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

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. [Display omitted] ► β2 integrins and FcγRs inhibit IFNAR and TLR signaling and cytokine production ► ITAM-induced calcium signaling via DAP12-Syk-Pyk2-p38-MSK, mediates inhibition ► ITAM receptors induce IL-10 and signaling inhibitors SOCS3, ABIN-3, A20, and Hes1 ► Inhibitory signaling is abrogated by IFN-γ and during inflammatory arthritis