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Inhibition of IL-34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in a model of chronic neurodegeneration

Inhibition of IL-34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in a model of chronic neurodegeneration
Inhibition of IL-34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in a model of chronic neurodegeneration
The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer´s disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cell types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF-1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signalling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in the the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophage populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34. Overall, our results highlight the challenges of targeting the CSF1R/IL34 axis in the systemic and central compartments, important for framing any therapeutic effort to tackle microglia/macrophage numbers during brain disease.
1664-3224
Obst, Juliane
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Simon, Emilie
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Martin Estebane, Maria
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Pipi, Eleni
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Barkwill, Liana May
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Gonzalez-Rivera, Ivette
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Buchanan, Fergus
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Prescott, Alan
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Faust, Dorte
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Fox, Simon
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Brownlees, Janet
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Taylor, Debra
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Perry, V. Hugh
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Nuthall, Hugh
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Atkinson, Peter J.
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Karran, Eric
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Routledge, Carol
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Gomez-Nicola, Diego
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Obst, Juliane
0c499ee6-0290-4792-8c99-049e05332227
Simon, Emilie
22a3ee84-1834-4038-91cb-15d6163b1c56
Martin Estebane, Maria
51e238f8-2ae3-4914-8e84-71f09e6b4f58
Pipi, Eleni
3d4a3279-5001-4c32-a83a-7ba1f5980994
Barkwill, Liana May
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Gonzalez-Rivera, Ivette
e003c978-1c8a-459d-a582-39b218b63b68
Buchanan, Fergus
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Prescott, Alan
aa5b503b-8729-40a8-9d3b-2089139662c3
Faust, Dorte
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Fox, Simon
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Brownlees, Janet
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Taylor, Debra
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Perry, V. Hugh
ad54448b-ed02-4dc4-af07-84fcd344e8cc
Nuthall, Hugh
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Atkinson, Peter J.
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Karran, Eric
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Routledge, Carol
769349a8-1806-47fe-80ca-787f92474769
Gomez-Nicola, Diego
0680aa66-9dee-47cf-a8d3-e39c988f85b5

Obst, Juliane, Simon, Emilie, Martin Estebane, Maria, Pipi, Eleni, Barkwill, Liana May, Gonzalez-Rivera, Ivette, Buchanan, Fergus, Prescott, Alan, Faust, Dorte, Fox, Simon, Brownlees, Janet, Taylor, Debra, Perry, V. Hugh, Nuthall, Hugh, Atkinson, Peter J., Karran, Eric, Routledge, Carol and Gomez-Nicola, Diego (2020) Inhibition of IL-34 unveils tissue-selectivity and is sufficient to reduce microglial proliferation in a model of chronic neurodegeneration. Frontiers in Immunology. (doi:10.3389/fimmu.2020.579000). (In Press)

Record type: Article

Abstract

The proliferation and activation of microglia, the resident macrophages in the brain, is a hallmark of many neurodegenerative diseases such as Alzheimer´s disease (AD) and prion disease. Colony stimulating factor 1 receptor (CSF1R) is critically involved in regulating microglial proliferation, and CSF1R blocking strategies have been recently used to modulate microglia in neurodegenerative diseases. However, CSF1R is broadly expressed by many cell types and the impact of its inhibition on the innate immune system is still unclear. CSF1R can be activated by two independent ligands, CSF-1 and interleukin 34 (IL-34). Recently, it has been reported that microglia development and maintenance depend on IL-34 signalling. In this study, we evaluate the inhibition of IL-34 as a novel strategy to reduce microglial proliferation in the the ME7 model of prion disease. Selective inhibition of IL-34 showed no effects on peripheral macrophage populations in healthy mice, avoiding the side effects observed after CSF1R inhibition on the systemic compartment. However, we observed a reduction in microglial proliferation after IL-34 inhibition in prion-diseased mice, indicating that microglia could be more specifically targeted by reducing IL-34. Overall, our results highlight the challenges of targeting the CSF1R/IL34 axis in the systemic and central compartments, important for framing any therapeutic effort to tackle microglia/macrophage numbers during brain disease.

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Frontiers Manuscript - Accepted Manuscript
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Accepted/In Press date: 27 August 2020

Identifiers

Local EPrints ID: 443577
URI: http://eprints.soton.ac.uk/id/eprint/443577
ISSN: 1664-3224
PURE UUID: e8c277cc-507d-4c93-8d39-0f2e98205709
ORCID for Diego Gomez-Nicola: ORCID iD orcid.org/0000-0002-5316-2682

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Date deposited: 03 Sep 2020 01:47
Last modified: 18 Feb 2021 17:15

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Contributors

Author: Juliane Obst
Author: Emilie Simon
Author: Maria Martin Estebane
Author: Eleni Pipi
Author: Liana May Barkwill
Author: Ivette Gonzalez-Rivera
Author: Fergus Buchanan
Author: Alan Prescott
Author: Dorte Faust
Author: Simon Fox
Author: Janet Brownlees
Author: Debra Taylor
Author: V. Hugh Perry
Author: Hugh Nuthall
Author: Peter J. Atkinson
Author: Eric Karran
Author: Carol Routledge

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