Cargando…

Targeting ETosis by miR-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation

Asthma is phenotypically heterogeneous with several distinctive pathological mechanistic pathways. Previous studies indicate that neutrophilic asthma has a poor response to standard asthma treatments comprising inhaled corticosteroids. Therefore, it is important to identify critical factors that con...

Descripción completa

Detalles Bibliográficos
Autores principales: Kim, Ji Young, Stevens, Patrick, Karpurapu, Manjula, Lee, Hyunwook, Englert, Joshua A., Yan, Pearlly, Lee, Tae Jin, Pabla, Navjot, Pietrzak, Maciej, Park, Gye Young, Christman, John W., Chung, Sangwoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9360579/
https://www.ncbi.nlm.nih.gov/pubmed/35958610
http://dx.doi.org/10.3389/fimmu.2022.943554
_version_ 1784764352128090112
author Kim, Ji Young
Stevens, Patrick
Karpurapu, Manjula
Lee, Hyunwook
Englert, Joshua A.
Yan, Pearlly
Lee, Tae Jin
Pabla, Navjot
Pietrzak, Maciej
Park, Gye Young
Christman, John W.
Chung, Sangwoon
author_facet Kim, Ji Young
Stevens, Patrick
Karpurapu, Manjula
Lee, Hyunwook
Englert, Joshua A.
Yan, Pearlly
Lee, Tae Jin
Pabla, Navjot
Pietrzak, Maciej
Park, Gye Young
Christman, John W.
Chung, Sangwoon
author_sort Kim, Ji Young
collection PubMed
description Asthma is phenotypically heterogeneous with several distinctive pathological mechanistic pathways. Previous studies indicate that neutrophilic asthma has a poor response to standard asthma treatments comprising inhaled corticosteroids. Therefore, it is important to identify critical factors that contribute to increased numbers of neutrophils in asthma patients whose symptoms are poorly controlled by conventional therapy. Leukocytes release chromatin fibers, referred to as extracellular traps (ETs) consisting of double-stranded (ds) DNA, histones, and granule contents. Excessive components of ETs contribute to the pathophysiology of asthma; however, it is unclear how ETs drive asthma phenotypes and whether they could be a potential therapeutic target. We employed a mouse model of severe asthma that recapitulates the intricate immune responses of neutrophilic and eosinophilic airway inflammation identified in patients with severe asthma. We used both a pharmacologic approach using miR-155 inhibitor-laden exosomes and genetic approaches using miR-155 knockout mice. Our data show that ETs are present in the bronchoalveolar lavage fluid of patients with mild asthma subjected to experimental subsegmental bronchoprovocation to an allergen and a severe asthma mouse model, which resembles the complex immune responses identified in severe human asthma. Furthermore, we show that miR-155 contributes to the extracellular release of dsDNA, which exacerbates allergic lung inflammation, and the inhibition of miR-155 results in therapeutic benefit in severe asthma mice. Our findings show that targeting dsDNA release represents an attractive therapeutic target for mitigating neutrophilic asthma phenotype, which is clinically refractory to standard care.
format Online
Article
Text
id pubmed-9360579
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-93605792022-08-10 Targeting ETosis by miR-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation Kim, Ji Young Stevens, Patrick Karpurapu, Manjula Lee, Hyunwook Englert, Joshua A. Yan, Pearlly Lee, Tae Jin Pabla, Navjot Pietrzak, Maciej Park, Gye Young Christman, John W. Chung, Sangwoon Front Immunol Immunology Asthma is phenotypically heterogeneous with several distinctive pathological mechanistic pathways. Previous studies indicate that neutrophilic asthma has a poor response to standard asthma treatments comprising inhaled corticosteroids. Therefore, it is important to identify critical factors that contribute to increased numbers of neutrophils in asthma patients whose symptoms are poorly controlled by conventional therapy. Leukocytes release chromatin fibers, referred to as extracellular traps (ETs) consisting of double-stranded (ds) DNA, histones, and granule contents. Excessive components of ETs contribute to the pathophysiology of asthma; however, it is unclear how ETs drive asthma phenotypes and whether they could be a potential therapeutic target. We employed a mouse model of severe asthma that recapitulates the intricate immune responses of neutrophilic and eosinophilic airway inflammation identified in patients with severe asthma. We used both a pharmacologic approach using miR-155 inhibitor-laden exosomes and genetic approaches using miR-155 knockout mice. Our data show that ETs are present in the bronchoalveolar lavage fluid of patients with mild asthma subjected to experimental subsegmental bronchoprovocation to an allergen and a severe asthma mouse model, which resembles the complex immune responses identified in severe human asthma. Furthermore, we show that miR-155 contributes to the extracellular release of dsDNA, which exacerbates allergic lung inflammation, and the inhibition of miR-155 results in therapeutic benefit in severe asthma mice. Our findings show that targeting dsDNA release represents an attractive therapeutic target for mitigating neutrophilic asthma phenotype, which is clinically refractory to standard care. Frontiers Media S.A. 2022-07-26 /pmc/articles/PMC9360579/ /pubmed/35958610 http://dx.doi.org/10.3389/fimmu.2022.943554 Text en Copyright © 2022 Kim, Stevens, Karpurapu, Lee, Englert, Yan, Lee, Pabla, Pietrzak, Park, Christman and Chung 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
Kim, Ji Young
Stevens, Patrick
Karpurapu, Manjula
Lee, Hyunwook
Englert, Joshua A.
Yan, Pearlly
Lee, Tae Jin
Pabla, Navjot
Pietrzak, Maciej
Park, Gye Young
Christman, John W.
Chung, Sangwoon
Targeting ETosis by miR-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation
title Targeting ETosis by miR-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation
title_full Targeting ETosis by miR-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation
title_fullStr Targeting ETosis by miR-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation
title_full_unstemmed Targeting ETosis by miR-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation
title_short Targeting ETosis by miR-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation
title_sort targeting etosis by mir-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9360579/
https://www.ncbi.nlm.nih.gov/pubmed/35958610
http://dx.doi.org/10.3389/fimmu.2022.943554
work_keys_str_mv AT kimjiyoung targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT stevenspatrick targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT karpurapumanjula targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT leehyunwook targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT englertjoshuaa targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT yanpearlly targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT leetaejin targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT pablanavjot targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT pietrzakmaciej targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT parkgyeyoung targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT christmanjohnw targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation
AT chungsangwoon targetingetosisbymir155inhibitionmitigatesmixedgranulocyticasthmaticlunginflammation