Electronic Poster | Session 1
050 – Glycolysis drives macrophage migration and subsequent neuropathology in an animal model of multiple sclerosis
Deepak Kumar Kaushik (1) – Anindita Bhattacharya (1) – V. Wee Yong (1)
Hotchkiss Brain Institute, University of Calgary, Calgary, Canada (1)
Multiple sclerosis (MS) is a demyelinating condition of the central nervous system (CNS) in which the inflammatory leukocytes migrate across the post-capillary venules and meningeal barriers into the parenchyma. Migration of leukocytes from periphery to the CNS likely requires significant amounts of energy, especially as they accumulate in perivascular spaces (structures referred to as perivascular cuffs) before migrating across the blood brain barrier (BBB). Using the inflammatory mouse model of MS, experimental autoimmune encephalomyelitis (EAE), we sought to study the metabolic requirements and its relevance to the leukocytes that cross the BBB in MS. During peak clinical disease activity in EAE, we found that leukocytes within the perivascular cuffs expressed lactate dehydrogenase A (LDHA), an inducible glycolytic enzyme that converts pyruvate to lactate. We also found that these leukocytes were strongly immuno-reactive for MCT-4, an important transporter for lactate, which was in turn regulated by extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) on macrophage membranes. These results were mirrored by strong expression of MCT-4, LDHA and EMMPRIN in inflammatory perivascular cuffs in brains from patients with MS. Functional relevance of glycolysis in the infiltrating leukocytes was demonstrated by significant reduction of macrophage transmigration in culture following exposure to the selective LDHA inhibitor, FX11, and the MCT-4 inhibitor, the cinnamon derivative alpha-cyano 4-hydroxy-cinnamic acid (CHCA). Similarly, siRNA-mediated knockdown of LDHA and MCT-4 decreased pro-inflammatory properties of macrophages in culture. Importantly, perturbation of the glycolytic machinery with CHCA in EAE mice reduced clinical severity and histopathology as compared to the PBS-treated sham group. Our results show that glycolysis plays a crucial role in conferring the infiltrating leukocytes a pro-inflammatory phenotype and identify CHCA as a potential modulator of neuroinflammation in MS with therapeutic and dietary implications.