Activation of nucleotide-binding oligomerization domain 2 by muramyl dipeptide negatively regulates Toll-like receptor 9-mediated colonic inflammation through the induction of deubiquitinating enzyme A expression
Activation of nucleotide-binding oligomerization domain 2 by muramyl dipeptide negatively regulates Toll-like receptor 9-mediated colonic inflammation through the induction of deubiquitinating enzyme A expression
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DOI：
10.1093/intimm/dxac045
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发表时间：
2022-09-29
影响因子：
4.4
通讯作者：
Watanabe, Tomohiro
中科院分区：
文献类型：
--
作者：
Masuta, Yasuhiro;Minaga, Kosuke;Watanabe, Tomohiro
核苷酸结合寡聚化结构域2（NOD 2）中的突变与克罗恩病（CD）相关。虽然NOD 2激活通过Toll样受体（TLR）介导的促炎细胞因子应答的负调节有助于维持肠道内稳态，但是NOD 2激活对由TLR 9诱导的干扰素（IFN）-α应答的影响还不清楚。为了探索NOD 2和TLR 9之间的相互作用，用NOD 2和/或TLR 9配体刺激人单核细胞或树突状细胞（DC）以测量IFN-α产生。在用NOD 2和/或TLR 9配体处理的小鼠中比较葡聚糖硫酸钠（DSS）诱导的结肠炎的严重程度。研究了炎症性肠病（IBD）患者结肠粘膜中IFN-α和IFN-刺激基因（ISG）的表达。NOD 2活化以去泛素化酶A（杜巴）依赖性方式减少单核细胞和DC的TLR 9诱导的IFN-α产生。由TLR 9和NOD 2的共刺激诱导的杜巴的活化抑制TRAF 3的Lys 63连接的多聚泛素化，并抑制TLR 9介导的IFN-α产生。造血细胞中的NOD 2活化通过下调IFN-α应答和上调杜巴表达保护小鼠免受TLR 9诱导的DSS诱导的结肠炎的恶化。IBD活动期和缓解期患者结肠黏膜ISGs表达分别增强和减少。在溃疡性结肠炎和CD患者的活动性结肠粘膜中，IFN-α和IL-6的表达水平呈正相关，而在CD患者中，杜巴表达与IFN-α呈负相关。总的来说，这些数据表明NOD 2对TLR 9介导的IFN-α应答的DUBA依赖性负作用有助于维持肠道稳态。
Mutations in nucleotide-binding oligomerization domain 2 (NOD2) are associated with Crohn's disease (CD). Although NOD2 activation contributes to the maintenance of intestinal homeostasis through the negative regulation of pro-inflammatory cytokine responses mediated by Toll-like receptors (TLRs), the effects of NOD2 activation on interferon (IFN)-alpha responses induced by TLR9 have been poorly defined. To explore the cross-talk between NOD2 and TLR9, human monocytes or dendritic cells (DCs) were stimulated with NOD2 and/or TLR9 ligands to measure IFN-alpha production. The severity of dextran sodium sulfate (DSS)-induced colitis was compared in mice treated with NOD2 and/or TLR9 ligands. Expression of IFN-alpha and IFN-stimulated genes (ISGs) was examined in the colonic mucosa of patients with inflammatory bowel disease (IBD). NOD2 activation reduced TLR9-induced IFN-alpha production by monocytes and DCs in a deubiquitinating enzyme A (DUBA)-dependent manner. Activation of DUBA induced by the co-stimulation of TLR9 and NOD2 inhibited Lys63-linked polyubiquitination of TRAF3 and suppressed TLR9-mediated IFN-alpha production. NOD2 activation in hematopoietic cells protected mice from TLR9-induced exacerbation of DSS-induced colitis by down-regulating IFN-alpha responses and up-regulating DUBA expression. Colonic mucosa of patients with active and remitted IBD phases was characterized by the enhanced and reduced expression of ISGs, respectively. Expression levels of IFN-alpha and IL-6 positively correlated in the active colonic mucosa of patients with ulcerative colitis and CD, whereas DUBA expression inversely correlated with that of IFN-alpha in patients with CD. Collectively, these data suggest that DUBA-dependent negative effect of NOD2 on TLR9-mediated IFN-alpha responses contributes to the maintenance of intestinal homeostasis.