PDF(Pubmed)
Abstract：
Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases. However, the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown. In this study, we demonstrated that S-nitrosoglutathione reductase (GSNOR) deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1β expression levels and interleukin-1β (IL-1β) secretion in response to NLRP3 inflammasome stimulation. Furthermore, in vivo experiments utilizing Gsnor-/- mice revealed increased disease severity in both lipopolysaccharide (LPS)-induced septic shock and dextran sodium sulfate (DSS)-induced colitis models. Additionally, we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor-/- Nlrp3-/- double-knockout (DKO) mice. Mechanistically, GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14 (MAPK14) at the Cys211 residue and augments MAPK14 kinase activity, thereby promoting Nlrp3 and Il-1β transcription and stimulating NLRP3 inflammasome activity. Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.
摘要：
NLRP3炎性体的过度激活与许多疾病的发病机理有关。然而,调控NLRP3转录调控的确切分子机制仍不清楚.在这项研究中,我们证明巨噬细胞中的S-亚硝基谷胱甘肽还原酶(GSNOR)缺乏导致NLRP3炎症小体刺激引起的Nlrp3和IL-1β表达水平和白细胞介素-1β(IL-1β)分泌显著增加。此外，使用Gsnor-/-小鼠的体内实验显示，在脂多糖（LPS）诱导的脓毒性休克和葡聚糖硫酸钠（DSS）诱导的结肠炎模型中，疾病严重程度均增加。此外,我们发现在Gsnor-/-Nlrp3-/-双基因敲除（DKO）小鼠中，LPS诱导的感染性休克和DSS诱导的结肠炎均得到改善。机械上,GSNOR缺乏增加了丝裂原活化蛋白激酶14（MAPK14）在Cys211残基的S-亚硝化，并增加了MAPK14激酶的活性，从而促进Nlrp3和Il-1β转录并刺激NLRP3炎性体活性。我们的研究结果表明，GSNOR是NLRP3炎症小体的调节因子，降低S-亚硝基化的MAPK14水平可能是缓解与NLRP3介导的炎症相关疾病的有效策略。
