Double-Stranded RNA of Intestinal Commensal but Not Pathogenic Bacteria Triggers Production of Protective Interferon-β

Kawashima, Tadaomi; Kosaka, Akemi; Hu, Yan; Guo, Zijin; Uchiyama, Ryosuke; Fukui, Ryutaro; Kaneko, Daisuke; Kumagai, Yutaro; You, Dong-Ju; Carreras, Joaquim; Uematsu, Satoshi; Jang, Myoung Ho; Takeuchi, Osamu; Kaisho, Tsuneyasu; Akira, Shizuo; Miyake, Kensuke; Tsutsui, Hiroko; Saito, Takashi; Nishimura, Ikuya; Tsuji, Noriko M.

doi:10.1016/j.immuni.2013.02.024

Cited by 189 publications

(207 citation statements)

References 47 publications

(52 reference statements)

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“…These findings are consistent with a recent study showing that TLR-induced type I IFN levels were reduced by a PIKfyve inhibitor in RAW264.7 murine macrophage cells via induction of ATF3 (21). Immune cells can rapidly respond to low systemic concentrations of type I IFNs, which are constitutively maintained under homeostatic conditions by the commensal microflora (48,49). Indeed, low-level basal IFN-b expression induces IFNAR signaling via an autocrine loop and is important for priming immune cells for rapid responses to microbial insults (3).…”

Section: Discussionsupporting

confidence: 90%

ATF3 Is a Key Regulator of Macrophage IFN Responses

Labzin

Schmidt

Masters

et al. 2015

The Journal of Immunology

105

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Cytokines and IFNs downstream of innate immune pathways are critical for mounting an appropriate immune response to microbial infection. However, the expression of these inflammatory mediators is tightly regulated, as uncontrolled production can result in tissue damage and lead to chronic inflammatory conditions and autoimmune diseases. Activating transcription factor 3 (ATF3) is an important transcriptional modulator that limits the inflammatory response by controlling the expression of a number of cytokines and chemokines. However, its role in modulating IFN responses remains poorly defined. In this study, we demonstrate that ATF3 expression in macrophages is necessary for governing basal IFN-β expression, as well as the magnitude of IFN-β cytokine production following activation of innate immune receptors. We found that ATF3 acted as a transcriptional repressor and regulated IFN-β via direct binding to a previously unidentified specific regulatory site distal to the Ifnb1 promoter. Additionally, we observed that ATF3 itself is a type I IFN–inducible gene, and that ATF3 further modulates the expression of a subset of inflammatory genes downstream of IFN signaling, suggesting it constitutes a key component of an IFN negative feedback loop. Consistent with this, macrophages deficient in Atf3 showed enhanced viral clearance in lymphocytic choriomeningitis virus and vesicular stomatitis virus infection models. Our study therefore demonstrates an important role for ATF3 in modulating IFN responses in macrophages by controlling basal and inducible levels of IFNβ, as well as the expression of genes downstream of IFN signaling.

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Section: Discussionsupporting

confidence: 90%

ATF3 Is a Key Regulator of Macrophage IFN Responses

Labzin

Schmidt

Masters

et al. 2015

The Journal of Immunology

105

View full text Add to dashboard Cite

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“…Endotoxin levels derived from food and the gut microbiota reach significant concentrations within the intestinal lumen (22). Although the local concentration of TLR3 ligands under healthy conditions is unknown, dsRNA species released from both exfoliated host cells and commensal bacteria were recently reported to drive TLR3/TRIF-dependent protective gene expression at the intestinal mucosa (67)(68)(69). This could also explain the sustained expression of Paneth cell antimicrobial peptides under GF conditions in accordance with a previous report (46).…”

Section: Discussionsupporting

confidence: 80%

“…We therefore hypothesize that the absence of also a third complex member, TRIF, might induce a milder form of epithelial necroptosis leading to reduced Paneth cell antimicrobial peptide synthesis in TRIF mutant mice. A recent report on continuous TLR3-mediated IFN stimulation by commensal enteric bacteria suggests that also the atypical death complex might be formed under homeostatic conditions (69). Paneth cell loss in TRIF-deficient mice was independent of TNF in accordance with a recent report (77); in fact, TNF by a so far uncharacterized pathway induced rapid enhancement of antimicrobial peptide expression.…”

Section: Discussionsupporting

confidence: 79%

TRIF Signaling Drives Homeostatic Intestinal Epithelial Antimicrobial Peptide Expression

Stockinger

Duerr

Fulde

et al. 2014

The Journal of Immunology

Self Cite

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Recent results indicate a significant contribution of innate immune signaling to maintain mucosal homeostasis, but the precise underlying signal transduction pathways are ill-defined. By comparative analysis of intestinal epithelial cells isolated from conventionally raised and germ-free mice, as well as animals deficient in the adaptor molecules MyD88 and TRIF, the TLR3 and TLR4, as well as the type I and III IFN receptors, we demonstrate significant TLR-mediated signaling under homeostatic conditions. Surprisingly, homeostatic expression of Reg3γ and Paneth cell enteric antimicrobial peptides critically relied on TRIF and, in part, TLR3 but was independent of IFN receptor signaling. Reduced antimicrobial peptide expression was associated with significantly lower numbers of Paneth cells and a reduced Paneth cell maturation and differentiation factor expression in TRIF mutant compared with wild-type epithelium. This phenotype was not transferred to TRIF-sufficient germ-free animals during cohousing. Low antimicrobial peptide expression in TRIF-deficient mice caused reduced immediate killing of orally administered bacteria but was not associated with significant alterations in the overall composition of the enteric microbiota. The phenotype was rapidly restored in a TRIF-independent fashion after transient epithelial damage. Our results identify TRIF signaling as a truly homeostatic pathway to maintain intestinal epithelial barrier function revealing fundamental differences in the innate immune signaling between mucosal homeostasis and tissue repair.

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“…Of note, another important source of tonic type I IFN production can origin via PRR-dependent mechanisms in myeloid cells of the gut. In this regard, it has been shown that commensal microbiota provide an important source of PRR ligands under steady state that are important to facilitate antiviral immunity [32][33][34]. While we can exclude this route of paracrine priming in our in vitro assays, this mode of action might be of relevance for optimal pDC responses in vivo.…”

Section: Discussionmentioning

confidence: 94%

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

et al. 2014

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Plasmacytoid dendritic cells (pDCs) are responsible for the robust and immediate production of type I IFNs during viral infection. pDCs employ TLR7 and TLR9 to detect RNA and CpG motifs present in microbial genomes. CpG-A was the first synthetic stimulus available that induced large amounts of IFN-α (type I IFN) in pDCs. CpG-B, however, only weakly activates pDCs to produce IFN-α. Here, we demonstrate that differences in the kinetics of TLR9 activation in human pDCs are essential for the understanding of the functional difference between CpG-A and CpG-B. While CpG-B quickly induces IFN-α production in pDCs, CpG-A stimulation results in delayed yet maximal IFN-α induction. Constitutive production of low levels of type I IFN in pDCs, acting in a paracrine and autocrine fashion, turned out to be the key mechanism responsible for this phenomenon. At high cell density, pDC-derived, constitutive type I IFN production primes pDCs for maximal TLR responsiveness. This accounts for the high activity of higher structured TLR agonists that trigger type I IFN production in a delayed fashion. Altogether, these data demonstrate that high type I IFN production by pDCs cannot be simply ascribed to cell-autonomous mechanisms, yet critically depends on the local immune context. Keywords:CpG-A r CpG-B r pDC r TLR9 r Type I IFN Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe recognition of invading pathogens and the initiation of an appropriate immune response are key functions of the innate immune system. TLRs are a family of PRRs that sense conserved microbial signatures, also known as PAMPs [1,2]. Among these, TLR9 detects unmethylated CpG-motifs, which are present in viral Correspondence: Prof. Veit Hornung e-mail: veit.hornung@uni-bonn.de and bacterial DNA, whereas TLR7 senses uridine-rich RNA. To prevent recognition of endogenous nucleic acids, both TLR7 and TLR9 are confined to endosomal compartments that are usually devoid of nucleic acids. While both TLR7 and TLR9 are broadly expressed in innate immune cells of the murine system, both TLR7 and TLR9 show a far more restricted expression pattern within the human system, with TLR9 expression restricted to B cells and pDCs. * These authors equally contributed to this work.C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 808Sarah Kim et al. Eur. J. Immunol. 2014. 44: 807-818 TLR9 traffics from the endoplasmic reticulum through the Golgi apparatus to acidic endosomal compartments, where it is proteolytically cleaved to achieve its signaling-competent state. Following ligand engagement, TLR9 initiates a signaling cascade, which is dependent on MyD88. In pDCs, MyD88 triggers a signaling complex consisting of IRAK1/4, TRAF3, and IKKα that leads to phosphorylation and nuclear translocation of interferon regulatory factor 7 (IRF7) and transcription of type I IFN genes. At the same time, TLR9 engagement activates NF-κB and subsequent proinflammatory gene expression [3]. For TLR9, di...

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Double-Stranded RNA of Intestinal Commensal but Not Pathogenic Bacteria Triggers Production of Protective Interferon-β

Cited by 189 publications

References 47 publications

ATF3 Is a Key Regulator of Macrophage IFN Responses

ATF3 Is a Key Regulator of Macrophage IFN Responses

TRIF Signaling Drives Homeostatic Intestinal Epithelial Antimicrobial Peptide Expression

Self‐priming determines high type I IFN production by plasmacytoid dendritic cells

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