[PDF][PDF] Indirect inhibition of Toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins

L Wang, RA Gordon, L Huynh, X Su, KHP Min, J Han… - Immunity, 2010 - cell.com
L Wang, RA Gordon, L Huynh, X Su, KHP Min, J Han, JS Arthur, GD Kalliolias, LB Ivashkiv
Immunity, 2010cell.com
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 …
Summary
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.
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