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L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis
Macrophage adhesion and stretching have been shown to induce interleukin (IL)-1β production, but the mechanism of this mechanotransduction remains unclear. Here we specify the molecular link between mechanical tension on tissue-resident macrophages and activation of the NLRP3 inflammasome, which gov...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998782/ https://www.ncbi.nlm.nih.gov/pubmed/35294888 http://dx.doi.org/10.1016/j.celrep.2022.110507 |
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author | Joshi, Hemant Almgren-Bell, Alison Anaya, Edgar P. Todd, Elizabeth M. Van Dyken, Steven J. Seth, Anushree McIntire, Katherine M. Singamaneni, Srikanth Sutterwala, Fayyaz Morley, Sharon C. |
author_facet | Joshi, Hemant Almgren-Bell, Alison Anaya, Edgar P. Todd, Elizabeth M. Van Dyken, Steven J. Seth, Anushree McIntire, Katherine M. Singamaneni, Srikanth Sutterwala, Fayyaz Morley, Sharon C. |
author_sort | Joshi, Hemant |
collection | PubMed |
description | Macrophage adhesion and stretching have been shown to induce interleukin (IL)-1β production, but the mechanism of this mechanotransduction remains unclear. Here we specify the molecular link between mechanical tension on tissue-resident macrophages and activation of the NLRP3 inflammasome, which governs IL-1β production. NLRP3 activation enhances antimicrobial defense, but excessive NLRP3 activity causes inflammatory tissue damage in conditions such as pulmonary fibrosis and acute respiratory distress syndrome. We find that the actin-bundling protein L-plastin (LPL) significantly enhances NLRP3 assembly. Specifically, LPL enables apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) oligomerization during NLRP3 assembly by stabilizing ASC interactions with the kinase Pyk2, a component of cell-surface adhesive structures called podosomes. Upon treatment with exogenous NLRP3 activators, lung-resident alveolar macrophages (AMs) lacking LPL exhibit reduced caspase-1 activity, IL-1β cleavage, and gasdermin-D processing. LPL(−/−) mice display resistance to bleomycin-induced lung injury and fibrosis. These findings identify the LPL-Pyk2-ASC pathway as a target for modulation in NLRP3-mediated inflammatory conditions. |
format | Online Article Text |
id | pubmed-8998782 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
record_format | MEDLINE/PubMed |
spelling | pubmed-89987822022-04-11 L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis Joshi, Hemant Almgren-Bell, Alison Anaya, Edgar P. Todd, Elizabeth M. Van Dyken, Steven J. Seth, Anushree McIntire, Katherine M. Singamaneni, Srikanth Sutterwala, Fayyaz Morley, Sharon C. Cell Rep Article Macrophage adhesion and stretching have been shown to induce interleukin (IL)-1β production, but the mechanism of this mechanotransduction remains unclear. Here we specify the molecular link between mechanical tension on tissue-resident macrophages and activation of the NLRP3 inflammasome, which governs IL-1β production. NLRP3 activation enhances antimicrobial defense, but excessive NLRP3 activity causes inflammatory tissue damage in conditions such as pulmonary fibrosis and acute respiratory distress syndrome. We find that the actin-bundling protein L-plastin (LPL) significantly enhances NLRP3 assembly. Specifically, LPL enables apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC) oligomerization during NLRP3 assembly by stabilizing ASC interactions with the kinase Pyk2, a component of cell-surface adhesive structures called podosomes. Upon treatment with exogenous NLRP3 activators, lung-resident alveolar macrophages (AMs) lacking LPL exhibit reduced caspase-1 activity, IL-1β cleavage, and gasdermin-D processing. LPL(−/−) mice display resistance to bleomycin-induced lung injury and fibrosis. These findings identify the LPL-Pyk2-ASC pathway as a target for modulation in NLRP3-mediated inflammatory conditions. 2022-03-15 /pmc/articles/PMC8998782/ /pubmed/35294888 http://dx.doi.org/10.1016/j.celrep.2022.110507 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) ). |
spellingShingle | Article Joshi, Hemant Almgren-Bell, Alison Anaya, Edgar P. Todd, Elizabeth M. Van Dyken, Steven J. Seth, Anushree McIntire, Katherine M. Singamaneni, Srikanth Sutterwala, Fayyaz Morley, Sharon C. L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis |
title | L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis |
title_full | L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis |
title_fullStr | L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis |
title_full_unstemmed | L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis |
title_short | L-plastin enhances NLRP3 inflammasome assembly and bleomycin-induced lung fibrosis |
title_sort | l-plastin enhances nlrp3 inflammasome assembly and bleomycin-induced lung fibrosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8998782/ https://www.ncbi.nlm.nih.gov/pubmed/35294888 http://dx.doi.org/10.1016/j.celrep.2022.110507 |
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