ABSTRACT
An integral component of the antiviral response, type I IFNs require regulation to modulate immune activation. We identify ß-arrestin 2 as a key modulator of type I IFN in primary human macrophages, an essential component of the innate immune response. ß-Arrestin 2 was selectively activated by CCL2/CCR2 signaling, which induced a decrease in IFN-α, but not IFN-ß expression. Small interfering RNA knockdown of ß-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 ß-arrestin 2 activation, as IFN-ß, IFN-γ, IFN-λ1, IRF7, TRAIL, and MxA expression were sustained. Similar effects of ß-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 ß-arrestin 2 as an integral regulator of type I IFN through its internalization of IFNAR1 and a subsequent selective loss of downstream IFN signaling.
