Blau syndrome NOD2 mutations result in loss of NOD2 cross-regulatory function.
Blau syndrome NOD2 mutations result in loss of NOD2 cross-regulatory function.
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DOI：
10.3389/fimmu.2022.988862
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发表时间：
2022
影响因子：
7.3
通讯作者：
Strober, Warren
中科院分区：
文献类型：
--
作者：
Mao, Liming;Dhar, Atika;Meng, Guangxun;Fuss, Ivan;Montgomery-Recht, Kim;Yang, Zhiqiong;Xu, Qiuyun;Kitani, Atsushi;Strober, Warren
本文描述的研究提供了Blau综合征发病机制的分析，从而通过Blau相关NOD 2核苷酸结合结构域（NBD）突变导致的NOD 2功能障碍的透镜观察NOD 2的功能。因此，这项分析也揭示了NOD 2风险多态性在克罗恩病中发生的LRR结构域中的作用。主要发现是Blau NOD 2突变导致经典NOD 2信号通过RIPK 2的丢失，并且这种丢失具有两个后果：首先，它导致有缺陷的NOD 2配体（MDP）介导的NF-κB激活，其次，它破坏NOD 2介导的交叉调节，从而NOD 2下调伴随的先天性（TLR）应答。也提出了强有力的证据支持这样的观点，即NOD 2介导的交叉调节是在IRF 4的机械控制下，并且由于错误的NOD 2信号传导而未能上调该因子是交叉调节缺陷的近端原因以及后者对Blau综合征炎症的影响。总的来说，这些研究突出了NOD 2作为调节因子的作用，从而为其在炎症性疾病中的功能提供了额外的见解。CARD 15（NOD 2）基因核苷酸结合域的突变是Blau综合征（BS）肉芽肿性炎症的基础。在探索这种炎症机制的研究中，我们发现在HEK 293细胞中表达各种Blau突变的NOD 2质粒导致RIPK 2的NOD 2活化减少，相应地NF-κB的NOD 2活化减少。这些NOD 2信号传导的体外研究伴随着体内研究，表明BS-NOD 2也表现出在炎症基础的先天反应的交叉调节中的缺陷。因此，尽管过表达的完整N 0 D 2抑制TNBS-结肠炎，但过表达的BS-N 0 D 2不抑制TNBS-结肠炎;此外，尽管施用N 0 D 2配体（胞壁酰二肽，MDP）在野生型（WT）小鼠中抑制DSS-结肠炎，但在携带N 0 D 2 Blau突变的纯合或杂合小鼠中不能这样做。类似地，携带Blau突变的小鼠表现出增强的抗胶原抗体诱导的关节炎。这种交叉调节失败的基础在研究中被揭示，这些研究显示，经MDP刺激的携带BS-NOD 2的细胞表现出通过RIPK 2发出信号的能力降低以及上调IRF 4的能力降低，IRF 4是先前显示的介导NOD 2抑制NF-κB活化的因子。事实上，TLR刺激的细胞携带Blau突变表现出增强的体外细胞因子应答，其通过IRF 4的慢病毒转导而平息。此外，在携带Blau突变的小鼠中增强的抗胶原诱导的关节炎症伴随着炎症关节组织中IRF 4表达的减少，并且在来自BS患者的MDP刺激的细胞中IRF 4表达减少。因此，Blau综合征的炎症特征至少部分是由错误的经典信号传导引起的，并减少了IRF 4介导的交叉调节。
The studies described here provide an analysis of the pathogenesis of Blau syndrome and thereby the function of NOD2 as seen through the lens of its dysfunction resulting from Blau-associated NOD2 mutations in its nucleotide-binding domain (NBD). As such, this analysis also sheds light on the role of NOD2 risk polymorphisms in the LRR domain occurring in Crohn’s disease. The main finding was that Blau NOD2 mutations precipitate a loss of canonical NOD2 signaling via RIPK2 and that this loss has two consequences: first, it results in defective NOD2 ligand (MDP)-mediated NF-κB activation and second, it disrupts NOD2-mediated cross-regulation whereby NOD2 downregulates concomitant innate (TLR) responses. Strong evidence is also presented favoring the view that NOD2-mediated cross-regulation is under mechanistic control by IRF4 and that failure to up-regulate this factor because of faulty NOD2 signaling is the proximal cause of defective cross-regulation and the latter’s effect on Blau syndrome inflammation. Overall, these studies highlight the role of NOD2 as a regulatory factor and thus provide additional insight into its function in inflammatory disease. Mutations in the nucleotide binding domain of the CARD15 (NOD2) gene underlie the granulomatous inflammation characterizing Blau syndrome (BS). In studies probing the mechanism of this inflammation we show here that NOD2 plasmids expressing various Blau mutations in HEK293 cells result in reduced NOD2 activation of RIPK2 and correspondingly reduced NOD2 activation of NF-κB. These in vitro studies of NOD2 signaling were accompanied by in vivo studies showing that BS-NOD2 also exhibit defects in cross-regulation of innate responses underlying inflammation. Thus, whereas over-expressed intact NOD2 suppresses TNBS-colitis, over-expressed BS-NOD2 does not; in addition, whereas administration of NOD2 ligand (muramyl dipeptide, MDP) suppresses DSS-colitis in Wild Type (WT) mice it fails to do so in homozygous or heterozygous mice bearing a NOD2 Blau mutation. Similarly, mice bearing a Blau mutation exhibit enhanced anti-collagen antibody-induced arthritis. The basis of such cross-regulatory failure was revealed in studies showing that MDP-stimulated cells bearing BS-NOD2 exhibit a reduced capacity to signal via RIPK2 as well as a reduced capacity to up-regulate IRF4, a factor shown previously to mediate NOD2 suppression of NF-κB activation. Indeed, TLR-stimulated cells bearing a Blau mutation exhibited enhanced in vitro cytokine responses that are quieted by lentivirus transduction of IRF4. In addition, enhanced anti-collagen-induced joint inflammation in mice bearing a Blau mutation was accompanied by reduced IRF4 expression in inflamed joint tissue and IRF4 expression was reduced in MDP-stimulated cells from BS patients. Thus, inflammation characterizing Blau syndrome are caused, at least in part, by faulty canonical signaling and reduce IRF4-mediated cross-regulation.
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