TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies
TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies
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DOI：
10.1172/jci90699
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发表时间：
2017-12-01
影响因子：
15.9
通讯作者：
Hoffman, Hal M.
中科院分区：
文献类型：
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作者：
McGeough, Matthew D.;Wree, Alexander;Hoffman, Hal M.
NLRP 3炎性体是一种蛋白质复合物，负责促炎细胞因子IL-1 β和IL-18的半胱天冬酶-1依赖性成熟。NLRP 3中的功能获得性错义突变导致称为cryopyrin相关周期性综合征（CAPS）的疾病谱。在这项研究中，我们在各种KO背景下产生了Nlrp 3-敲入小鼠，包括IL 1b/IL 18-，caspase-1-，caspase-11-（Casp 1/11-）和TNF-缺陷株。Nlrp 3（L351 P）Il 1b（-/-）Il 18（-/-）突变小鼠存活并正常生长直至成年，并且在6个月龄时表现出显著的脾肿大和白细胞增多。与Nlrp 3（L351 P）Casp 1/11（-/-）小鼠和Illb（-/-）Il 18（-/-）同窝小鼠相比，用低剂量LPS注射这些小鼠导致血清TNF水平升高。用TNF抑制剂依那西普治疗Nlrp 3（A350 V）小鼠，所有幼仔均存活至成年，体重和脾/体重比正常。Nlrp 3（A350 V）Tnf（-/-）小鼠表现出相似的表型拯救，血清IL-1 β和IL-18显著降低，皮肤和脾脏中骨髓炎性浸润减少，炎症体组分（Nlrp 3、Pycard、pro-Casp 1）和前细胞因子（Il 1b、Il 18）的脾脏mRNA表达显著降低。同样，我们观察到在培养的Nlrp 3（A350 V）Tnf（-/-）BM衍生的DC中pro-Casp 1和pro-Illb的表达减少。我们的数据表明，TNF是一个重要的转录调节因子的NLRP 3炎性体成分在小鼠炎症。此外，这些结果可能对对IL-1靶向治疗有部分反应的CAPS患者具有治疗意义。
The NLRP3 inflammasome is a protein complex responsible for caspase-1-dependent maturation of the proinflammatory cytokines IL-1 beta and IL-18. Gain-of-function missense mutations in NLRP3 cause the disease spectrum known as the cryopyrin-associated periodic syndromes (CAPS). In this study, we generated Nlrp3-knockin mice on various KO backgrounds including Il1b/Il18-, caspase-1-, caspase-11-(Casp1/11-), and Tnf-deficient strains. The Nlrp3(L351P) Il1b(-/-) Il18(-/-) mutant mice survived and grew normally until adulthood and, at 6 months of age, exhibited marked splenomegaly and leukophilia. Injection of these mice with low-dose LPS resulted in elevated serum TNF levels compared with Nlrp3(L351P) Casp1/11(-/-) mice and Il1b(-/-) Il18(-/-) littermates. Treatment of Nlrp3(A350V) mice with the TNF inhibitor etanercept resulted in all pups surviving to adulthood, with normal body and spleen/body weight ratios. Nlrp3(A350V) Tnf(-/-) mice showed a similar phenotypic rescue, with marked reductions in serum IL-1 beta and IL-18, reduced myeloid inflammatory infiltrate in the skin and spleen, and substantial decreases in splenic mRNA expression of both inflammasome components (Nlrp3, Pycard, pro-Casp1) and pro-cytokines (Il1b, Il18). Likewise, we observed a reduction in the expression of both pro-Casp1 and pro-Il1b in cultured Nlrp3(A350V) Tnf(-/-) BM-derived DCs. Our data show that TNF is an important transcriptional regulator of NLRP3 inflammasome components in murine inflammasomopathies. Moreover, these results may have therapeutic implications for CAPS patients with partial responses to IL-1-targeted therapies.