Pasi Shweta, Kant Ravi, Surolia Avadhesha
From the Molecular Science Laboratory, National Institute of Immunology, New Delhi 110067, India and Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
From the Molecular Science Laboratory, National Institute of Immunology, New Delhi 110067, India and Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India
J Biol Chem. 2016 Jun 3;291(23):12358-69. doi: 10.1074/jbc.M116.722801. Epub 2016 Mar 28.
Evasion through immunomodulation is one of the several strategies adopted by pathogens to prolong their survival within the host. One such pathogen, Escherichia coli CFT073, utilizes an immunomodulatory protein, TcpC, to combat the host's innate immune defense. TcpC abrogates the function of MyD88 in macrophages, thus perturbing all the signaling processes that involve this adaptor protein. Although central to various signaling pathways initiated by IL-1, IL-18, and toll-like receptors, the precise contribution of MyD88 to the development of autoimmunity, particularly rheumatoid arthritis, still needs extensive exploration. Herein, by using the toll/interleukin-1 receptor (TIR) domain homologous C-terminal motif of TcpC, i.e. TIR-TcpC, we found MyD88 to be critical for the induction and progression of rheumatoid arthritis through its pivotal role in the development of Th17 cells, the subset of CD4(+) T-cells widely implicated in various autoimmune disorders. The TIR-TcpC mediated inhibition of signaling through MyD88, and subsequent amelioration of experimental autoimmune arthritis was observed to be an outcome of perturbations in the NFκB-RORγt (RAR-related orphan receptor γt) axis.
通过免疫调节实现逃逸是病原体在宿主体内延长存活时间所采用的几种策略之一。一种这样的病原体，即大肠杆菌CFT073，利用一种免疫调节蛋白TcpC来对抗宿主的固有免疫防御。TcpC消除巨噬细胞中MyD88的功能，从而扰乱所有涉及这种衔接蛋白的信号传导过程。尽管MyD88在由IL-1、IL-18和Toll样受体启动的各种信号通路中至关重要，但MyD88对自身免疫性疾病，尤其是类风湿性关节炎发展的确切作用仍需要广泛探索。在此，通过使用TcpC的Toll/白细胞介素-1受体（TIR）结构域同源C末端基序，即TIR-TcpC，我们发现MyD88通过其在Th17细胞发育中的关键作用，对类风湿性关节炎的诱导和进展至关重要，Th17细胞是CD4(+) T细胞的一个亚群，广泛参与各种自身免疫性疾病。观察到TIR-TcpC介导的通过MyD88的信号传导抑制以及随后实验性自身免疫性关节炎的改善是NFκB-RORγt（视黄酸相关孤儿受体γt）轴紊乱的结果。
