ITAM-coupled receptors inhibit IFNAR signaling and alter macrophage responses to TLR4 and Listeria monocytogenes

L Huynh, L Wang, C Shi, KH Park-Min… - The Journal of …, 2012 - journals.aai.org
L Huynh, L Wang, C Shi, KH Park-Min, LB Ivashkiv
The Journal of Immunology, 2012journals.aai.org
ITAM-coupled receptors play an essential role in regulating macrophage activation and
function by cross-regulating signaling from heterologous receptors. We investigated
mechanisms by which ITAM-associated receptors inhibit type I IFN (IFN-α/β) signaling in
primary human macrophages and tested the effects of simultaneous ligation of ITAM-
associated receptors and TLR4 on TLR4-induced Jak–STAT signaling that is mediated by
autocrine IFN-β. Preligation of ITAM-coupled β2 integrins and FcγRs inhibited proximal …
Abstract
ITAM-coupled receptors play an essential role in regulating macrophage activation and function by cross-regulating signaling from heterologous receptors. We investigated mechanisms by which ITAM-associated receptors inhibit type I IFN (IFN-α/β) signaling in primary human macrophages and tested the effects of simultaneous ligation of ITAM-associated receptors and TLR4 on TLR4-induced Jak–STAT signaling that is mediated by autocrine IFN-β. Preligation of ITAM-coupled β2 integrins and FcγRs inhibited proximal signaling by the type I IFN receptor IFNAR. Cross-inhibition of IFNAR signaling by β2 integrins resulted in decreased Jak1 activation and was mediated by partial downregulation of the IFNAR1 subunit and MAPK-dependent induction of USP18, which blocks the association of Jak1 with IFNAR2. Simultaneous engagement of ITAM-coupled β2 integrins or Dectin-1 with TLR4 did not affect TLR4-induced direct activation of inflammatory target genes such as TNF or IL6 but abrogated subsequent induction of IFN response genes that is mediated by autocrine IFN-β signaling. Type I IFNs promote macrophage death postinfection by Listeria monocytogenes. Consequently, attenuation of IFN responses by β2 integrins protected primary human macrophages from L. monocytogenes-induced apoptosis. These results provide a mechanism for cross-inhibition of type I IFN signaling by ITAM-coupled β2 integrins and demonstrate that ITAM signaling qualitatively modulates macrophage responses to pathogen-associated molecular patterns and pathogens by selectively suppressing IFN responses.
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