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 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.
Wang
Lu
L
Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY 10021, USA.
Gordon
Rachael A
RA
Huynh
Linda
L
Su
Xiaodi
X
Park Min
Kyung-Hyun
KH
Han
Jiahuai
J
Arthur
J Simon
JS
Kalliolias
George D
GD
Ivashkiv
Lionel B
LB
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D018821:CD18 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D051418:Focal Adhesion Kinase 2 / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000276:immunology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology*; D015398:Signal Transduction; D000072377:Syk Kinase; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D018821:CD18 Antigens; D007370:Interferon Type I; D047908:Intracellular Signaling Peptides and Proteins; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; C484963:Tyrobp protein, mouse; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse