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Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury

BACKGROUND: Links between acute lung injury (ALI), infectious disease, and neurological outcomes have been frequently discussed over the past few years, especially due to the COVID-19 pandemic. Yet, much of the cross-communication between organs, particularly the lung and the brain, has been underst...

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Autores principales: Li, Herman, Le, Linh, Marrero, Mariah, David-Bercholz, Jennifer, Caceres, Ana I, Lim, Claire, Chiang, Wesley, Majewska, Ania K, Terrando, Niccolò, Gelbard, Harris A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614777/
https://www.ncbi.nlm.nih.gov/pubmed/37905036
http://dx.doi.org/10.1101/2023.10.16.562508
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author Li, Herman
Le, Linh
Marrero, Mariah
David-Bercholz, Jennifer
Caceres, Ana I
Lim, Claire
Chiang, Wesley
Majewska, Ania K
Terrando, Niccolò
Gelbard, Harris A
author_facet Li, Herman
Le, Linh
Marrero, Mariah
David-Bercholz, Jennifer
Caceres, Ana I
Lim, Claire
Chiang, Wesley
Majewska, Ania K
Terrando, Niccolò
Gelbard, Harris A
author_sort Li, Herman
collection PubMed
description BACKGROUND: Links between acute lung injury (ALI), infectious disease, and neurological outcomes have been frequently discussed over the past few years, especially due to the COVID-19 pandemic. Yet, much of the cross-communication between organs, particularly the lung and the brain, has been understudied. Here, we have focused on the role of neutrophils in driving changes to the brain endothelium with ensuing microglial activation and neuronal loss in a model of ALI. METHODS: We have applied a three-dose paradigm of 10μg/40μl intranasal lipopolysaccharide (LPS) to induce neutrophilia accompanied by proteinaceous exudate in bronchoalveolar lavage fluid (BALF) in adult C57BL/6 mice. Brain endothelial markers, microglial activation, and neuronal cytoarchitecture were evaluated 24hr after the last intranasal dose of LPS or saline. C57BL/6-Ly6g(tm2621(Cre-tdTomato)Arte (Catchup mice) were used to measure neutrophil and blood-brain barrier permeability following LPS exposure with intravital 2-photon imaging. RESULTS: Three doses of intranasal LPS induced robust neutrophilia accompanied by proteinaceous exudate in BALF. ALI triggered central nervous system pathology as highlighted by robust activation of the cerebrovascular endothelium (VCAM1, CD31), accumulation of plasma protein (fibrinogen), microglial activation (IBA1, CD68), and decreased expression of proteins associated with postsynaptic terminals (PSD-95) in the hippocampal stratum lacunosum moleculare, a relay station between the entorhinal cortex and CA1 of the hippocampus. 2-photon imaging of Catchup mice revealed neutrophil homing to the cerebral endothelium in the blood-brain barrier and neutrophil extravasation from cerebral vasculature 24hr after the last intranasal treatment. CONCLUSIONS: Overall, these data demonstrate ensuing brain pathology resulting from ALI, highlighting a key role for neutrophils in driving brain endothelial changes and subsequent neuroinflammation. This paradigm may have a considerable translational impact on understanding how infectious disease with ALI can lead to neurodegeneration, particularly in the elderly.
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spelling pubmed-106147772023-10-31 Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury Li, Herman Le, Linh Marrero, Mariah David-Bercholz, Jennifer Caceres, Ana I Lim, Claire Chiang, Wesley Majewska, Ania K Terrando, Niccolò Gelbard, Harris A bioRxiv Article BACKGROUND: Links between acute lung injury (ALI), infectious disease, and neurological outcomes have been frequently discussed over the past few years, especially due to the COVID-19 pandemic. Yet, much of the cross-communication between organs, particularly the lung and the brain, has been understudied. Here, we have focused on the role of neutrophils in driving changes to the brain endothelium with ensuing microglial activation and neuronal loss in a model of ALI. METHODS: We have applied a three-dose paradigm of 10μg/40μl intranasal lipopolysaccharide (LPS) to induce neutrophilia accompanied by proteinaceous exudate in bronchoalveolar lavage fluid (BALF) in adult C57BL/6 mice. Brain endothelial markers, microglial activation, and neuronal cytoarchitecture were evaluated 24hr after the last intranasal dose of LPS or saline. C57BL/6-Ly6g(tm2621(Cre-tdTomato)Arte (Catchup mice) were used to measure neutrophil and blood-brain barrier permeability following LPS exposure with intravital 2-photon imaging. RESULTS: Three doses of intranasal LPS induced robust neutrophilia accompanied by proteinaceous exudate in BALF. ALI triggered central nervous system pathology as highlighted by robust activation of the cerebrovascular endothelium (VCAM1, CD31), accumulation of plasma protein (fibrinogen), microglial activation (IBA1, CD68), and decreased expression of proteins associated with postsynaptic terminals (PSD-95) in the hippocampal stratum lacunosum moleculare, a relay station between the entorhinal cortex and CA1 of the hippocampus. 2-photon imaging of Catchup mice revealed neutrophil homing to the cerebral endothelium in the blood-brain barrier and neutrophil extravasation from cerebral vasculature 24hr after the last intranasal treatment. CONCLUSIONS: Overall, these data demonstrate ensuing brain pathology resulting from ALI, highlighting a key role for neutrophils in driving brain endothelial changes and subsequent neuroinflammation. This paradigm may have a considerable translational impact on understanding how infectious disease with ALI can lead to neurodegeneration, particularly in the elderly. Cold Spring Harbor Laboratory 2023-10-17 /pmc/articles/PMC10614777/ /pubmed/37905036 http://dx.doi.org/10.1101/2023.10.16.562508 Text en https://creativecommons.org/licenses/by-nd/4.0/This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, and only so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
Li, Herman
Le, Linh
Marrero, Mariah
David-Bercholz, Jennifer
Caceres, Ana I
Lim, Claire
Chiang, Wesley
Majewska, Ania K
Terrando, Niccolò
Gelbard, Harris A
Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury
title Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury
title_full Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury
title_fullStr Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury
title_full_unstemmed Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury
title_short Neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury
title_sort neutrophilia with damage to the blood-brain barrier and neurovascular unit following acute lung injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10614777/
https://www.ncbi.nlm.nih.gov/pubmed/37905036
http://dx.doi.org/10.1101/2023.10.16.562508
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