Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection.
Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection.
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DOI：
10.1084/jem.20180118
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发表时间：
2018-04-02
期刊：
影响因子：
--
通讯作者：
Diamond MS
中科院分区：
文献类型：
--
作者：
Nair S;Huynh JP;Lampropoulou V;Loginicheva E;Esaulova E;Gounder AP;Boon ACM;Schwarzkopf EA;Bradstreet TR;Edelson BT;Artyomov MN;Stallings CL;Diamond MS
Nair等人定义了Irg 1在最大限度地减少与Mtb感染相关的病理性免疫应答中的关键作用。使用Irg 1 −/−和Irg 1fl/fl条件小鼠，详细的免疫细胞分析和转录分析，他们的数据支持一个模型，其中骨髓细胞亚群中的Irg 1表达缓和炎症并控制Mtb感染期间中性粒细胞的招募和感染。免疫应答基因1（Irg 1）是一种线粒体酶，主要在髓系细胞中在炎症条件下产生衣康酸。细胞培养研究表明，衣康酸通过其对细胞因子和活性氧产生的抑制作用来调节炎症。为了评估Irg 1在体内的功能，我们用结核分枝杆菌（Mtb）攻击野生型（WT）和Irg 1 −/−小鼠，并监测疾病进展。Irg 1 −/−小鼠（而非WT小鼠）迅速死于结核分枝杆菌，死亡率与感染、炎症和病理学增加相关。感染LysM-Cre Irg 1fl/fl、Mrp 8-Cre Irg 1fl/fl和CD 11 c-Cre Irg 1fl/fl条件性敲除小鼠沿着中性粒细胞耗竭实验，揭示了Irg 1在LysM+骨髓细胞中预防嗜中性粒细胞介导的免疫病理学和疾病中的作用。RNA测序分析表明，Irg 1和其生产的衣康酸回火结核分枝杆菌诱导的炎症反应在骨髓细胞的转录水平。因此，Irg 1调节轴调节炎症以减少结核分枝杆菌诱导的肺部疾病。
Nair et al. define a key role for Irg1 in minimizing the pathological immune response associated with Mtb infection. Using Irg1−/− and Irg1fl/fl conditional mice, detailed immune cell analysis, and transcriptional profiling, their data supports a model where Irg1 expression in myeloid cell subsets tempers inflammation and controls the recruitment and infection of neutrophils during Mtb infection. Immune-Responsive Gene 1 (Irg1) is a mitochondrial enzyme that produces itaconate under inflammatory conditions, principally in cells of myeloid lineage. Cell culture studies suggest that itaconate regulates inflammation through its inhibitory effects on cytokine and reactive oxygen species production. To evaluate the functions of Irg1 in vivo, we challenged wild-type (WT) and Irg1−/− mice with Mycobacterium tuberculosis (Mtb) and monitored disease progression. Irg1−/−, but not WT, mice succumbed rapidly to Mtb, and mortality was associated with increased infection, inflammation, and pathology. Infection of LysM-Cre Irg1fl/fl, Mrp8-Cre Irg1fl/fl, and CD11c-Cre Irg1fl/fl conditional knockout mice along with neutrophil depletion experiments revealed a role for Irg1 in LysM+ myeloid cells in preventing neutrophil-mediated immunopathology and disease. RNA sequencing analyses suggest that Irg1 and its production of itaconate temper Mtb-induced inflammatory responses in myeloid cells at the transcriptional level. Thus, an Irg1 regulatory axis modulates inflammation to curtail Mtb-induced lung disease.
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Itaconate连接琥珀酸脱氢酶与巨噬细胞代谢重塑和调节炎症的联系。
影响因子：
29
作者：
Lampropoulou V;Sergushichev A;Bambouskova M;Nair S;Vincent EE;Loginicheva E;Cervantes-Barragan L;Ma X;Huang SC;Griss T;Weinheimer CJ;Khader S;Randolph GJ;Pearce EJ;Jones RG;Diwan A;Diamond MS;Artyomov MN
通讯作者：
Artyomov MN
影响因子：
82.9
作者：
Muñoz-Elías, EJ;McKinney, JD
通讯作者：
McKinney, JD
影响因子：
64.8
作者：
Kimmey JM;Huynh JP;Weiss LA;Park S;Kambal A;Debnath J;Virgin HW;Stallings CL
通讯作者：
Stallings CL
影响因子：
3.6
作者：
Muñoz-Elías, Ernesto J.;Upton, Anna M.;McKinney, John D.
通讯作者：
McKinney, John D.
影响因子：
24.1
作者：
Jamal Uddin M;Joe Y;Kim SK;Oh Jeong S;Ryter SW;Pae HO;Chung HT
通讯作者：
Chung HT