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Peripheral macrophages drive CNS disease in the Ndufs4(−/−) model of Leigh syndrome

Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi‐system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in t...

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Autores principales: Hanaford, Allison R., Khanna, Asheema, Truong, Vivian, James, Katerina, Chen, Yihan, Mulholland, Michael, Kayser, Bernhard, Liao, Ryan W., Sedensky, Margaret, Morgan, Phil, Andrew Baertsch, Nathan, Kalia, Vandana, Sarkar, Surojit, Johnson, Simon C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10580015/
https://www.ncbi.nlm.nih.gov/pubmed/37552802
http://dx.doi.org/10.1111/bpa.13192
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author Hanaford, Allison R.
Khanna, Asheema
Truong, Vivian
James, Katerina
Chen, Yihan
Mulholland, Michael
Kayser, Bernhard
Liao, Ryan W.
Sedensky, Margaret
Morgan, Phil
Andrew Baertsch, Nathan
Kalia, Vandana
Sarkar, Surojit
Johnson, Simon C.
author_facet Hanaford, Allison R.
Khanna, Asheema
Truong, Vivian
James, Katerina
Chen, Yihan
Mulholland, Michael
Kayser, Bernhard
Liao, Ryan W.
Sedensky, Margaret
Morgan, Phil
Andrew Baertsch, Nathan
Kalia, Vandana
Sarkar, Surojit
Johnson, Simon C.
author_sort Hanaford, Allison R.
collection PubMed
description Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi‐system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high‐dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(−/−) mouse model of LS. While the dose–response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony‐stimulating Factor 1 receptor (CSF1R) macrophage super‐enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(−/−) animals, but onset of CNS lesions and sequalae in the Ndufs4(−/−), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(−/−) model.
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spelling pubmed-105800152023-10-18 Peripheral macrophages drive CNS disease in the Ndufs4(−/−) model of Leigh syndrome Hanaford, Allison R. Khanna, Asheema Truong, Vivian James, Katerina Chen, Yihan Mulholland, Michael Kayser, Bernhard Liao, Ryan W. Sedensky, Margaret Morgan, Phil Andrew Baertsch, Nathan Kalia, Vandana Sarkar, Surojit Johnson, Simon C. Brain Pathol Research Articles Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi‐system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high‐dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(−/−) mouse model of LS. While the dose–response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony‐stimulating Factor 1 receptor (CSF1R) macrophage super‐enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(−/−) animals, but onset of CNS lesions and sequalae in the Ndufs4(−/−), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(−/−) model. John Wiley and Sons Inc. 2023-08-08 /pmc/articles/PMC10580015/ /pubmed/37552802 http://dx.doi.org/10.1111/bpa.13192 Text en © 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Hanaford, Allison R.
Khanna, Asheema
Truong, Vivian
James, Katerina
Chen, Yihan
Mulholland, Michael
Kayser, Bernhard
Liao, Ryan W.
Sedensky, Margaret
Morgan, Phil
Andrew Baertsch, Nathan
Kalia, Vandana
Sarkar, Surojit
Johnson, Simon C.
Peripheral macrophages drive CNS disease in the Ndufs4(−/−) model of Leigh syndrome
title Peripheral macrophages drive CNS disease in the Ndufs4(−/−) model of Leigh syndrome
title_full Peripheral macrophages drive CNS disease in the Ndufs4(−/−) model of Leigh syndrome
title_fullStr Peripheral macrophages drive CNS disease in the Ndufs4(−/−) model of Leigh syndrome
title_full_unstemmed Peripheral macrophages drive CNS disease in the Ndufs4(−/−) model of Leigh syndrome
title_short Peripheral macrophages drive CNS disease in the Ndufs4(−/−) model of Leigh syndrome
title_sort peripheral macrophages drive cns disease in the ndufs4(−/−) model of leigh syndrome
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10580015/
https://www.ncbi.nlm.nih.gov/pubmed/37552802
http://dx.doi.org/10.1111/bpa.13192
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