Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
Department of Clinical Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
J Immunol. 2019 Jan 1;202(1):105-118. doi: 10.4049/jimmunol.1800598. Epub 2018 Nov 30.
An integral component of the antiviral response, type I IFNs require regulation to modulate immune activation. We identify β-arrestin 2 as a key modulator of type I IFN in primary human macrophages, an essential component of the innate immune response. β-Arrestin 2 was selectively activated by CCL2/CCR2 signaling, which induced a decrease in IFN-α, but not IFN-β expression. Small interfering RNA knockdown of β-arrestin 2 demonstrated its role in IFNAR1 internalization, as well as STAT1 and IRF3 activation. As a result, cytokine responses were not propagated following HIV infection and TLR3 activation. However, remnants of IFN signaling remained intact, despite β-arrestin 2 activation, as IFN-β, IFN-γ, IFN-λ1, IRF7, TRAIL, and MxA expression were sustained. Similar effects of β-arrestin 2 on IFN signaling occurred in hepatocytes, suggesting that arrestins may broadly modulate IFN responses in multiple cell types. In summary, we identify a novel role of β-arrestin 2 as an integral regulator of type I IFN through its internalization of IFNAR1 and a subsequent selective loss of downstream IFN signaling.
作为抗病毒反应的一个组成部分，I 型干扰素需要调节来调节免疫激活。我们发现β-arrestin 2 是原代人巨噬细胞中 I 型 IFN 的关键调节剂，是先天免疫反应的重要组成部分。β-arrestin 2 被 CCL2/CCR2 信号选择性激活，这诱导 IFN-α的表达减少，但 IFN-β的表达不受影响。β-arrestin 2 的小干扰 RNA 敲低表明其在 IFNAR1 内化以及 STAT1 和 IRF3 激活中的作用。因此，HIV 感染和 TLR3 激活后不会产生细胞因子反应。然而，尽管β-arrestin 2 被激活，但 IFN 信号仍然完整，因为 IFN-β、IFN-γ、IFN-λ1、IRF7、TRAIL 和 MxA 的表达持续存在。β-arrestin 2 在肝细胞中对 IFN 信号的类似作用表明， arrestins 可能在多种细胞类型中广泛调节 IFN 反应。总之，我们发现β-arrestin 2 通过 IFNAR1 的内化及其随后下游 IFN 信号的选择性丧失，作为 I 型 IFN 的一个完整调节剂发挥新的作用。
