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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 Article has an altmetric score of 5

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

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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 7

MCT-4 inhibition decreases glycolysis in BMDMs and dampens their proinflammatory activity.

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MCT-4 inhibition decreases glycolysis in BMDMs and dampens their proinfl...
(A) Live/dead assay as measured by calcein-AM (live cells; gray) and PI (dead cells; red) staining in macrophages in different conditions. (B) Lactate levels in supernatants of LPS-stimulated BMDMs in the presence or absence of 200 and 400 μM CHCA. (C) ECAR measurements of LPS-stimulated cells treated with 400 μM CHCA. Results are representative of 2 independent experiments run in quadruplicate. (D and E) Graphs depict (D) glycolysis and (E) glycolytic capacity in LPS and LPS plus CHCA conditions. Values were normalized to micrograms of protein. Means compared with 2-tailed Student’s t test. (F) IB of LPS-stimulated BMDMs shows a reduction in EMMPRIN, LDHA, and HIF-1α within 12 hours of CHCA treatment. (G) IB shows different glycosylated forms of EMMPRIN when lysates from CHCA-treated inflammatory BMDMs were “pulled” with MCT-4 antibody (co-IP: MCT-4). The MCT-4 band is shown for specificity of the co-IP antibody. (H) Graph represents the relative change in protein levels of MCT-4 and EMMPRIN (>100 kDa; high glycosylated or multimeric form) in co-IP conditions upon CHCA treatment in LPS-stimulated BMDMs. Graph represents 2 experiments, with protein pooled from triplicate treatments each. (I) Representative bright-field images of BMDMs transmigrated in LPS and LPS plus CHCA conditions in a Boyden chamber setup. Scale bar: 50 μm (original magnification, ×20 for insets). (J) Graph represents the average number of cells that migrated across the chamber in different conditions. Results are representative of 2 independent experiments run in quadruplicate. Graphs show the mean ± SD. Means were compared using 1-way ANOVA with Tukey’s post hoc test unless otherwise indicated. *P < 0.05 and **P < 0.01.

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