EMMPRIN confers metabolic advantage for monocytes and macrophages to promote disease in a model of multiple sclerosis

Abstract

AbstractMonocytes and monocyte-derived macrophages have important roles in the initiation and progression of multiple sclerosis (MS). These cells undergo metabolic reprogramming to generate immunophenotypes that promote leukocyte infiltration, axonal degeneration and demyelination, worsening MS pathology. The mechanisms that dictate metabolic programs in monocytes and macrophages in MS remain unclear. We previously reported that extracellular matrix metalloproteinase inducer (EMMPRIN, CD147), a glycoprotein that acts as a chaperone of monocarboxylate transporter 4 (MCT4), assisted with glycolysis-driven pro-inflammatory phenotype in macrophages in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Using newly-generated CCR2CreERT2:EMMPRINfl/fl(CCR2:EMMP) mice, we report that presymptomatic deletion of EMMPRIN in CCR2+ monocytes prevented or reduced clinical disability of EAE. This was correspondent with decreased infiltration of leukocytes into the CNS. Single cell RNA-seq of blood monocytes from EAE and proteomics analysis of macrophages from CCR2:EMMP−/−mice revealed significant alterations in metabolic programs, particularly reduced glycolysis and elevated mitochondrial electron transport and fatty acid oxidation, which were linked to their reduced pro-inflammatory traits. Our findings implicate EMMPRIN as a key regulator of metabolic pathways that exacerbate pro-inflammatory functions of monocytes in MS.