Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome.
Neutrophil-specific gain-of-function mutations in Nlrp3 promote development of cryopyrin-associated periodic syndrome.
复制标题
DOI：
10.1084/jem.20201466
复制
发表时间：
2021-10-04
期刊：
影响因子：
--
通讯作者：
Reber LL
中科院分区：
文献类型：
--
作者：
Stackowicz J;Gaudenzio N;Serhan N;Conde E;Godon O;Marichal T;Starkl P;Balbino B;Roers A;Bruhns P;Jönsson F;Moguelet P;Georgin-Lavialle S;Broderick L;Hoffman HM;Galli SJ;Reber LL
CAPS是一种由NLRP 3功能获得性突变引起的IL-1β介导的自身炎症性疾病。这项工作表明，皮肤浸润中性粒细胞是CAPS患者中IL-1β的重要来源。在小鼠中，仅限于中性粒细胞的Nlrp 3功能获得突变足以引发严重的CAPS。NLRP 3中的功能获得性突变负责一系列自身炎症性疾病，统称为“cryopyrin相关周期性综合征”（CAPS）。用IL-1靶向疗法治疗CAPS患者是有效的，证实了IL-1β的中心致病作用。然而，在CAPS中表现出炎性小体活性和持续IL-1β产生的特定骨髓细胞群仍然难以捉摸。以往的研究表明肥大细胞在这一过程中起着重要作用。在这里，我们报告说，在小鼠中，Nlrp 3的功能获得性突变仅限于中性粒细胞，在较小程度上是巨噬细胞/树突状细胞，但不是MC，足以触发严重的CAPS。此外，在临床确诊的CAPS患者中，我们发现皮肤浸润中性粒细胞是IL-1β的重要生物来源。总之，我们的数据表明，中性粒细胞，而不是MC，可以代表CAPS病理的主要细胞驱动程序。
CAPS is an IL-1β–mediated autoinflammatory disease due to gain-of-function mutations in NLRP3. This work shows that skin-infiltrating neutrophils represent a substantial source of IL-1β in CAPS patients. In mice, gain-of-function mutations in Nlrp3 restricted to neutrophils are sufficient to trigger severe CAPS. Gain-of-function mutations in NLRP3 are responsible for a spectrum of autoinflammatory diseases collectively referred to as “cryopyrin-associated periodic syndromes” (CAPS). Treatment of CAPS patients with IL-1–targeted therapies is effective, confirming a central pathogenic role for IL-1β. However, the specific myeloid cell population(s) exhibiting inflammasome activity and sustained IL-1β production in CAPS remains elusive. Previous reports suggested an important role for mast cells (MCs) in this process. Here, we report that, in mice, gain-of-function mutations in Nlrp3 restricted to neutrophils, and to a lesser extent macrophages/dendritic cells, but not MCs, are sufficient to trigger severe CAPS. Furthermore, in patients with clinically established CAPS, we show that skin-infiltrating neutrophils represent a substantial biological source of IL-1β. Together, our data indicate that neutrophils, rather than MCs, can represent the main cellular drivers of CAPS pathology.
登录
查看更多内容
影响因子：
158.5
作者：
Lachmann, Helen J.;Kone-Paut, Isabelle;Hawkins, Philip N.
通讯作者：
Hawkins, Philip N.
影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
15.9
作者：
Gaudenzio, Nicolas;Sibilano, Riccardo;Galli, Stephen J.
通讯作者：
Galli, Stephen J.
影响因子：
2.2
作者：
Abram CL;Roberge GL;Hu Y;Lowell CA
通讯作者：
Lowell CA
影响因子：
4.4
作者：
Kool, Mirjam;Petrilli, Virginie;Tschopp, Juerg
通讯作者：
Tschopp, Juerg