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Microgliopathies

A polarizing answer — microglia in Nasu-Hakola disease

Nature Immunology volume 24, pages 379–381 (2023)Cite this article

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A new study by Zhou et al. identifies a unique microglia state in Nasu-Hakola disease and new potential therapeutic targets.

Microgliopathies are newly appreciated diseases caused by primary dysfunction of microglia, the parenchymal tissue-resident macrophages of the brain and spinal cord. Nasu-Hakola disease (NHD), also called polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), is a Mendelian disorder caused by biallelic loss-of-function mutations in either TREM2 or its adapter DAP12 (also known as TYROBP)1. As the prototypical microgliopathy, NHD gained increased notoriety with the discovery of hypofunctional risk variants in TREM2 and DAP12 as critical gene network regulators in Alzheimer’s disease. In this issue of Nature Immunology, Zhou et al.2 use single-nuclear RNA sequencing (snRNA-seq) of specimens from individuals with rare NHD to understand better how DAP12 loss contributes to disease. This NHD ‘transcriptional map’ suggests vascular changes and a wound-healing response that are not replicated by a DAP12 mouse model. The unique brain macrophage signature of NHD is reminiscent of ‘M2-polarized’ macrophages, a description that has lost favor in the microglia field3, that points to interleukin-10 (IL-10) signaling as a critical mediator of disease. This work provides a new hypothesis for NHD pathogenesis and suggests therapeutic strategies.

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Fig. 1: Nasu-Hakola disease transcriptional map is notable for a unique microglia and macrophage state.

References

  1. Paloneva, J. et al. Am. J. Hum. Genet. 71, 656–662 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhou, Y. et al. Nat Immunol. https://doi.org/10.1038/s41590-022-01403-y (2023).

    Article  PubMed  Google Scholar 

  3. Ransohoff, R. M. Nat. Neurosci. 19, 987–991 (2016).

    Article  CAS  PubMed  Google Scholar 

  4. Satoh, J.-I., Kino, Y., Yanaizu, M. & Saito, Y. Intractable Rare Dis. Res. 7, 32–36 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Paolicelli, R. C. et al. Neuron 110, 3458–3483 (2022).

    Article  CAS  PubMed  Google Scholar 

  6. Paloneva, B. M. & J et al. Neurology 56, 1552–1558 (2001).

    Article  CAS  PubMed  Google Scholar 

  7. Jairaman, A. et al. Elife 11, e73021 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Konishi, H. & Kiyama, H. Neurochem. Int. 141, 104878 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Ennerfelt, H. et al. Cell 185, 4135–4152.e22 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang, S. et al. Cell 185, 4153–4169.e19 (2022).

    Article  CAS  PubMed  Google Scholar 

  11. Chakrabarty, P. et al. Neuron 85, 519–533 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sumpter, T. L. et al. J. Immunol. 186, 1970–1980 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. Turnbull, I. R. & Colonna, M. Nat. Rev. Immunol. 7, 155–161 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

M.L.B. would like to thank H. Song, G. Ming and other lab members for their continued support. Work is supported by NINDS R25 NS065745.

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  1. Department of Pediatrics, Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Mariko L. Bennett

  2. Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Mariko L. Bennett

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  1. Mariko L. Bennett
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Correspondence to Mariko L. Bennett.

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M.L.B. is a former consultant for Alector LLC.

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Bennett, M.L. A polarizing answer — microglia in Nasu-Hakola disease. Nat Immunol 24, 379–381 (2023). https://doi.org/10.1038/s41590-023-01440-1

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