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Front. Mol. Neurosci. | doi: 10.3389/fnmol.2018.00057

Lipoprotein Lipase is a feature of alternatively-activated microglia and may facilitate lipid uptake in the CNS during demyelination

 Kimberley D. Bruce1*,  Sachi Gorkhali1, Katherine Given2, Alison M. Coates3,  Kristen E. Boyle4, Wendy B. Macklin2 and Robert H. Eckel1
  • 1Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, United States
  • 2Department of Cell and Developmental Biology, University of Colorado Anschutz Medical Campus, United States
  • 3Sansom Institute for Health Research, University of South Australia, Australia
  • 4Department of Pediatrics, University of Colorado Anschutz Medical Campus, United States

Severe demyelinating disorders of the central nervous system (CNS) such as multiple sclerosis (MS), can be devastating for many young lives. To date, the factors resulting in poor remyelination and repair are not well understood, and reparative therapies that benefit MS patients have yet to be developed. We have previously shown that the activity and abundance of Lipoprotein Lipase (LPL)—the rate-limiting enzyme in the hydrolysis of triglyceride-rich lipoproteins—is increased in Schwann cells and macrophages following nerve crush injury in the peripheral nervous system (PNS), suggesting that LPL may help scavenge myelin-derived lipids. We hypothesized that LPL may play a similar role in the CNS. To test this, mice were immunized with MOG35–55 peptide to induce experimental allergic encephalomyelitis (EAE). LPL activity was increased (p<0.05) in the brain at 30 days post-injection, coinciding with partial remission of clinical symptoms. Furthermore, LPL abundance and activity was up-regulated (p<0.05) at the transition between de- and re-myelination in lysolecithin-treated ex vivo cerebellar slices. Since microglia are the key immune effector cells of the CNS we determined the role of LPL in microglia. Lipid uptake was decreased (p<0.001) in LPL-deficient BV-2 microglial cells compared to WT. In addition, LPL-deficient cells showed dramatically reduced expression of anti-inflammatory markers, YM1 (-22 fold, p<0.001), and Arg1 (-265 fold, p<0.001) and increased expression of pro-inflammatory markers, such as iNOS compared to WT cells (+53 fold, p<0.001). This suggests that LPL is a feature of reparative microglia, further supported by the metabolic and inflammatory profile of LPL-deficient microglia. Taken together, our data strongly suggest that LPL expression is a novel feature of a microglial phenotype that supports remyelination and repair through the clearance of lipid debris. This mechanism may be exploited to develop future reparative therapies for MS and primary neurodegenerative disorders (Alzheimer’s disease and Parkinson’s disease).

Keywords: Lipoprotein Lipase, microgli, Multple Sclerosis, Myelination, Lipid Metabolism

Received: 22 Nov 2017; Accepted: 12 Feb 2018.

Edited by:

Vladimir Parpura, University of Alabama at Birmingham, United States

Reviewed by:

Björn Spittau, Albert-Ludwigs-University Freiburg, Germany
Xiaolai Zhou, Cornell University, United States  

Copyright: © 2018 Bruce, Gorkhali, Given, Coates, Boyle, Macklin and Eckel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Kimberley D. Bruce, University of Colorado Anschutz Medical Campus, Endocrinology, Metabolism and Diabetes, Aurora, 80045, Colorado, United States, kimberley.bruce@ucdenver.edu