Inflammatory, metabolic, and sex-dependent gene-regulatory dynamics of microglia and macrophages in neonatal hippocampus after hypoxia-ischemia

Elena Di Martino; Anoop 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

doi:10.1016/j.isci.2024.109346

Inflammatory, metabolic, and sex-dependent gene-regulatory dynamics of microglia and macrophages in neonatal hippocampus after hypoxia-ischemia

iScience. 2024 Feb 28;27(4):109346. doi: 10.1016/j.isci.2024.109346. eCollection 2024 Apr 19.

Authors

Elena Di Martino^{1

2}, Anoop Ambikan³, Daniel Ramsköld⁴, Takashi Umekawa¹, Sarantis Giatrellis⁴, Davide Vacondio¹, Alejandro Lastra Romero¹, Marta Gómez Galán⁵, Rickard Sandberg⁴, Ulrika Ådén^{1

2

6}, Volker M Lauschke^{5

7

8}, Ujjwal Neogi³, Klas Blomgren^{1

9}, Julianna Kele^{5

10}

Affiliations

¹ Department of Women's and Children's Health, Karolinska Institutet, 17177 Stockholm, Sweden.
² Department of Biomedical and Clinical Sciences, Linköping University, 58183 Linköping, Sweden.
³ The Systems Virology Lab, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 14152 Huddinge, Sweden.
⁴ Department of Cell and Molecular Biology, Karolinska Institutet, 17165 Stockholm, Sweden.
⁵ Department of Physiology and Pharmacology, Karolinska Institutet, 17165 Stockholm, Sweden.
⁶ Neonatology, Karolinska University Hospital, Stockholm, Sweden.
⁷ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, 70376 Stuttgart, Germany.
⁸ University of Tuebingen, 72074 Tuebingen, Germany.
⁹ Pediatric Oncology, Karolinska University Hospital, Stockholm, Sweden.
¹⁰ Team Neurovascular Biology and Health, Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet, 14152 Huddinge, Sweden.

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.

Keywords: Immunology; Molecular biology; Neuroscience; Physiology; Transcriptomics.