Indirect Inhibition of Toll-like Receptor and Type I Interferon Responses by ITAM-coupled Receptors and Integrins

Overview

Journal Immunity

Publisher Cell Press

Specialty Allergy & Immunology

Date 2010 Apr 6

PMID 20362473

Citations 85

Authors

Lu Wang

Rachael A Gordon

Linda Huynh

Xiaodi Su

Kyung-Hyun Park Min

Jiahuai Han

J Simon Arthur

George D Kalliolias

Lionel B Ivashkiv

Affiliations

Soon will be listed here.

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.

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