Microglia regulate myelin growth and integrity in the central nervous system

Niamh McNamara; David Munro; Nadine Bestard-Cuche; Akiko Uyeda; Jeroen F J Bogie; Alana Hoffmann; Rebecca  Holloway; Irene Molina-Gonzalez; Katie Askew; Stephen Mitchell; William Mungall; Michael Dodds; Carsten Dittmayer; Jon Moss; Jamie Rose; Stefan Szymkowiak; Lukas Amann; Barry W McColl; Marco Prinz; Tara Spires-Jones; Werner Stenzel; Karen Horsburgh; Jerome J A Hendriks; Clare Pridans; Rieko Muramatsu; Anna C Williams; Josef Priller; Véronique E Miron

doi:10.1038/s41586-022-05534-y

Microglia regulate myelin growth and integrity in the central nervous system

Niamh McNamara, David Munro, Nadine Bestard-Cuche, Akiko Uyeda, Jeroen F J Bogie, Alana Hoffmann, Rebecca Holloway, Irene Molina-Gonzalez, Katie Askew, Stephen Mitchell, William Mungall, Michael Dodds, Carsten Dittmayer, Jon Moss, Jamie Rose, Stefan Szymkowiak, Lukas Amann, Barry W McColl, Marco Prinz, Tara Spires-JonesWerner Stenzel, Karen Horsburgh, Jerome J A Hendriks, Clare Pridans, Rieko Muramatsu, Anna C Williams, Josef Priller, Véronique E Miron^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.

Original language	English
Pages (from-to)	120-129
Journal	Nature
Volume	613
Early online date	14 Dec 2022
DOIs	https://doi.org/10.1038/s41586-022-05534-y
Publication status	Published - 5 Jan 2023

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McNamara, N., Munro, D., Bestard-Cuche, N., Uyeda, A., Bogie, J. F. J., Hoffmann, A., Holloway, R., Molina-Gonzalez, I., Askew, K., Mitchell, S., Mungall, W., Dodds, M., Dittmayer, C., Moss, J., Rose, J., Szymkowiak, S., Amann, L., McColl, B. W., Prinz, M., ... Miron, V. E. (2023). Microglia regulate myelin growth and integrity in the central nervous system. Nature, 613, 120-129. https://doi.org/10.1038/s41586-022-05534-y

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title = "Microglia regulate myelin growth and integrity in the central nervous system",

abstract = "Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.",

author = "Niamh McNamara and David Munro and Nadine Bestard-Cuche and Akiko Uyeda and Bogie, {Jeroen F J} and Alana Hoffmann and Rebecca Holloway and Irene Molina-Gonzalez and Katie Askew and Stephen Mitchell and William Mungall and Michael Dodds and Carsten Dittmayer and Jon Moss and Jamie Rose and Stefan Szymkowiak and Lukas Amann and McColl, {Barry W} and Marco Prinz and Tara Spires-Jones and Werner Stenzel and Karen Horsburgh and Hendriks, {Jerome J A} and Clare Pridans and Rieko Muramatsu and Williams, {Anna C} and Josef Priller and Miron, {V{\'e}ronique E}",

year = "2023",

month = jan,

day = "5",

doi = "10.1038/s41586-022-05534-y",

language = "English",

volume = "613",

pages = "120--129",

journal = "Nature",

issn = "0028-0836",

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McNamara, N, Munro, D, Bestard-Cuche, N, Uyeda, A, Bogie, JFJ, Hoffmann, A, Holloway, R, Molina-Gonzalez, I, Askew, K, Mitchell, S, Mungall, W, Dodds, M, Dittmayer, C, Moss, J, Rose, J, Szymkowiak, S, Amann, L, McColl, BW, Prinz, M, Spires-Jones, T, Stenzel, W, Horsburgh, K, Hendriks, JJA, Pridans, C, Muramatsu, R, Williams, AC , Priller, J & Miron, VE 2023, 'Microglia regulate myelin growth and integrity in the central nervous system', Nature, vol. 613, pp. 120-129. https://doi.org/10.1038/s41586-022-05534-y

TY - JOUR

T1 - Microglia regulate myelin growth and integrity in the central nervous system

AU - McNamara, Niamh

AU - Munro, David

AU - Bestard-Cuche, Nadine

AU - Uyeda, Akiko

AU - Bogie, Jeroen F J

AU - Hoffmann, Alana

AU - Holloway, Rebecca

AU - Molina-Gonzalez, Irene

AU - Askew, Katie

AU - Mitchell, Stephen

AU - Mungall, William

AU - Dodds, Michael

AU - Dittmayer, Carsten

AU - Moss, Jon

AU - Rose, Jamie

AU - Szymkowiak, Stefan

AU - Amann, Lukas

AU - McColl, Barry W

AU - Prinz, Marco

AU - Spires-Jones, Tara

AU - Stenzel, Werner

AU - Horsburgh, Karen

AU - Hendriks, Jerome J A

AU - Pridans, Clare

AU - Muramatsu, Rieko

AU - Williams, Anna C

AU - Priller, Josef

AU - Miron, Véronique E

PY - 2023/1/5

Y1 - 2023/1/5

N2 - Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.

AB - Myelin is required for the function of neuronal axons in the central nervous system, but the mechanisms that support myelin health are unclear. Although macrophages in the central nervous system have been implicated in myelin health1, it is unknown which macrophage populations are involved and which aspects they influence. Here we show that resident microglia are crucial for the maintenance of myelin health in adulthood in both mice and humans. We demonstrate that microglia are dispensable for developmental myelin ensheathment. However, they are required for subsequent regulation of myelin growth and associated cognitive function, and for preservation of myelin integrity by preventing its degeneration. We show that loss of myelin health due to the absence of microglia is associated with the appearance of a myelinating oligodendrocyte state with altered lipid metabolism. Moreover, this mechanism is regulated through disruption of the TGFβ1–TGFβR1 axis. Our findings highlight microglia as promising therapeutic targets for conditions in which myelin growth and integrity are dysregulated, such as in ageing and neurodegenerative disease2,3.

U2 - 10.1038/s41586-022-05534-y

DO - 10.1038/s41586-022-05534-y

M3 - Article

VL - 613

SP - 120

EP - 129

JO - Nature

JF - Nature

SN - 0028-0836

ER -

Microglia regulate myelin growth and integrity in the central nervous system

Abstract

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