CD1d1 intrinsic signaling in macrophages controls NLRP3 inflammasome expression during inflammation.
CD1d1 intrinsic signaling in macrophages controls NLRP3 inflammasome expression during inflammation.
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巨噬细胞中的 CD1d1 内在信号传导在炎症过程中控制 NLRP3 炎性体的表达
DOI：
10.1126/sciadv.aaz7290
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发表时间：
2020-10
期刊：
影响因子：
13.6
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Cui S;Wang C;Bai W;Li J;Pan Y;Huang X;Yang H;Feng Z;Xiang Q;Fei L;Zheng L;Huang J;Zhang Q;Wu Y;Chen Y
iGB 3/CD 1d 1通过抑制巨噬细胞中的Nlrp 3、Illb和Il 18转录来决定DSS-结肠炎的严重程度。肠道免疫反应失调通常与炎症性肠病（IBD）有关。小鼠CD 1d 1是人CD 1d的直系同源物，主要参与向NKT细胞的脂质抗原呈递，能够在刺激时产生内在信号。巨噬细胞特异性CD 1d 1缺陷（CD 1d 1 −/−）小鼠获得对葡聚糖硫酸钠（DSS）诱导的结肠炎的抗性，这归因于NLRP 3炎性体成分的转录抑制。NLRP 3炎性体的过度活化解释了肠上皮细胞增殖和肠-血屏障完整性。从机制上讲，天然配体鞘糖脂iGb 3、CD 1d 1的占据与细胞内Ser 330去磷酸化反应，从而减少过氧化物氧还蛋白1（PRDX 1）相关的AKT-STAT 1磷酸化和随后的NF-κB活化，最终导致巨噬细胞中Nlrp 3及其直接底物Il 1 B和Il 18的转录下调。因此，CD 1d 1在巨噬细胞中的平衡作用似乎决定了小鼠DSS介导的结肠炎的严重程度。这些发现为治疗IBD和其他炎症性疾病提出了新的干预策略。
iGB3/CD1d1 determines the severity of DSS-colitis through inhibiting Nlrp3, Il1b, and Il18 transcription in macrophages. Dysregulation of immune responses in the gut often associates with inflammatory bowel diseases (IBD). Mouse CD1d1, an ortholog of human CD1d mainly participating in lipid-antigen presentation to NKT cells, is able to generate intrinsic signals upon stimulation. Mice with macrophage-specific CD1d1 deficiency (LymCD1d1−/−) acquire resistance to dextran sodium sulfate (DSS)–induced colitis, attributing to the transcriptional inhibition of NLRP3 inflammasome components. The hyperactivation of NLRP3 inflammasome accounts for gut epithelial proliferation and intestine-blood barrier integrity. Mechanistically, occupancy by the natural ligand glycosphingolipid iGb3, CD1d1 responds with intracellular Ser330 dephosphorylation thus to reduce the Peroxiredoxin 1 (PRDX1)–associated AKT-STAT1 phosphorylation and subsequent NF-κB activation, eventually causing transcriptional down-regulation of Nlrp3 and its immediate substrates Il1b and Il18 in macrophages. Therefore, the counterbalancing role of CD1d1 in macrophages appears to determine severity of DSS-mediated colitis in mice. These findings propose new intervention strategies for treating IBD and other inflammatory disorders.
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作者：
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影响因子：
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作者：
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发表时间：
2008-03-01
影响因子：
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