Cargando…
Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish
The NOD-like receptors (NLRs) have been shown to be involved in infection and autoinflammatory disease. Previously, we identified a zebrafish NLR, nlrc3-like, required for macrophage homeostasis in the brain under physiological conditions. Here, we found that a deficiency of nlrc3-like leads to decr...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174460/ https://www.ncbi.nlm.nih.gov/pubmed/35693809 http://dx.doi.org/10.3389/fimmu.2022.893611 |
_version_ | 1784722238263525376 |
---|---|
author | Niu, Liangfei Luo, Geyang Liang, Rui Qiu, Chenli Yang, Jianwei Xie, Lingling Zhang, Kaile Tian, Yu Wang, Decheng Song, Shu Takiff, Howard E. Wong, Ka-Wing Fan, Xiaoyong Gao, Qian Yan, Bo |
author_facet | Niu, Liangfei Luo, Geyang Liang, Rui Qiu, Chenli Yang, Jianwei Xie, Lingling Zhang, Kaile Tian, Yu Wang, Decheng Song, Shu Takiff, Howard E. Wong, Ka-Wing Fan, Xiaoyong Gao, Qian Yan, Bo |
author_sort | Niu, Liangfei |
collection | PubMed |
description | The NOD-like receptors (NLRs) have been shown to be involved in infection and autoinflammatory disease. Previously, we identified a zebrafish NLR, nlrc3-like, required for macrophage homeostasis in the brain under physiological conditions. Here, we found that a deficiency of nlrc3-like leads to decreased bacterial burden at a very early stage of Mycobacterium marinum infection, along with increased production of pro-inflammatory cytokines, such as il-1β and tnf-α. Interestingly, myeloid-lineage specific overexpression of nlrc3-like achieved the opposite effects, suggesting that the impact of nlrc3-like on the host anti-mycobacterial response is mainly due to its expression in the innate immune system. Fluorescence-activated cell sorting (FACS) and subsequent gene expression analysis demonstrated that inflammasome activation-related genes were upregulated in the infected macrophages of nlrc3-like deficient embryos. By disrupting asc, encoding apoptosis-associated speck-like protein containing a CARD, a key component for inflammasome activation, the bacterial burden increased in asc and nlrc3-like double deficient embryos compared with nlrc3-like single deficient embryos, implying the involvement of inflammasome activation in infection control. We also found extensive neutrophil infiltration in the nlrc3-like deficient larvae during infection, which was associated with comparable bacterial burden but increased tissue damage and death at a later stage that could be alleviated by administration of dexamethasone. Our findings uncovered an important role of nlrc3-like in the negative regulation of macrophage inflammasome activation and neutrophil infiltration during mycobacterial infection. This highlights the importance of a balanced innate immune response during mycobacterial infection and provides a potential molecular basis to explain how anti-inflammatory drugs can improve treatment outcomes in TB patients whose infection is accompanied by a hyperinflammatory response. |
format | Online Article Text |
id | pubmed-9174460 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91744602022-06-09 Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish Niu, Liangfei Luo, Geyang Liang, Rui Qiu, Chenli Yang, Jianwei Xie, Lingling Zhang, Kaile Tian, Yu Wang, Decheng Song, Shu Takiff, Howard E. Wong, Ka-Wing Fan, Xiaoyong Gao, Qian Yan, Bo Front Immunol Immunology The NOD-like receptors (NLRs) have been shown to be involved in infection and autoinflammatory disease. Previously, we identified a zebrafish NLR, nlrc3-like, required for macrophage homeostasis in the brain under physiological conditions. Here, we found that a deficiency of nlrc3-like leads to decreased bacterial burden at a very early stage of Mycobacterium marinum infection, along with increased production of pro-inflammatory cytokines, such as il-1β and tnf-α. Interestingly, myeloid-lineage specific overexpression of nlrc3-like achieved the opposite effects, suggesting that the impact of nlrc3-like on the host anti-mycobacterial response is mainly due to its expression in the innate immune system. Fluorescence-activated cell sorting (FACS) and subsequent gene expression analysis demonstrated that inflammasome activation-related genes were upregulated in the infected macrophages of nlrc3-like deficient embryos. By disrupting asc, encoding apoptosis-associated speck-like protein containing a CARD, a key component for inflammasome activation, the bacterial burden increased in asc and nlrc3-like double deficient embryos compared with nlrc3-like single deficient embryos, implying the involvement of inflammasome activation in infection control. We also found extensive neutrophil infiltration in the nlrc3-like deficient larvae during infection, which was associated with comparable bacterial burden but increased tissue damage and death at a later stage that could be alleviated by administration of dexamethasone. Our findings uncovered an important role of nlrc3-like in the negative regulation of macrophage inflammasome activation and neutrophil infiltration during mycobacterial infection. This highlights the importance of a balanced innate immune response during mycobacterial infection and provides a potential molecular basis to explain how anti-inflammatory drugs can improve treatment outcomes in TB patients whose infection is accompanied by a hyperinflammatory response. Frontiers Media S.A. 2022-05-25 /pmc/articles/PMC9174460/ /pubmed/35693809 http://dx.doi.org/10.3389/fimmu.2022.893611 Text en Copyright © 2022 Niu, Luo, Liang, Qiu, Yang, Xie, Zhang, Tian, Wang, Song, Takiff, Wong, Fan, Gao and Yan 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 Niu, Liangfei Luo, Geyang Liang, Rui Qiu, Chenli Yang, Jianwei Xie, Lingling Zhang, Kaile Tian, Yu Wang, Decheng Song, Shu Takiff, Howard E. Wong, Ka-Wing Fan, Xiaoyong Gao, Qian Yan, Bo Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish |
title | Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish |
title_full | Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish |
title_fullStr | Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish |
title_full_unstemmed | Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish |
title_short | Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish |
title_sort | negative regulator nlrc3-like maintain the balanced innate immune response during mycobacterial infection in zebrafish |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174460/ https://www.ncbi.nlm.nih.gov/pubmed/35693809 http://dx.doi.org/10.3389/fimmu.2022.893611 |
work_keys_str_mv | AT niuliangfei negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT luogeyang negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT liangrui negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT qiuchenli negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT yangjianwei negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT xielingling negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT zhangkaile negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT tianyu negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT wangdecheng negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT songshu negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT takiffhowarde negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT wongkawing negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT fanxiaoyong negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT gaoqian negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish AT yanbo negativeregulatornlrc3likemaintainthebalancedinnateimmuneresponseduringmycobacterialinfectioninzebrafish |