CCR2 signaling selectively regulates IFN-α: Role of β-arrestin 2 in IFNAR1 internalization

Dionna Williams, Lauren C. Askew, Elonna Jones, Janice E Clements

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)105-118
Number of pages14
JournalJournal of Immunology
Volume202
Issue number1
DOIs
StatePublished - Jan 1 2019

Fingerprint

Arrestins
Innate Immunity
Small Interfering RNA
HIV Infections
Antiviral Agents
beta-Arrestin 1
Hepatocytes
Macrophages
Cytokines

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 journalArticle

@article{f112cee99f4b4f1786932be987bce929,
title = "CCR2 signaling selectively regulates IFN-α: Role of β-arrestin 2 in IFNAR1 internalization",
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.",
author = "Dionna Williams and Askew, {Lauren C.} and Elonna Jones and Clements, {Janice E}",
year = "2019",
month = "1",
day = "1",
doi = "10.4049/jimmunol.1800598",
language = "English (US)",
volume = "202",
pages = "105--118",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "1",

}

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.

UR - http://www.scopus.com/inward/record.url?scp=85059239920&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059239920&partnerID=8YFLogxK

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 -