Treatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species

Microglia activation and proliferation are hallmarks of many neurodegenerative disorders and may contribute to disease pathogenesis. Neurons actively regulate microglia survival and function, in part by secreting the microglia mitogen interleukin (IL)-34. Both IL-34 and colony stimulating factor (CS...

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Autores principales:	Katiria Soto-Diaz, Mario Vailati-Riboni, Allison Y. Louie, Daniel B. McKim, H. Rex Gaskins, Rodney W. Johnson, Andrew J. Steelman
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	microglia Csf1r GW2580 reactive oxygen species in vivo in vitro Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/185334dc51354d5985830fbbc29456a3
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spelling	oai:doaj.org-article:185334dc51354d5985830fbbc29456a32021-12-01T08:22:40ZTreatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species1664-322410.3389/fimmu.2021.734349https://doaj.org/article/185334dc51354d5985830fbbc29456a32021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.734349/fullhttps://doaj.org/toc/1664-3224Microglia activation and proliferation are hallmarks of many neurodegenerative disorders and may contribute to disease pathogenesis. Neurons actively regulate microglia survival and function, in part by secreting the microglia mitogen interleukin (IL)-34. Both IL-34 and colony stimulating factor (CSF)-1 bind colony stimulating factor receptor (CSFR)1 expressed on microglia. Systemic treatment with central nervous system (CNS) penetrant, CSFR1 antagonists, results in microglia death in a dose dependent matter, while others, such as GW2580, suppress activation during disease states without altering viability. However, it is not known how treatment with non-penetrant CSF1R antagonists, such as GW2580, affect the normal physiology of microglia. To determine how GW2580 affects microglia function, C57BL/6J mice were orally gavaged with vehicle or GW2580 (80mg/kg/d) for 8 days. Body weights and burrowing behavior were measured throughout the experiment. The effects of GW2580 on circulating leukocyte populations, brain microglia morphology, and the transcriptome of magnetically isolated adult brain microglia were determined. Body weights, burrowing behavior, and circulating leukocytes were not affected by treatment. Analysis of Iba-1 stained brain microglia indicated that GW2580 treatment altered morphology, but not cell number. Analysis of RNA-sequencing data indicated that genes related to reactive oxygen species (ROS) regulation and survival were suppressed by treatment. Treatment of primary microglia cultures with GW2580 resulted in a dose-dependent reduction in viability only when the cells were concurrently treated with LPS, an inducer of ROS. Pre-treatment with the ROS inhibitor, YCG063, blocked treatment induced reductions in viability. Finally, GW2580 sensitized microglia to hydrogen peroxide induced cell death. Together, these data suggest that partial CSF1R antagonism may render microglia more susceptible to reactive oxygen and nitrogen species.Katiria Soto-DiazMario Vailati-RiboniAllison Y. LouieDaniel B. McKimDaniel B. McKimDaniel B. McKimH. Rex GaskinsH. Rex GaskinsH. Rex GaskinsH. Rex GaskinsH. Rex GaskinsH. Rex GaskinsRodney W. JohnsonRodney W. JohnsonRodney W. JohnsonAndrew J. SteelmanAndrew J. SteelmanAndrew J. SteelmanAndrew J. SteelmanFrontiers Media S.A.articlemicrogliaCsf1rGW2580reactive oxygen speciesin vivoin vitroImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	microglia Csf1r GW2580 reactive oxygen species in vivo in vitro Immunologic diseases. Allergy RC581-607
spellingShingle	microglia Csf1r GW2580 reactive oxygen species in vivo in vitro Immunologic diseases. Allergy RC581-607 Katiria Soto-Diaz Mario Vailati-Riboni Allison Y. Louie Daniel B. McKim Daniel B. McKim Daniel B. McKim H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins Rodney W. Johnson Rodney W. Johnson Rodney W. Johnson Andrew J. Steelman Andrew J. Steelman Andrew J. Steelman Andrew J. Steelman Treatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species
description	Microglia activation and proliferation are hallmarks of many neurodegenerative disorders and may contribute to disease pathogenesis. Neurons actively regulate microglia survival and function, in part by secreting the microglia mitogen interleukin (IL)-34. Both IL-34 and colony stimulating factor (CSF)-1 bind colony stimulating factor receptor (CSFR)1 expressed on microglia. Systemic treatment with central nervous system (CNS) penetrant, CSFR1 antagonists, results in microglia death in a dose dependent matter, while others, such as GW2580, suppress activation during disease states without altering viability. However, it is not known how treatment with non-penetrant CSF1R antagonists, such as GW2580, affect the normal physiology of microglia. To determine how GW2580 affects microglia function, C57BL/6J mice were orally gavaged with vehicle or GW2580 (80mg/kg/d) for 8 days. Body weights and burrowing behavior were measured throughout the experiment. The effects of GW2580 on circulating leukocyte populations, brain microglia morphology, and the transcriptome of magnetically isolated adult brain microglia were determined. Body weights, burrowing behavior, and circulating leukocytes were not affected by treatment. Analysis of Iba-1 stained brain microglia indicated that GW2580 treatment altered morphology, but not cell number. Analysis of RNA-sequencing data indicated that genes related to reactive oxygen species (ROS) regulation and survival were suppressed by treatment. Treatment of primary microglia cultures with GW2580 resulted in a dose-dependent reduction in viability only when the cells were concurrently treated with LPS, an inducer of ROS. Pre-treatment with the ROS inhibitor, YCG063, blocked treatment induced reductions in viability. Finally, GW2580 sensitized microglia to hydrogen peroxide induced cell death. Together, these data suggest that partial CSF1R antagonism may render microglia more susceptible to reactive oxygen and nitrogen species.
format	article
author	Katiria Soto-Diaz Mario Vailati-Riboni Allison Y. Louie Daniel B. McKim Daniel B. McKim Daniel B. McKim H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins Rodney W. Johnson Rodney W. Johnson Rodney W. Johnson Andrew J. Steelman Andrew J. Steelman Andrew J. Steelman Andrew J. Steelman
author_facet	Katiria Soto-Diaz Mario Vailati-Riboni Allison Y. Louie Daniel B. McKim Daniel B. McKim Daniel B. McKim H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins H. Rex Gaskins Rodney W. Johnson Rodney W. Johnson Rodney W. Johnson Andrew J. Steelman Andrew J. Steelman Andrew J. Steelman Andrew J. Steelman
author_sort	Katiria Soto-Diaz
title	Treatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species
title_short	Treatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species
title_full	Treatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species
title_fullStr	Treatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species
title_full_unstemmed	Treatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species
title_sort	treatment with the csf1r antagonist gw2580, sensitizes microglia to reactive oxygen species
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/185334dc51354d5985830fbbc29456a3
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Treatment With the CSF1R Antagonist GW2580, Sensitizes Microglia to Reactive Oxygen Species

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