title: ITAM-coupled receptors inhibit IFNAR signaling and alter macrophage responses to TLR4 and Listeria monocytogenes.
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.
authors.affiliation: Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Huynh
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Shi
authors.forename: Kyung-Hyun
authors.initials: KH
authors.lastname: Park-Min
authors.forename: Lionel B
authors.initials: LB
authors.lastname: Ivashkiv
mesh_terms: D020816:Amino Acid Motifs; D017209:Apoptosis; D019898:Autocrine Communication; D018821:CD18 Antigens / Q000276:immunology*; D002478:Cells, Cultured / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000276:immunology; D053612:Janus Kinases / Q000502:physiology; D008089:Listeria monocytogenes / Q000276:immunology*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D034622:RNA Interference; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors* / Q000276:immunology; D011971:Receptors, Immunologic / Q000737:chemistry / Q000276:immunology*; D050791:STAT Transcription Factors / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000276:immunology*
chemical_list: D018821:CD18 Antigens; D016207:Cytokines; C507964:IFNAR1 protein, human; D007370:Interferon Type I; D011971:Receptors, Immunologic; D050791:STAT Transcription Factors; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D053633:Receptor, Interferon alpha-beta; D053612:Janus Kinases