Enhanced glycolytic metabolism supports transmigration of brain-infiltrating macrophages in multiple sclerosis
Deepak Kumar Kaushik, … , Jong M. Rho, V. Wee Yong
Deepak Kumar Kaushik, … , Jong M. Rho, V. Wee Yong
Published May 21, 2019
Citation Information: J Clin Invest. 2019;129(8):3277-3292. https://doi.org/10.1172/JCI124012.
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Research Article Autoimmunity Metabolism

Enhanced glycolytic metabolism supports transmigration of brain-infiltrating macrophages in multiple sclerosis

Abstract

The migration of leukocytes into the CNS drives the neuropathology of multiple sclerosis (MS). It is likely that this penetration utilizes energy resources that remain to be defined. Using the experimental autoimmune encephalomyelitis (EAE) model of MS, we determined that macrophages within the perivascular cuff of postcapillary venules are highly glycolytic, as manifested by strong expression of lactate dehydrogenase A (LDHA), which converts pyruvate to lactate. These macrophages expressed prominent levels of monocarboxylate transporter-4 (MCT-4), which is specialized in the secretion of lactate from glycolytic cells. The functional relevance of glycolysis was confirmed by siRNA-mediated knockdown of LDHA and MCT-4, which decreased lactate secretion and macrophage transmigration. MCT-4 was in turn regulated by EMMPRIN (also known as CD147), as determined through coexpression and co-IP studies and siRNA-mediated EMMPRIN silencing. The functional relevance of MCT-4–EMMPRIN interaction was confirmed by lower macrophage transmigration in culture using the MCT-4 inhibitor α-cyano-4-hydroxy-cinnamic acid (CHCA), a cinnamon derivative. CHCA also reduced leukocyte infiltration and the clinical severity of EAE. Relevance to MS was corroborated by the strong expression of MCT-4, EMMPRIN, and LDHA in perivascular macrophages in MS brains. These results detail the metabolism of macrophages for transmigration from perivascular cuffs into the CNS parenchyma and identify CHCA and diet as potential modulators of neuroinflammation in MS.

Authors

Deepak Kumar Kaushik, Anindita Bhattacharya, Reza Mirzaei, Khalil S. Rawji, Younghee Ahn, Jong M. Rho, V. Wee Yong

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Figure 3

Leukocytes exiting the perivascular cuffs in D16 EAE express MCT-4, a key transporter of lactate in glycolytic cells.

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Leukocytes exiting the perivascular cuffs in D16 EAE express MCT-4, a ke...
(A) Low-magnification image of MCT-4 staining shows its expression restricted to the cells within and in the proximity of cuffs in D16 EAE cerebellum. Scale bar: 100 μm. (B) High-magnification micrographs of perivascular cuffs in cerebellum and spinal cord highlight the expression of MCT-4 within CD45+ cells; images are representative of 8 mice from 3 independent experiments. Scale bar: 50 μm. Insets show magnified cells (original magnification, ×120). 3D reconstructed images confirm the expression of MCT-4 within CD45+ leukocytes (scale bars: 20 μm). (C) Representative images of the spinal cord of a D16 EAE mouse depicting F4/80+ macrophages with prominent levels of MCT-4. Scale bar: 50 μm. Images are representative of 6 mice from 3 independent experiments. 3D reconstructed image confirmed the expression of F4/80+ macrophages (scale bar: 10 μm). (D) Graph shows the percentage of MCT-4+ leukocytes in perivascular cuffs in D16 EAE mice (n = 3 mice; 2 sections per mouse were analyzed).