Indirect inhibition of toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins

TY - JOUR

T1 - Indirect inhibition of toll-like receptor and type I interferon responses by ITAM-coupled receptors and integrins

AU - Wang, Lu

AU - Gordon, Rachael A.

AU - Huynh, Linda

AU - Su, Xiaodi

AU - Min, Kyung Hyun Park

AU - Han, Jiahuai

AU - Arthur, J. Simon

AU - Kalliolias, George D.

AU - Ivashkiv, Lionel B.

N1 - Funding Information: We thank V. Tybulewicz (National Institute for Medical Research, London, UK) for providing Syk-deficient mice and X. Hu for critically reviewing the manuscript. We thank M. Hong and M. Otsuka for assistance with obtaining p38α-deficient macrophages and A. Ding for providing MyD88- and Trif-deficient mice. We thank the Hospital for Special Surgery rheumatologists for providing synovial specimens. This work was supported by grants from the NIH to L.B.I. and the Kirkland Center for Lupus Research. L.W. was supported by a training grant from the NIH (T32 AR07517). K.H.-P.M. is supported by a grant from the Arthritis Foundation. L.W. designed and performed most of the experiments and wrote the manuscript; R.A.G. performed the experiments with arthritic macrophages; L.H., X.S., and K.H.-P.M. contributed to experiments with IFNs; J.H. and J.S.C.A. provided mice and cells; G.D.K. oversaw the arthritic macrophage experiments; and L.B.I. conceptualized the project, designed and supervised research, and wrote the manuscript.

PY - 2010/4/23

Y1 - 2010/4/23

N2 - 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.

AB - 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.

KW - Cellimmuno

KW - Molimmuno

KW - Signaling

UR - https://www.scopus.com/pages/publications/77951892594

U2 - 10.1016/j.immuni.2010.03.014

DO - 10.1016/j.immuni.2010.03.014

M3 - Article

C2 - 20362473

AN - SCOPUS:77951892594

SN - 1074-7613

VL - 32

SP - 518

EP - 530

JO - Immunity

JF - Immunity

IS - 4

ER -