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Rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo

INTRODUCTION: Neutrophils are critical for host immune defense; yet, aberrant neutrophil tissue infiltration triggers tissue damage. Neutrophils are heterogeneous functionally, and adopt ‘normal’ or ‘pathogenic’ effector function responses. Understanding neutrophil heterogeneity could provide specif...

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Autores principales: Chowdhury, Chanchal Sur, Wareham, Elizabeth, Xu, Juying, Kumar, Sachin, Kofron, Matthew, Lakshmikanthan, Sribalaji, Chrzanowska, Magdalena, Filippi, Marie-Dominique
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733537/
https://www.ncbi.nlm.nih.gov/pubmed/36505495
http://dx.doi.org/10.3389/fimmu.2022.1061544
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author Chowdhury, Chanchal Sur
Wareham, Elizabeth
Xu, Juying
Kumar, Sachin
Kofron, Matthew
Lakshmikanthan, Sribalaji
Chrzanowska, Magdalena
Filippi, Marie-Dominique
author_facet Chowdhury, Chanchal Sur
Wareham, Elizabeth
Xu, Juying
Kumar, Sachin
Kofron, Matthew
Lakshmikanthan, Sribalaji
Chrzanowska, Magdalena
Filippi, Marie-Dominique
author_sort Chowdhury, Chanchal Sur
collection PubMed
description INTRODUCTION: Neutrophils are critical for host immune defense; yet, aberrant neutrophil tissue infiltration triggers tissue damage. Neutrophils are heterogeneous functionally, and adopt ‘normal’ or ‘pathogenic’ effector function responses. Understanding neutrophil heterogeneity could provide specificity in targeting inflammation. We previously identified a signaling pathway that suppresses neutrophilmediated inflammation via integrin-mediated Rap1b signaling pathway. METHODS: Here, we used Rap1-deficient neutrophils and proteomics to identify pathways that specifically control pathogenic neutrophil effector function. RESULTS: We show neutrophil acidity is normally prevented by Rap1b during normal immune response with loss of Rap1b resulting in increased neutrophil acidity via enhanced Ldha activity and abnormal neutrophil behavior. Acidity drives the formation of abnormal invasive-like protrusions in neutrophils, causing a shift to transcellular migration through endothelial cells. Acidity increases neutrophil extracellular matrix degradation activity and increases vascular leakage in vivo. Pathogenic inflammatory condition of ischemia/reperfusion injury is associated with increased neutrophil transcellular migration and vascular leakage. Reducing acidity with lactate dehydrogenase inhibition in vivo limits tissue infiltration of pathogenic neutrophils but less so of normal neutrophils, and reduces vascular leakage. DISCUSSION: Acidic milieu renders neutrophils more dependent on Ldha activity such that their effector functions are more readily inhibited by small molecule inhibitor of Ldha activity, which offers a therapeutic window for antilactate dehydrogenase treatment in specific targeting of pathogenic neutrophils in vivo.
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spelling pubmed-97335372022-12-10 Rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo Chowdhury, Chanchal Sur Wareham, Elizabeth Xu, Juying Kumar, Sachin Kofron, Matthew Lakshmikanthan, Sribalaji Chrzanowska, Magdalena Filippi, Marie-Dominique Front Immunol Immunology INTRODUCTION: Neutrophils are critical for host immune defense; yet, aberrant neutrophil tissue infiltration triggers tissue damage. Neutrophils are heterogeneous functionally, and adopt ‘normal’ or ‘pathogenic’ effector function responses. Understanding neutrophil heterogeneity could provide specificity in targeting inflammation. We previously identified a signaling pathway that suppresses neutrophilmediated inflammation via integrin-mediated Rap1b signaling pathway. METHODS: Here, we used Rap1-deficient neutrophils and proteomics to identify pathways that specifically control pathogenic neutrophil effector function. RESULTS: We show neutrophil acidity is normally prevented by Rap1b during normal immune response with loss of Rap1b resulting in increased neutrophil acidity via enhanced Ldha activity and abnormal neutrophil behavior. Acidity drives the formation of abnormal invasive-like protrusions in neutrophils, causing a shift to transcellular migration through endothelial cells. Acidity increases neutrophil extracellular matrix degradation activity and increases vascular leakage in vivo. Pathogenic inflammatory condition of ischemia/reperfusion injury is associated with increased neutrophil transcellular migration and vascular leakage. Reducing acidity with lactate dehydrogenase inhibition in vivo limits tissue infiltration of pathogenic neutrophils but less so of normal neutrophils, and reduces vascular leakage. DISCUSSION: Acidic milieu renders neutrophils more dependent on Ldha activity such that their effector functions are more readily inhibited by small molecule inhibitor of Ldha activity, which offers a therapeutic window for antilactate dehydrogenase treatment in specific targeting of pathogenic neutrophils in vivo. Frontiers Media S.A. 2022-11-25 /pmc/articles/PMC9733537/ /pubmed/36505495 http://dx.doi.org/10.3389/fimmu.2022.1061544 Text en Copyright © 2022 Chowdhury, Wareham, Xu, Kumar, Kofron, Lakshmikanthan, Chrzanowska and Filippi https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Chowdhury, Chanchal Sur
Wareham, Elizabeth
Xu, Juying
Kumar, Sachin
Kofron, Matthew
Lakshmikanthan, Sribalaji
Chrzanowska, Magdalena
Filippi, Marie-Dominique
Rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo
title Rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo
title_full Rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo
title_fullStr Rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo
title_full_unstemmed Rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo
title_short Rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo
title_sort rap1b-loss increases neutrophil lactate dehydrogenase activity to enhance neutrophil migration and acute inflammation in vivo
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9733537/
https://www.ncbi.nlm.nih.gov/pubmed/36505495
http://dx.doi.org/10.3389/fimmu.2022.1061544
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