Itaconate confers tolerance to late NLRP3 inflammasome activation.
Itaconate confers tolerance to late NLRP3 inflammasome activation.
复制标题
衣康酸盐赋予对晚期NLRP 3炎性体活化的耐受性。
DOI：
10.1016/j.celrep.2021.108756
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发表时间：
2021-03-09
期刊：
影响因子：
8.8
通讯作者：
Artyomov MN
中科院分区：
文献类型：
--
作者：
Bambouskova M;Potuckova L;Paulenda T;Kerndl M;Mogilenko DA;Lizotte K;Swain A;Hayes S;Sheldon RD;Kim H;Kapadnis U;Ellis AE;Isaguirre C;Burdess S;Laha A;Amarasinghe GK;Chubukov V;Roddy TP;Diamond MS;Jones RG;Simons DM;Artyomov MN
衣康酸是一种独特的调节代谢物，在髓样细胞中Toll样受体（TLR）刺激后诱导。在这里，我们证明了主要的炎症耐受性和细胞死亡表型与衣康酸生产在活化的巨噬细胞。我们表明，内源性衣康酸是长时间脂多糖（LPS）引发后NLR家族pyrin domain containing 3（NLRP 3）炎性小体激活的信号2的关键调节因子，这建立了对晚期NLRP 3炎性小体激活的耐受性。我们发现衣康酸与诱导型一氧化氮合酶（iNOS）协同作用，并且各种TLR配体建立NLRP 3炎性小体耐受的能力取决于IRG 1和iNOS的共表达模式。从机制上讲，衣康酸积累后，长期的炎症刺激，防止完全半胱天冬酶-1激活和gasdermin D的处理，我们证明是后免疫修饰的内源性衣康酸。总而言之，我们的数据表明，炎症巨噬细胞中的代谢重新布线建立了对NLRP 3炎性体激活的耐受性，如果不受控制，则可导致细胞死亡和组织损伤。Bambouskova等人确定了Irg 1 −/−巨噬细胞的体外表型，并将衣康酸盐定义为对晚期NLRP 3炎性小体活化耐受的关键调节剂。
Itaconate is a unique regulatory metabolite that is induced upon Toll-like receptor (TLR) stimulation in myeloid cells. Here, we demonstrate major inflammatory tolerance and cell death phenotypes associated with itaconate production in activated macrophages. We show that endogenous itaconate is a key regulator of the signal 2 of NLR family pyrin domain containing 3 (NLRP3) inflammasome activation after long lipopolysaccharide (LPS) priming, which establishes tolerance to late NLRP3 inflammasome activation. We show that itaconate acts synergistically with inducible nitric oxide synthase (iNOS) and that the ability of various TLR ligands to establish NLRP3 inflammasome tolerance depends on the pattern of co-expression of IRG1 and iNOS. Mechanistically, itaconate accumulation upon prolonged inflammatory stimulation prevents full caspase-1 activation and processing of gasdermin D, which we demonstrate to be post-translationally modified by endogenous itaconate. Altogether, our data demonstrate that metabolic rewiring in inflammatory macrophages establishes tolerance to NLRP3 inflammasome activation that, if uncontrolled, can result in pyroptotic cell death and tissue damage. Bambouskova et al. determine the in vitro phenotype of Irg1−/− macrophages and define itaconate as a key regulator of tolerance to late NLRP3 inflammasome activation.
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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：
32.4
作者：
Iyer SS;He Q;Janczy JR;Elliott EI;Zhong Z;Olivier AK;Sadler JJ;Knepper-Adrian V;Han R;Qiao L;Eisenbarth SC;Nauseef WM;Cassel SL;Sutterwala FS
通讯作者：
Sutterwala FS
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
29
作者：
Hooftman, Alexander;Angiari, Stefano;O'Neill, Luke A. J.
通讯作者：
O'Neill, Luke A. J.
影响因子：
64.8
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan