Laboratory of Innate Immunity, National Institute of Immunology, New Delhi, India.
Department of Biological Sciences, Laboratory of Immunology and Infectious Disease Biology, Indian Institute of Science Education and Research (IISER) Bhopal, Bhopal 462066, India.
Cell Immunol. 2020 Mar;349:104043. doi: 10.1016/j.cellimm.2020.104043. Epub 2020 Jan 27.
Type I Interferon (IFN) signaling plays a critical role in dendritic cell (DC) development and functions. Inhibition of hyper type I IFN signaling promotes cDC2 subtype development. Relb is essential to development of cDC2 subtype and here we analyzed its effect on type I IFN signaling in DCs. We show that Relb suppresses the homeostatic type I IFN signaling in cDC2 cultures. TLR stimulation of FL-DCs led to RelB induction coinciding with fall in IFN signatures; conforming with the observation Relb expression reduced TLR stimulated IFN induction along with decrease in ISGs. Towards understanding mechanism, we show that effects of RelB are mediated by increased levels of IκBα. We demonstrate that RelB dampened antiviral responses by lowering ISG levels and the defect in cDC2 development in RelB null mice can be rescued in Ifnar1 background. Overall, we propose a novel role of RelB as a negative regulator of the type I IFN signaling pathway; fine tuning development of cDC2 subtype.
I 型干扰素（IFN）信号通路在树突状细胞（DC）的发育和功能中起着关键作用。高活性 I 型 IFN 信号通路的抑制促进 cDC2 亚型的发育。Relb 对于 cDC2 亚型的发育是必需的，在这里我们分析了它对 DC 中 I 型 IFN 信号通路的影响。我们发现 Relb 抑制 cDC2 培养物中的稳态 I 型 IFN 信号通路。TLR 刺激 FL-DC 导致 RelB 的诱导，同时 IFN 特征下降；这与 Relb 表达减少 TLR 刺激的 IFN 诱导以及 ISGs 减少的观察结果一致。为了理解作用机制，我们发现 RelB 的作用是通过增加 IκBα 的水平来介导的。我们证明，RelB 通过降低 ISG 水平来抑制抗病毒反应，并且在 Relb 缺失小鼠中 cDC2 发育缺陷可以在 Ifnar1 背景下得到挽救。总的来说，我们提出了 RelB 作为 I 型 IFN 信号通路的负调节剂的新作用；微调 cDC2 亚型的发育。
