Molecular pathological examination of valvulitis developed in TAX1BP1 deficient mice.

tax1结合蛋白1 （Tax1bp1）通过与催化伙伴A20编辑靶分子的泛素化而负调控NF-κB。基因工程的tax1bp1缺陷（KO）小鼠在多个器官中出现年龄依赖性炎症，表现为心瓣膜炎或皮炎，并导致过早死亡。对TAX1BP1-KO小鼠（8周龄和16周龄）的二尖瓣进行激光捕获解剖和基因表达微阵列分析，发现野生型有588个基因转录改变。SAA3（血清淀粉样蛋白A3）表现出1180倍的诱导（FI）， CHI3L1(361-FI)， HP(187-FI), IL1B（122-FI）和SPP1/OPN（101-FI）。Wnt抑制因子1 （WIF1）降低了11倍。Saa3染色强烈，I-κBα明显减少，炎症淋巴细胞大量浸润，水肿形成。抗生素诱导的“无菌”状态或额外的MyD88缺乏显著改善了TAX1BP1-KO小鼠的炎症损伤。这些病理状况，正如我们所命名的“伪感染性心内膜炎”，是由共生微生物群促进的，而共生微生物群通常是无害的。这一实验结果提出了泛素重塑免疫调节因子引起的内皮炎症与致命性心功能障碍之间的新机制联系。

Tax1-binding protein 1 (Tax1bp1) negatively regulates NF-κB by editing the ubiquitylation of target molecules with its catalytic partner A20. Genetically engineered TAX1BP1-deficient (KO) mice develop age-dependent inflammatory constitutions in multiple organs manifested as valvulitis or dermatitis and succumb to premature death. Laser capture dissection and gene expression microarray analysis on the mitral valves of TAX1BP1-KO mice (8 and 16 week old) revealed 588 gene transcription alterations from the wild type. SAA3 (serum amyloid A3) exhibited a 1,180-fold induction (FI), CHI3L1(361-FI), HP(187-FI), IL1B(122-FI) and SPP1/OPN(101-FI). WIF1 (Wnt inhibitory factor 1) exhibited 11-fold reduction. Intense Saa3 staining and significant I-κBα reduction were reconfirmed and massive infiltration of inflammatory lymphocytes and edema formation in the area. Antibiotics-induced ‘germ free’ status or the additional MyD88 deficiency significantly ameliorated TAX1BP1-KO mice’s inflammatory lesions. These pathological conditions, as we named ‘pseudo-infective endocarditis’ were boosted by the commensal microbiota who are usually harmless by their nature. This experimental outcome raises a novel mechanistic linkage between endothelial inflammation caused by the ubiquitin remodeling immune regulators and fatal cardiac dysfunction.