcriptomic signatures of CX3CR1 GFP/+ and CCR2 RFP/+ cells isolated from hippocampi showed a partial convergence. Interestingly, microglia-specific genes in CX3CR1 GFP/+ cells showed a sexual dimorphism, where expression returned to control levels in males but not in females during the experimental time frame. These results highlight the importance of further investigations on metabolic rewiring to pave the way for future interventions in asphyxiated neonates.