Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.
Negative regulation of the NLRP3 inflammasome by A20 protects against arthritis.
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DOI：
10.1038/nature13322
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发表时间：
2014-08-07
期刊：
影响因子：
64.8
通讯作者：
Lamkanfi, Mohamed
中科院分区：
文献类型：
--
作者：
Vande Walle, Lieselotte;Van Opdenbosch, Nina;Jacques, Peggy;Fossoul, Amelie;Verheugen, Eveline;Vogel, Peter;Beyaert, Rudi;Elewaut, Dirk;Kanneganti, Thirumala-Devi;van Loo, Geert;Lamkanfi, Mohamed
风湿性关节炎（RA）是一种慢性自身炎症性疾病，影响世界人口的1-2%，其特征在于广泛的关节炎症。IL-1是风湿性疾病中软骨破坏的重要介质，但我们对类风湿性关节炎中导致IL-1β产生的上游机制的理解受到缺乏合适的RA小鼠模型的限制，其中炎性小体有助于病理学。骨髓细胞特异性缺失RA易感基因A20/TNFAIP 3的小鼠（A20 myel-KO小鼠）触发了类似于RA患者的自发性糜烂性多关节炎。值得注意的是，A20 myel-KO小鼠中的RA不能通过肿瘤坏死因子受体1（TNF-R1）缺失来挽救，但我们表明它关键依赖于白细胞介素-1受体（IL-1 R）信号传导。缺乏A20的巨噬细胞增加了炎性小体衔接子Nlrp 3和proIL-1β的基础和LPS诱导的表达水平。结果，巨噬细胞中A20缺乏显著增强了可溶性和结晶Nlrp 3刺激引起的Nlrp 3炎性小体介导的半胱天冬酶-1活化、焦亡和IL-1β分泌。相反，Nlrc 4和AIM 2炎性小体的活化没有改变。重要的是，增加的Nlrp 3炎性体激活有助于体内RA病理学，因为Nlrp 3和半胱天冬酶-1的缺失显著保护A20髓-KO小鼠免受RA相关炎症和软骨破坏。这些结果揭示了A20作为Nlrp 3炎性小体激活的新的负调节剂，并且描述了A20髓-KO小鼠作为研究炎性小体在RA病理学中的作用的第一个实验模型。
Rheumatoid arthritis (RA) is a chronic autoinflammatory disease that affects 1-2% of the world population and is characterized by widespread joint inflammation. IL-1 is an important mediator of cartilage destruction in rheumatic diseases, but our understanding of the upstream mechanisms leading to IL-1β production in rheumatoid arthritis is limited by the absence of suitable RA mouse models in which inflammasomes contribute to pathology. Myeloid-cell-specific deletion of the RA-susceptibility gene A20/TNFAIP3 in mice (A20myel-KO mice) triggers a spontaneous erosive polyarthritis that resembles RA in patients. Notably, RA in A20myel-KO mice was not rescued by tumor necrosis factor receptor 1 (TNF-R1) deletion, but we showed it to crucially rely on interleukin-1 receptor (IL-1R) signaling. Macrophages lacking A20 had increased basal and LPS-induced expression levels of the inflammasome adaptor Nlrp3 and proIL-1β. As a result, A20-deficiency in macrophages significantly enhanced Nlrp3 inflammasome-mediated caspase-1 activation, pyroptosis and IL-1β secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 and AIM2 inflammasomes was not altered. Importantly, increased Nlrp3 inflammasome activation contributed to RA pathology in vivo, because deletion of Nlrp3 and caspase-1 markedly protected against RA-associated inflammation and cartilage destruction in A20myel-KO mice. These results reveal A20 as a novel negative regulator of Nlrp3 inflammasome activation, and describe A20myel-KO mice as the first experimental model to study the role of inflammasomes in RA pathology.
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影响因子：
4.4
作者：
Kolly, Laeticia;Karababa, Mahir;Busso, Nathalie
通讯作者：
Busso, Nathalie
影响因子：
30.8
作者：
Matmati, Mourad;Jacques, Peggy;van Loo, Geert
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影响因子：
56.9
作者：
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DOI：
10.1124/jpet.104.074484
发表时间：
2005-01-01
影响因子：
3.5
作者：
Podolin, PL;Callahan, JF;Roshak, AK
通讯作者：
Roshak, AK
影响因子：
4.9
作者：
Dieguez-Gonzalez R;Calaza M;Perez-Pampin E;Balsa A;Blanco FJ;Cañete JD;Caliz R;Carreño L;de la Serna AR;Fernandez-Gutierrez B;Ortiz AM;Herrero-Beaumont G;Pablos JL;Narvaez J;Navarro F;Marenco JL;Gomez-Reino JJ;Gonzalez A
通讯作者：
Gonzalez A