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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...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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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 |
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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 |
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