Canonical Stimulation of the NLRP3 Inflammasome by Fungal Antigens Links Innate and Adaptive B-Lymphocyte Responses by Modulating IL-1β and IgM Production.
Canonical Stimulation of the NLRP3 Inflammasome by Fungal Antigens Links Innate and Adaptive B-Lymphocyte Responses by Modulating IL-1β and IgM Production.
复制标题
DOI：
10.3389/fimmu.2017.01504
复制
发表时间：
2017
影响因子：
7.3
通讯作者：
Carmona EM
中科院分区：
文献类型：
--
作者：
Ali MF;Dasari H;Van Keulen VP;Carmona EM
NLRP3 炎症小体响应不同的细菌、病毒和真菌病原体而被激活，并作为不同模式识别受体信号通路的调节剂。 NLRP3 的主要功能之一是参与 IL-1β 成熟，这对于宿主防御肺孢子虫和其他真菌感染非常重要。然而，NLRP3 和 IL-1β 分泌失调也与许多自身炎症性疾病的病理生理学有关。通常，炎症爆发之前会出现传染病，人们质疑感染在自身免疫性恶化中的作用。然而，我们仍然不完全了解感染甚至定植作为炎症触发因素的确切作用。在此，我们研究了两种主要微生物抗原（β-葡聚糖和 CpG）激活后 NLRP3 在循环 B 淋巴细胞中的作用。 NLRP3 被确定在两个独立的 B 淋巴细胞过程中至关重要：促炎细胞因子分泌和抗体调节。我们的结果表明，β-葡聚糖真菌细胞壁碳水化合物刺激 B 淋巴细胞分泌 IL-1β，该过程部分由 Dectin-1 通过 SYK 和转录因子 NF-κB 和 AP-1 激活介导。这种 IL-1β 分泌受 NLRP3 炎性体调节，并依赖于钾流出和 Caspase-1。有趣的是，由细菌和真菌 DNA 中发现的未甲基化 CpG 基序激活的 B 淋巴细胞无法诱导 IL-1β。然而，CpG 刺激 B 淋巴细胞会导致 NLRP3 和 Caspase-1 激活以及 IgM 抗体的产生和分泌。此外，与 β-葡聚糖介导的 IL-1β 产生不同，CpG 刺激的 IgM 分泌是由哺乳动物雷帕霉素靶点 (mTOR) 介导的。 CpG 激活的 B 淋巴细胞中 NLRP3 和 mTOR 通路的抑制导致 IgM 分泌受损，表明它们参与抗体调节。总之，本研究描述了 NLRP3 对 β-葡聚糖和 CpG 抗原的差异反应，并确定了人类循环 B 淋巴细胞的 NLRP3 炎性体作为先天性和适应性免疫系统的调节剂。
The NLRP3 inflammasome is activated in response to different bacterial, viral, and fungal pathogens and serves as modulator of different pattern recognition receptors signaling pathways. One of the main functions of NLRP3 is to participate in IL-1β maturation which is important in the host defense against Pneumocystis and other fungal infections. However, dysregulation of NLRP3 and IL-1β secretion are also implicated in the pathophysiology of many auto-inflammatory disorders. Often time’s inflammatory flares are preceded by infectious illnesses questioning the role of infection in autoimmune exacerbations. However, we still do not fully understand the exact role that infection or even colonization plays as a trigger of inflammation. Herein, we investigated the role of NLRP3 in circulating B-lymphocytes following activation with two major microbial antigens (β-glucan and CpG). NLRP3 was determined essential in two independent B-lymphocytes processes: pro-inflammatory cytokine secretion and antibody regulation. Our results show that the β-glucan fungal cell wall carbohydrate stimulated B-lymphocytes to secrete IL-1β in a process partially mediated by Dectin-1 activation via SYK and the transcription factors NF-κB and AP-1. This IL-1β secretion was regulated by the NLRP3 inflammasome and was dependent on potassium efflux and Caspase-1. Interestingly, B-lymphocytes activated by unmethylated CpG motifs, found in bacterial and fungal DNA, failed to induce IL-1β. However, B-lymphocyte stimulation by CpG resulted in NLRP3 and Caspase-1 activation and the production and secretion of IgM antibodies. Furthermore, CpG-stimulated IgM secretion, unlike β-glucan-mediated IL-1β production, was mediated by the mammalian target of rapamycin (mTOR). Inhibition of NLRP3 and the mTOR pathway in CpG activated B-lymphocytes resulted in impaired IgM secretion suggesting their participation in antibody regulation. In conclusion, this study describes a differential response of NLRP3 to β-glucan and CpG antigens and identifies the NLRP3 inflammasome of human circulating B-lymphocytes as a modulator of the innate and adaptive immune systems.
登录
查看更多内容
影响因子：
4.8
作者：
Endo, K;Takino, T;Sato, H
通讯作者：
Sato, H
影响因子：
4.4
作者：
Kankkunen, Paivi;Teirila, Laura;Matikainen, Sampsa
通讯作者：
Matikainen, Sampsa
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
30.5
作者：
Gringhuis, Sonja I.;den Dunnen, Jeroen;Geijtenbeek, Teunis B. H.
通讯作者：
Geijtenbeek, Teunis B. H.
影响因子：
30.5
作者：
通讯作者：
--