EMMPRIN-mediated metabolism of monocytes promotes disease progression in a mouse model of multiple sclerosis

Abstract

Monocytes and monocyte-derived macrophages are increasingly recognized as key contributors to the initiation and progression of inflammatory conditions, in part through metabolic reprogramming that drives pathogenic inflammatory phenotypes. However, the upstream mechanisms that coordinate these early metabolic transitions in multiple sclerosis (MS) remain largely undefined. We previously identified extracellular matrix metalloproteinase inducer (EMMPRIN/CD147), a chaperone of monocarboxylate transporter 4 (MCT4), as a regulator of lactate efflux and glycolysis-dependent activation in murine macrophages. Here, we investigate the role of EMMPRIN in circulating CCR2+ monocytes during experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. Using the newly generated CCR2CreERT2:EMMPRINfl/fl (CCR2:EMMP−/−) mice, we demonstrate that presymptomatic deletion of EMMPRIN prevents or significantly attenuates clinical disability and is associated with a marked reduction in CNS infiltration by CD45+ leukocytes, including macrophages and T cells. Single cell RNA-sequencing of blood monocytes during pre-onset EAE, combined with proteomic profiling of bone marrow–derived macrophages from CCR2:EMMP−/− mice, reveals coordinated metabolic reprogramming characterized by reduced glycolytic activity, enhanced mitochondrial electron transport, and increased fatty acid oxidation. These data identify EMMPRIN-mediated lactate export as a pivotal regulator of immunometabolic programming in monocytes and monocyte-derived macrophages and implicate this pathway as an upstream driver of early neuroinflammatory pathology in MS. Targeting this pathway during presymptomatic phases may therefore represent a promising strategy to prevent disease progression by modulating early inflammatory metabolism. Multiple sclerosis (MS) develops long before neurological symptoms, in part due to early inflammatory activation of circulating monocytes. Our study shows that metabolic reprogramming, mediated by EMMPRIN-dependent lactate export and enhanced glycolysis, primes monocytes for CNS infiltration and early immune activation. Deleting EMMPRIN in CCR2+ monocytes during the presymptomatic phase markedly reduced or prevented disease, highlighting a critical window for early intervention. The newly generated CCR2CreERT2:EMMPRINfl/fl mice provide a versatile tool to manipulate monocyte metabolism in vivo, enabling detailed studies of monocyte-driven inflammation and immunometabolic regulation. These findings will inform strategies for targeting metabolic pathways in other inflammatory and neurodegenerative disorders.