Indirect inhibition of toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins

Lu Wang, Rachael A. Gordon, Linda Huynh, Xiaodi Su, Kyung Hyun Park Min, Jiahuai Han, J. Simon Arthur, George D. Kalliolias, Lionel B. Ivashkiv (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    118 Citations (Scopus)

    Abstract

    An important function of immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptors is cross-regulation of heterologous receptor signaling, but mechanisms of cross-inhibition are poorly understood. We show that high-avidity ligation of ITAM-coupled β2 integrins and FcγRs in macrophages inhibited type I interferon receptor and Toll-like receptor (TLR) signaling and induced expression of interleukin-10 (IL-10); signaling inhibitors SOCS3, ABIN-3, and A20; and repressors of cytokine gene transcription STAT3 and Hes1. Induction of inhibitors was dependent on a pathway composed of signaling molecules DAP12, Syk, and Pyk2 that coupled to downstream kinases p38 and MSKs and required integration of IL-10-dependent and -independent signals. ITAM-induced inhibitors abrogated TLR responses by cooperatively targeting distinct steps in TLR signaling. Inhibitory signaling was suppressed by IFN-γ and attenuated in inflammatory arthritis synovial macrophages. These results provide an indirect mechanism of cross-inhibition of TLRs and delineate a signaling pathway important for deactivation of macrophages.

    Original languageEnglish
    Pages (from-to)518-530
    Number of pages13
    JournalImmunity
    Volume32
    Issue number4
    DOIs
    Publication statusPublished - 23 Apr 2010

    Keywords

    • Cellimmuno
    • Molimmuno
    • Signaling

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology
    • Infectious Diseases

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