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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...

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Autores principales: 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
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
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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.
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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
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