Dysregulation of macrophage lipid metabolism underlies intracellular bacterial neuroinvasion

Abstract

SummaryAcute infection of the central nervous system is one of the deadliest diseases, but the mechanisms by which intracellular bacteria infiltrate the brain remain poorly understood. Phagocytic cells are usually recognized as the battlefield on which war is waged against intracellular bacteria; however, little is known about how the intracellular bacteria take advantage of infected phagocytes to access the brain. In this study, we find that a novel CD36+Fabp4+Pparg+macrophage subpopulation (CD36+macrophage) participates in penetration of the brain by intracellular bacteria without disruption of the brain-blood barrier. Biomechanical analysis reveals that abundant protrusions and adhesion molecules on CD36+macrophages confer significant resistance to the mechanical stress of blood flow, thereby providing more opportunities for these macrophages to adhere to the vascular endothelial surface. Through metabolomics analysis, we find that macrophage lipid metabolism is dysregulated during bacterial neuroinvasion, and that β-hydroxybutyrate promotes the formation and survival of CD36+macrophages. Importantly, ketogenesis exacerbates symptoms during bacterial neuroinvasion, which could be alleviated by supplementing with physiological level of glucose. Taken together, our findings uncover a pathway by which intracellular bacteria hijack macrophages to invade the brain, suggesting that lipid metabolism might play a role in the prevention or resolution of bacterial neuroinvasion.Graphic Abstract