NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex during septic immunosuppression.
NLRC3 expression in macrophage impairs glycolysis and host immune defense by modulating the NF-κB-NFAT5 complex during septic immunosuppression.
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DOI：
10.1016/j.ymthe.2022.08.023
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发表时间：
2023-01-04
影响因子：
12.4
通讯作者：
Shang, You
中科院分区：
文献类型：
--
作者：
Xu, Jiqian;Gao, Chenggang;He, Yajun;Fang, Xiangzhi;Sun, Deyi;Peng, Zhekang;Xiao, Hairong;Sun, Miaomiao;Zhang, Pei;Zhou, Ting;Yang, Xiaobo;Yu, Yuan;Li, Ruiting;Zou, Xiaojing;Shu, Huaqing;Qiu, Yang;Zhou, Xi;Yuan, Shiying;Yao, Shanglong;Shang, You
先天性免疫细胞功能和代谢受损是脓毒症免疫抑制的基础;然而，目前缺乏一种有希望的治疗方法来协调这种损伤。在这项研究中，高水平的NOD样受体家族CARD结构域包含3（NLRC 3）与糖酵解缺陷的单核细胞/巨噬细胞从败血症患者和小鼠，发展免疫抑制。骨髓特异性NLRC 3缺失改善巨噬细胞糖酵解和脓毒症诱导的免疫抑制在机制上，NLRC 3抑制核因子（NF）-κB p65与活化T细胞核因子5（NFAT 5）的结合，这进一步控制免疫抑制性巨噬细胞的糖酵解基因和促炎细胞因子的表达。这是通过减少NF-κB激活-由TNF-受体相关因子6（TRAF 6）或雷帕霉素的哺乳动物靶标（mTOR）共诱导-和通过诱导mTOR和p300的NLRC 3隔离来降低转录共激活因子p300活性来实现的。NLRC 3的遗传抑制破坏了NLRC 3-mTOR-p300复合物，并增强了NF-κB与NFAT 5启动子和p300的结合。此外，肺内递送携带巨噬细胞特异性NLRC 3缺失载体的重组腺相关病毒显著改善了脓毒症小鼠的防御，所述脓毒症小鼠在继发性肺内细菌攻击后产生免疫抑制。总的来说，这些发现表明NLRC 3介导先天免疫的关键方面，这些方面导致脓毒症期间的免疫功能低下状态，并确定潜在的治疗靶点。这项研究将髓系细胞中的NLRC 3表达与脓毒症诱导的免疫抑制机制联系起来，其中NLRC 3抑制NF-κ B与p300协同结合NFAT 5，从而调节巨噬细胞的代谢重编程，并表明靶向肺内巨噬细胞的NLRC 3基因治疗改善了肺部对继发性感染的防御。
Impairment of innate immune cell function and metabolism underlies immunosuppression in sepsis; however, a promising therapy to orchestrate this impairment is currently lacking. In this study, high levels of NOD-like receptor family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of monocytes/macrophages from septic patients and mice that developed immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear factor (NF)-κB p65 binding to nuclear factor of activated T cells 5 (NFAT5), which further controls the expression of glycolytic genes and proinflammatory cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-κB activation—co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian target of rapamycin (mTOR)—and decreasing transcriptional co-activator p300 activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-κB binding to the NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion vector significantly improved the defense of septic mice that developed immunosuppression upon secondary intratracheal bacterial challenge. Collectively, these findings indicate that NLRC3 mediates critical aspects of innate immunity that contribute to an immunocompromised state during sepsis and identify potential therapeutic targets. This study connects NLRC3 expression in myeloid cells to the mechanism of sepsis-induced immunosuppression, where NLRC3 inhibits the binding of NF-kB to NFAT5 in concert with p300, thereby regulating metabolic reprogramming of macrophages, and shows that NLRC3 gene therapy targeting intrapulmonary macrophage improves lung defenses against secondary infections.
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DOI：
10.1186/cc5055
发表时间：
2006
期刊：
Critical care (London, England)
影响因子：
--
作者：
Cavaillon JM;Adib-Conquy M
通讯作者：
Adib-Conquy M
DOI：
10.1038/nri3552
发表时间：
2013-12
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
9
作者：
Brakenridge, Scott C.;Efron, Philip A.;Moore, Frederick A.
通讯作者：
Moore, Frederick A.
NLRC3 负向调节 CD4 T 细胞并影响结核分枝杆菌感染期间的保护性免疫
影响因子：
6.7
作者：
Hu S;Du X;Huang Y;Fu Y;Yang Y;Zhan X;He W;Wen Q;Zhou X;Zhou C;Zhong XP;Yang J;Xiong W;Wang R;Gao Y;Ma L
通讯作者：
Ma L
DOI：
10.1084/jem.20180314
发表时间：
2018-11-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Buxadé M;Huerga Encabo H;Riera-Borrull M;Quintana-Gallardo L;López-Cotarelo P;Tellechea M;Martínez-Martínez S;Redondo JM;Martín-Caballero J;Flores JM;Bosch E;Rodríguez-Fernández JL;Aramburu J;López-Rodríguez C
通讯作者：
López-Rodríguez C