Enhanced glycolytic metabolism supports transmigration of brain-infiltrating macrophages in multiple sclerosis
Journal of Clinical Investigation, ISSN: 1558-8238, Vol: 129, Issue: 8, Page: 3277-3292
2019
- 73Citations
- 81Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
Citation Benchmarking is provided by Scopus and SciVal and is different from the metrics context provided by PlumX Metrics.
Metrics Details
- Citations73
- Citation Indexes73
- 73
- CrossRef61
- Captures81
- Readers81
- 81
Article Description
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.
Bibliographic Details
American Society for Clinical Investigation
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