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Lipoprotein Lipase Is a Feature of Alternatively-Activated Microglia and May Facilitate Lipid Uptake in the CNS During Demyelination.

ABSTRACT: 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 arginase 1 (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 (AD) and Parkinson's disease).

SUBMITTER: Bruce KD

PROVIDER: S-EPMC5862862 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Lipoprotein Lipase Is a Feature of Alternatively-Activated Microglia and May Facilitate Lipid Uptake in the CNS During Demyelination.

Bruce Kimberley D KD Gorkhali Sachi S Given Katherine K Coates Alison M AM Boyle Kristen E KE Macklin Wendy B WB Eckel Robert H RH

Frontiers in molecular neuroscience 20180315

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 an ...[more]

PMID: 29599706

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Project description:Introduction: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis, a serious neurological autoimmune disorder caused by autoantibodies with diverse clinical manifestations, may simultaneously onset with antimyelin oligodendrocyte glycoprotein (MOG) demyelination after recurrent central nervous system (CNS) demyelination. Case Report: We present a case of anti-NMDAR encephalitis combining with anti-MOG CNS demyelination following recurrent CNS demyelination. A 38-year-old man admitted to hospital developed epileptic seizures following recurrent episodes of cross-sensory disturbance and dizziness. Magnetic resonance imaging (MRI) showed a demyelinating lesion in the right brainstem initially. Despite a good response to methylprednisolone pulse therapy at the beginning, the patient still had relapses and progression after corticosteroid reduction or withdrawal. Then brain MRI discovered new serpentine lesions involving extensive cerebral cortex on his second relapse. Repeat autoantibodies test indicated cerebrospinal fluid (CSF) NMDAR antibodies coexisted with MOG-Abs simultaneously, suggesting the diagnosis of anti-NMDAR encephalitis with anti-MOG CNS demyelination. Results: After a definite diagnosis, the patient was treated with mycophenolate mofetil (MMF) and corticosteroid. He was discharged after his symptoms ameliorated. No neurological sequels remained, and there were no effects on his activities of daily living after 6 months of immunoregulatory therapy of MMF and corticosteroid. Conclusion: For individuals with recurrent CNS demyelination, especially combining with cortical encephalitis, repeated detection of autoantibodies against AE, and demyelination in CSF/serum can be helpful to enable a definite early diagnosis. For patients who suffer from anti-NMDAR encephalitis combining with anti-MOG CNS demyelination, second-line immunotherapy is recommended when first-line treatment such as steroids, intravenous immunoglobulin G (IVIG) and plasma exchange has been proven ineffective to prevent the relapse of disease.

Dataset Information

Lipoprotein Lipase Is a Feature of Alternatively-Activated Microglia and May Facilitate Lipid Uptake in the CNS During Demyelination.

Publications

Lipoprotein Lipase Is a Feature of Alternatively-Activated Microglia and May Facilitate Lipid Uptake in the CNS During Demyelination.

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