Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 105-118 |
| Number of pages | 14 |
| Journal | Journal of Immunology |
| Volume | 202 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 1 2019 |
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ASJC Scopus subject areas
- Immunology and Allergy
- Immunology
Cite this
CCR2 signaling selectively regulates IFN-α : Role of β-arrestin 2 in IFNAR1 internalization. / Williams, Dionna; Askew, Lauren C.; Jones, Elonna; Clements, Janice E.
In: Journal of Immunology, Vol. 202, No. 1, 01.01.2019, p. 105-118.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - CCR2 signaling selectively regulates IFN-α
T2 - Role of β-arrestin 2 in IFNAR1 internalization
AU - Williams, Dionna
AU - Askew, Lauren C.
AU - Jones, Elonna
AU - Clements, Janice E
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
VL - 202
SP - 105
EP - 118
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 1
ER -