Indirect inhibition of Toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins. Academic Article uri icon

Overview

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 beta2 integrins and FcgammaRs 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-gamma 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.

publication date

  • April 1, 2010

Research

keywords

  • CD18 Antigens
  • Interferon Type I
  • Receptors, Immunologic
  • Toll-Like Receptors

Identity

PubMed Central ID

  • PMC2862476

Scopus Document Identifier

  • 77951892594

Digital Object Identifier (DOI)

  • 10.1016/j.immuni.2010.03.014

PubMed ID

  • 20362473

Additional Document Info

volume

  • 32

issue

  • 4