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

Abstract

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 comprised 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.

Involvement of the HCK and FGR src-Family Kinases in FCRL4-Mediated Immune Regulation

“…Regulation of TLR signaling by ITAM/ITIM-bearing receptors has been reported, and an incompletely understood mechanism involving src-family kinases has been suggested (45)(46)(47). Our observations of enhanced cytokine expression levels in FCRL4 wt transfected Bmem cells after CpG treatment are in agreement with observations of increased CD23 expression in R2G6 cells and primary human B cells in response to TLR9 engagement (24).…”

Fibrin deposition following bile duct injury limits fibrosis through an αMβ2-dependent mechanism

“…Interestingly, there is precedent for this pathway, as other studies have suggested that ITAM-coupled integrins can inhibit IFN signaling in macrophages. 36 Collectively, the results suggest a mechanism wherein fibrin(ogen)-a M b 2 binding inhibits bile duct hyperplasia and the ensuing fibrosis in ANITexposed mice by inhibiting IFNg-mediated macrophage activation (supplemental Figure 7). Although additional experimentation is required, this hypothesis is consistent with the exciting concept that fibrin(ogen) deposition is not just reactive to tissue injury, but instead can carefully tailor local leukocyte activity to modify disease progression.…”

“…36 Thus, we tested the hypothesis that the fibrin(ogen)-a M b 2 binding could suppress IFNg-mediated NOS2 induction. Fibrinogen adhered to a surface, such as cell culture plastic, and engages a M b 2 , allowing us to test this hypothesis in vitro.…”

Targeting DAMP Activation of Toll-Like Receptors: Novel Pathways to Treat Rheumatoid Arthritis?

“…Some such as TREM1 appear to cooperate with TLR molecules, amplifying the production of pro-inflammatory cytokines (Bleharski et al, 2003) whilst others such as the FcR and the CD300F molecule inhibit TLR signalling (Wang et al, 2010). Other cell surface molecules able to modulate TLR activity include the TAM (Tyro3, Axl, Mer) receptors and SIGIRR (Rothlin et al, 2007;Drexler et al, 2010).…”