Interferon‐regulatory‐factor 1 controls Toll‐like receptor 9‐mediated IFN‐β production in myeloid dendritic cells

Abstract

Activation of interferon regulatory factor (IRF)-3 and/or IRF-7 drives the expression of antiviral genes and the production of a/b IFN, a hallmark of antiviral responses triggered by Toll-like receptors (TLR). Here we describe a novel antiviral signaling pathway operating in myeloid (m) dendritic cells (DC) and macrophages that does not require IRF-3 and/or IRF-7 but is driven by IRF-1. IRF-1 together with myeloid differentiation factor 88 (MyD88) or IL-1 receptor-associated kinase (IRAK)-1 triggered IFN-b promoter activation. IRF-1 physically interacted with MyD88 and activation of mDC via TLR-9 induced IRF-1-dependent IFN-b production paralleled by rapid transcriptional activation of IFN-stimulated genes. The NF-jB-dependent production of pro-inflammatory cytokines, however, was not influenced by IRF-1. TLR-9 signaling through this pathway conferred cellular antiviral resistance while IRF-1-deficient mice displayed enhanced susceptibility to viral infection. These results demonstrate that TLR-9 activation of mDC and macrophages contributes to antiviral immunity via IRF-1. See accompanying commentary: http://dx

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

“…TLR9 agonists (e.g. type B CpG DNA) stimulate robust IFN-b induction in myeloid DC and macrophages through MyD88 and IRF-1 independently of IRF3 or IRF7 [12,41]. Lack of synergy with the TLR9 agonist is consistent with specificity of IFN-b synergy for the IRF3 activating pathways.…”

“…PRR in the retinoic acid-inducible gene (RIG)-like helicase family, RIG-I and melanoma differentiation-associated antigen 5 (MDA5), recognize cytoplasmic dsRNA, and mediate IFN-b induction through IFN-b promoter stimulator-1 and downstream IRF3 and NF-jB activation [10]. In addition, in plasmacytoid and myeloid DC, engagement of endosomal TLR9 family members results in robust induction of type I IFN via MyD88-IRF7 and MyD88-IRF1, respectively, rather than IRF3 [11,12].…”

“…In both instances increased IFN-b gene transcription occurs via TLR/IL-1R domain-containing adapter inducing IFN-b (TRIF)-dependent IRF3 and NF-jB activation. PRR in the retinoic acid-inducible gene (RIG)-like helicase family, RIG-I and melanoma differentiation-associated antigen 5 (MDA5), recognize cytoplasmic dsRNA, [11,12]. Even as cells of the innate immune system are poised to respond to microbial 'danger' signals via PRR, there are also mechanisms in place to deal with intracellular threats.…”

MAVS-dependent IRF3/7 bypass of interferon β-induction restricts the response to measles infection in CD150Tg mouse bone marrow-derived dendritic cells

“…, 2013). IRF1 is also involved in TLR9-mediated IFN- production in BMDCs (Schmitz et al, 2007). In the case of MV infection, IRF5…”

Papel dos receptores do tipo Toll na morte celular induzida por ativação (AICD) de linfócitos T.

“…Ao contrário das pDCs, a produção de IFN do tipo I pelas cDCs é dependente de IRF1. Em cDCs deficientes em IRF1 a indução de IFNβ em resposta a agonistas de TLR9 está comprometida, enquanto que em pDCs a produção de IFN-β e IFN-α apresenta-se em quantidades normais [12,13].…”