Negative Regulator Nlrc3-like Maintain the Balanced Innate Immune Response During Mycobacterial Infection in Zebrafish.

Abstract

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.

• Authors: Liangfei Niu, Geyang Luo, Rui Liang, Chenli Qiu, Jianwei Yang, Lingling Xie, Kaile Zhang, Yu Tian, Decheng Wang, Shu Song, Howard E Takiff, Ka-Wing Wong, Xiaoyong Fan, Qian Gao, Bo Yan
• Journal: Frontiers in immunology (Front Immunol) Vol. 13 Pg. 893611 ( 2022) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 35693809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Niu, Luo, Liang, Qiu, Yang, Xie, Zhang, Tian, Wang, Song, Takiff, Wong, Fan, Gao and Yan.

Chemical References

• Inflammasomes
• Intercellular Signaling Peptides and Proteins
• Intracellular Signaling Peptides and Proteins
• NLR Proteins
• Zebrafish Proteins
• nlrc3l protein, zebrafish

Topics

• Animals
• Humans
• Immunity, Innate
• Inflammasomes (metabolism)
• Intercellular Signaling Peptides and Proteins (genetics)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Mycobacterium Infections, Nontuberculous
• NLR Proteins (metabolism)
• Zebrafish (metabolism)
• Zebrafish Proteins (metabolism)