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Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance
Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals. Since exposure to LPS often renders cells hyporesponsive to subsequent LPS exposures (“tolerant”), we tested the hypothesis that LPS...
Autores principales: | , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10409266/ https://www.ncbi.nlm.nih.gov/pubmed/37498977 http://dx.doi.org/10.1371/journal.ppat.1011556 |
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author | Cheng, Xiaofang Jiang, Wei Chen, Yeying Zou, Benkun Wang, Zhiyan Gan, Lu Xiao, Zeling Li, Changshun Yu, Cheng-Yun Lu, Yimeng Han, Zeyao Zeng, Jiashun Gu, Jie Chu, Tianqing Fu, Mingsheng Chu, Yiwei Zhang, Wenhong Tang, Jianguo Lu, Mingfang |
author_facet | Cheng, Xiaofang Jiang, Wei Chen, Yeying Zou, Benkun Wang, Zhiyan Gan, Lu Xiao, Zeling Li, Changshun Yu, Cheng-Yun Lu, Yimeng Han, Zeyao Zeng, Jiashun Gu, Jie Chu, Tianqing Fu, Mingsheng Chu, Yiwei Zhang, Wenhong Tang, Jianguo Lu, Mingfang |
author_sort | Cheng, Xiaofang |
collection | PubMed |
description | Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals. Since exposure to LPS often renders cells hyporesponsive to subsequent LPS exposures (“tolerant”), we tested the hypothesis that LPS produced in the intestine reaches the lungs and stimulates AMs, rendering them tolerant. We found that resting AMs were more likely to be tolerant in mice lacking acyloxyacyl hydrolase (AOAH), the host lipase that degrades and inactivates LPS; isolated Aoah(-/-) AMs were less responsive to LPS stimulation and less phagocytic than were Aoah(+/+) AMs. Upon innate stimulation in the airways, Aoah(-/-) mice had reduced epithelium- and macrophage-derived chemokine/cytokine production. Aoah(-/-) mice also developed greater and more prolonged loss of body weight and higher bacterial burdens after pulmonary challenge with Pseudomonas aeruginosa than did wildtype mice. We also found that bloodborne or intrarectally-administered LPS desensitized (“tolerized”) AMs while antimicrobial drug treatment that reduced intestinal commensal Gram-negative bacterial abundance largely restored the innate responsiveness of Aoah(-/-) AMs. Confirming the role of LPS stimulation, the absence of TLR4 prevented Aoah(-/-) AM tolerance. We conclude that commensal LPSs may stimulate and desensitize (tolerize) alveolar macrophages in a TLR4-dependent manner and compromise pulmonary immunity. By inactivating LPS in the intestine, AOAH promotes antibacterial host defenses in the lung. |
format | Online Article Text |
id | pubmed-10409266 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-104092662023-08-09 Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance Cheng, Xiaofang Jiang, Wei Chen, Yeying Zou, Benkun Wang, Zhiyan Gan, Lu Xiao, Zeling Li, Changshun Yu, Cheng-Yun Lu, Yimeng Han, Zeyao Zeng, Jiashun Gu, Jie Chu, Tianqing Fu, Mingsheng Chu, Yiwei Zhang, Wenhong Tang, Jianguo Lu, Mingfang PLoS Pathog Research Article Although alveolar macrophages (AMs) play important roles in preventing and eliminating pulmonary infections, little is known about their regulation in healthy animals. Since exposure to LPS often renders cells hyporesponsive to subsequent LPS exposures (“tolerant”), we tested the hypothesis that LPS produced in the intestine reaches the lungs and stimulates AMs, rendering them tolerant. We found that resting AMs were more likely to be tolerant in mice lacking acyloxyacyl hydrolase (AOAH), the host lipase that degrades and inactivates LPS; isolated Aoah(-/-) AMs were less responsive to LPS stimulation and less phagocytic than were Aoah(+/+) AMs. Upon innate stimulation in the airways, Aoah(-/-) mice had reduced epithelium- and macrophage-derived chemokine/cytokine production. Aoah(-/-) mice also developed greater and more prolonged loss of body weight and higher bacterial burdens after pulmonary challenge with Pseudomonas aeruginosa than did wildtype mice. We also found that bloodborne or intrarectally-administered LPS desensitized (“tolerized”) AMs while antimicrobial drug treatment that reduced intestinal commensal Gram-negative bacterial abundance largely restored the innate responsiveness of Aoah(-/-) AMs. Confirming the role of LPS stimulation, the absence of TLR4 prevented Aoah(-/-) AM tolerance. We conclude that commensal LPSs may stimulate and desensitize (tolerize) alveolar macrophages in a TLR4-dependent manner and compromise pulmonary immunity. By inactivating LPS in the intestine, AOAH promotes antibacterial host defenses in the lung. Public Library of Science 2023-07-27 /pmc/articles/PMC10409266/ /pubmed/37498977 http://dx.doi.org/10.1371/journal.ppat.1011556 Text en © 2023 Cheng et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Cheng, Xiaofang Jiang, Wei Chen, Yeying Zou, Benkun Wang, Zhiyan Gan, Lu Xiao, Zeling Li, Changshun Yu, Cheng-Yun Lu, Yimeng Han, Zeyao Zeng, Jiashun Gu, Jie Chu, Tianqing Fu, Mingsheng Chu, Yiwei Zhang, Wenhong Tang, Jianguo Lu, Mingfang Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance |
title | Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance |
title_full | Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance |
title_fullStr | Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance |
title_full_unstemmed | Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance |
title_short | Acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance |
title_sort | acyloxyacyl hydrolase promotes pulmonary defense by preventing alveolar macrophage tolerance |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10409266/ https://www.ncbi.nlm.nih.gov/pubmed/37498977 http://dx.doi.org/10.1371/journal.ppat.1011556 |
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