The inflammasome pyrin contributes to pertussis toxin-induced IL-1β synthesis, neutrophil intravascular crawling and autoimmune encephalomyelitis.
The inflammasome pyrin contributes to pertussis toxin-induced IL-1β synthesis, neutrophil intravascular crawling and autoimmune encephalomyelitis.
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炎性小呼林有助于百日咳毒素诱导的IL-1β合成，中性粒细胞血管内爬行和自身免疫性脑脊髓炎。
DOI：
10.1371/journal.ppat.1004150
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发表时间：
2014-05
期刊：
影响因子：
6.7
通讯作者：
Vallières L
中科院分区：
文献类型：
--
作者：
Dumas A;Amiable N;de Rivero Vaccari JP;Chae JJ;Keane RW;Lacroix S;Vallières L
微生物因子可加重炎症性疾病，如多发性硬化（MS）及其动物模型、实验性自身免疫性脑脊髓炎（EAE）。一个例子是百日咳毒素（PTX），一种细菌毒力因子，通常用作佐剂，以促进EAE，但其作用机制尚不清楚。我们已经报道了PTX触发IL-6介导的信号级联，其通过在其管腔表面上爬行来增加在脉管系统中巡逻的白细胞的数量。在本研究中，我们在缺乏TLR 4或炎性体成分的小鼠中研究了这种反应，并使用酶活性和非活性形式的PTX。我们的研究结果表明，PTX通过其ADP-核糖基转移酶活性诱导IL-6上游的两系列事件：1）髓样细胞中TLR 4信号传导的激活，导致pro-IL-1β合成;和2）将pro-IL-1β切割成其活性形式的芘依赖性炎性小体的形成。反过来，IL-1β刺激附近的基质细胞分泌IL-6，已知IL-6可诱导白细胞粘附所需的血管变化。在没有pyrin的情况下，PTX不会诱导中性粒细胞粘附到脑毛细血管，并且在具有致脑炎性T淋巴细胞的转基因小鼠中诱导EAE的有效性较低。这项研究确定了第一个激活pyrin的微生物分子，这是一种感染可能影响MS的机制，也是免疫疾病的潜在治疗靶点。微生物因子可加重炎症性疾病，如多发性硬化（MS）及其动物模型、实验性自身免疫性脑脊髓炎（EAE）。一个例子是百日咳毒素（PTX），它是用来促进EAE的一个模糊的机制。我们已经报道了PTX触发IL-6介导的信号级联，其通过在其管腔表面上爬行来增加在脉管系统中巡逻的白细胞的数量。我们在这里表明，PTX通过其ADP-核糖基转移酶活性诱导：1）髓样细胞中的TLR 4信号传导，导致pro-IL-1β合成;和2）将pro-IL-1β切割成其活性形式的芘依赖性炎性小体。然后，IL-1β刺激附近的基质细胞分泌IL-6。在没有pyrin的情况下，PTX不会诱导中性粒细胞粘附到脑毛细血管，并且在具有致脑炎性T淋巴细胞的小鼠中诱导EAE的有效性较低。这项研究确定了第一个激活pyrin的微生物分子，这是一种感染可能影响MS的机制，也是免疫疾病的潜在治疗靶点。
Microbial agents can aggravate inflammatory diseases, such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). An example is pertussis toxin (PTX), a bacterial virulence factor commonly used as an adjuvant to promote EAE, but whose mechanism of action is unclear. We have reported that PTX triggers an IL-6-mediated signaling cascade that increases the number of leukocytes that patrol the vasculature by crawling on its luminal surface. In the present study, we examined this response in mice lacking either TLR4 or inflammasome components and using enzymatically active and inactive forms of PTX. Our results indicate that PTX, through its ADP-ribosyltransferase activity, induces two series of events upstream of IL-6: 1) the activation of TLR4 signaling in myeloid cells, leading to pro-IL-1β synthesis; and 2) the formation of a pyrin-dependent inflammasome that cleaves pro-IL-1β into its active form. In turn, IL-1β stimulates nearby stromal cells to secrete IL-6, which is known to induce vascular changes required for leukocyte adhesion. Without pyrin, PTX does not induce neutrophil adhesion to cerebral capillaries and is less effective at inducing EAE in transgenic mice with encephalitogenic T lymphocytes. This study identifies the first microbial molecule that activates pyrin, a mechanism by which infections may influence MS and a potential therapeutic target for immune disorders. Microbial agents can aggravate inflammatory diseases, such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). An example is pertussis toxin (PTX), which is used to promote EAE by an obscure mechanism. We have reported that PTX triggers an IL-6-mediated signaling cascade that increases the number of leukocytes that patrol the vasculature by crawling on its luminal surface. We show here that PTX, through its ADP-ribosyltransferase activity, induces: 1) TLR4 signaling in myeloid cells, leading to pro-IL-1β synthesis; and 2) a pyrin-dependent inflammasome that cleaves pro-IL-1β into its active form. Then, IL-1β stimulates nearby stromal cells to secrete IL-6. Without pyrin, PTX does not induce neutrophil adhesion to cerebral capillaries and is less effective at inducing EAE in mice with encephalitogenic T lymphocytes. This study identifies the first microbial molecule that activates pyrin, a mechanism by which infections may influence MS and a potential therapeutic target for immune disorders.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
3.1
作者：
Carbonetti NH
通讯作者：
Carbonetti NH
DOI：
10.4049/jimmunol.1102272
发表时间：
2012-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Gavrilin MA;Abdelaziz DH;Mostafa M;Abdulrahman BA;Grandhi J;Akhter A;Abu Khweek A;Aubert DF;Valvano MA;Wewers MD;Amer AO
通讯作者：
Amer AO
影响因子：
3.5
作者：
Bernot, A;da Silva, C;Touitou, I
通讯作者：
Touitou, I
影响因子：
14.5
作者：
Buljevac, D;Flack, HZ;Hintzen, RQ
通讯作者：
Hintzen, RQ