Small heat shock protein CRYAB inhibits intestinal mucosal inflammatory responses and protects barrier integrity through suppressing IKK beta activity
Small heat shock protein CRYAB inhibits intestinal mucosal inflammatory responses and protects barrier integrity through suppressing IKK beta activity
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小热休克蛋白 CRYAB 通过抑制 IKK β 活性抑制肠粘膜炎症反应并保护屏障完整性
DOI：
10.1038/s41385-019-0198-5
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发表时间：
2019
影响因子：
8
通讯作者：
Du Peng
中科院分区：
文献类型：
--
作者：
Xu Weimin;Guo Yuegui;Huang Zhenyu;Zhao Haoxin;Zhou Mingxia;Huang Yuji;Wen Dongpeng;Song Jinglue;Zhu Zhehui;Sun Mingming;Liu Chen-Ying;Chen Yingwei;Cui Long;Wang Xiaolei;Liu Zhanju;Yang Yili;Du Peng
α B-晶体蛋白（AlphaB-crystallin，α B-AB）是小分子热休克蛋白家族的重要成员，在神经系统炎症中起着保护和治疗作用。在培养的HT 29和Caco-2细胞以及患有炎症性肠病（IBD）和小鼠结肠炎模型的患者的发炎粘膜中评估HLAAB表达。在不同的细胞中使用慢病毒过表达和CRSIPR/Cas9系统以分别上调和沉默CRS 1AB表达。通过腹腔注射细胞渗透性重组融合蛋白TAT-TATAB，观察其对葡聚糖硫酸钠（DSS）和2，4，6-三硝基苯磺酸（TNBS）诱导的小鼠结肠炎模型的抗炎作用。IBD患者炎症黏膜和DSS诱导的小鼠结肠炎黏膜中的TNF-α和IL-6水平均显著降低，并分别与TNF-α和IL-6水平呈负相关。增强的ESTAB表达抑制促炎细胞因子（例如，TNF-α、IL-6、IL-1β和IL-8）通过抑制IKK复合物的形成而增强，而缺乏TNF-α AB表达显著增强促炎反应。一致地，施用TAT-TPAAB融合蛋白显著减轻了小鼠中DSS或TNBS诱导的结肠炎并保护了肠屏障完整性。ESTABAB通过抑制IKKβ介导的信号传导调节肠粘膜炎症反应，可能成为IBD治疗的一种新方法。
Alpha B-crystallin (CRYAB) is an important member of the small heat shock protein family, and plays a protective and therapeutic role in neurological inflammation. CRYAB expression was assessed in cultured HT29 and Caco-2 cells and inflamed mucosa of patients with inflammatory bowel disease (IBD) and colitis models in mice. Lentivirus-overexpressing and CRSIPR/Cas9 systems were used in different cells to upregulate and silence CRYAB expression, respectively. Cell permeable recombined fusion protein TAT-CRYAB was injected intraperitoneally into dextran sulfate sodium (DSS)- or 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in mice to assess its anti-inflammatory effects. CRYAB was found to be significantly decreased in the inflamed mucosa from IBD patients and DSS-induced colitis in mice, and negatively correlated with the levels of TNF-α and IL-6, respectively. Enforced expression of CRYAB suppressed expression of proinflammatory cytokines (e.g., TNF-α, IL-6, IL-1β, and IL-8) via inhibiting the IKK complex formation, whereas lack of CRYAB expression markedly enhanced proinflammatory responses. Consistently, administration of TAT-CRYAB fusion protein significantly alleviated DSS- or TNBS-induced colitis in mice and protected intestinal barrier integrity. CRYAB regulates inflammatory response in intestinal mucosa by inhibiting IKKβ-mediated signaling and may serve as a novel therapeutic approach in the treatment of IBD.