TY - JOUR
T1 - CCR2 signaling selectively regulates IFN-α
T2 - Role of β-arrestin 2 in IFNAR1 internalization
AU - Williams, Dionna W.
AU - Askew, Lauren C.
AU - Jones, Elonna
AU - Clements, Janice E.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) research Grants K99/ R00 DA044838 (to D.W.W.), R01 AI127142 (to J.E.C.), R01 NS076357 (to J.E.C.), and R01 NS077869 (to J.E.C.), and a Johns Hopkins University Provost’s Postdoctoral Fellowship (to D.W.W.). L.C.A. was supported by the Hopkins Postbaccalaureate Research Education Program (NIH Grant R25 GM109441), E.J. was supported by the Johns Hopkins Internship in Brain Sciences Program (NIH Grant R25 MH100711), and D.W.W. received pilot funds from the Translational Research in NeuroAIDS and Mental Health Center (NIH Grant R25 MH080661). This research has been facilitated by the infrastructure and resources provided by the Johns Hopkins University Center for AIDS Research, an NIH-funded program (Grant P30 AI094189).
Publisher Copyright:
© 2018 by The American Association of Immunologists, Inc.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.1800598
DO - 10.4049/jimmunol.1800598
M3 - Article
C2 - 30504423
AN - SCOPUS:85059239920
SN - 0022-1767
VL - 202
SP - 105
EP - 118
JO - Journal of Immunology
JF - Journal of Immunology
IS - 1
ER -