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Perilipin-2 limits remyelination by preventing lipid droplet degradation

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Abstract

Foamy macrophages and microglia containing lipid droplets (LDs) are a pathological hallmark of demyelinating disorders affecting the central nervous system (CNS). We and others showed that excessive accumulation of intracellular lipids drives these phagocytes towards a more inflammatory phenotype, thereby limiting CNS repair. To date, however, the mechanisms underlying LD biogenesis and breakdown in lipid-engorged phagocytes in the CNS, as well as their impact on foamy phagocyte biology and lesion progression, remain poorly understood. Here, we provide evidence that LD-associated protein perilipin-2 (PLIN2) controls LD metabolism in myelin-containing phagocytes. We show that PLIN2 protects LDs from lipolysis-mediated degradation, thereby impairing intracellular processing of myelin-derived lipids in phagocytes. Accordingly, loss of Plin2 stimulates LD turnover in foamy phagocytes, driving them towards a less inflammatory phenotype. Importantly, Plin2-deficiency markedly improves remyelination in the ex vivo brain slice model and in the in vivo cuprizone-induced demyelination model. In summary, we identify PLIN2 as a novel therapeutic target to prevent the pathogenic accumulation of LDs in foamy phagocytes and to stimulate remyelination.

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Data availability

The datasets generated during and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Acknowledgements

We thank M.P. Tulleners and L. Timmermans for excellent technical assistance.

Funding

The work has been supported by the Flemish Fund for Scientific Research (FWO Vlaanderen; 1141920N, 1S15519N), and the special research fund UHasselt (BOF).

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Author notes

  1. Mansour Haidar, Jeroen F. J. Bogie and Jerome J. A. Hendriks have contributed equally to this article.

Authors and Affiliations

  1. Department of Immunology and Infection, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium

    Melanie Loix, Elien Wouters, Sam Vanherle, Hannelore Kemps, Mansour Haidar, Jeroen F. J. Bogie & Jerome J. A. Hendriks

  2. University MS Center Hasselt, Pelt, Belgium

    Melanie Loix, Elien Wouters, Sam Vanherle, Hannelore Kemps, Mansour Haidar, Jeroen F. J. Bogie & Jerome J. A. Hendriks

  3. Department of Oncology, Laboratory of Lipid Metabolism and Cancer, LKI–Louvain Cancer Institute, KU Leuven-University of Leuven, Leuven, Belgium

    Jonas Dehairs & Johannes V. Swinnen

  4. Department of Obstetrics and Gynaecology, School of Medicine, University of Colorado, Denver, USA

    James L. McManaman

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Contributions

ML, EW, MH, JFJB, and JJAH conceived experiments. ML, EW, SV, JD, and MH performed experiments. ML, EW, SV, JD and MH analysed data. ML, EW, SV, HK, MH, JFJB, and JJAH discussed results. JLM provided the animals. ML, EW, and JFJB wrote the manuscript. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Jerome J. A. Hendriks.

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The authors declare no competing interests exist.

Ethics statement

Animal experiments in this study were carried out in accordance with the recommendations of the institutional animal care and use committee of Hasselt University. The protocol was approved by the institutional animal care and use committee of Hasselt University (protocol numbers: 201840, 201920, 201953).

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Loix, M., Wouters, E., Vanherle, S. et al. Perilipin-2 limits remyelination by preventing lipid droplet degradation. Cell. Mol. Life Sci. 79, 515 (2022). https://doi.org/10.1007/s00018-022-04547-0

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