TRIL, a Functional Component of the TLR4 Signaling Complex, Highly Expressed in Brain

Carpenter, Susan; Carlson, Thaddeus; Dellacasagrande, Jérôme; Garcia, Amaya; Gibbons, Sharon; Hertzog, Paul J.; Lyons, Alan M.; Lin, Lih-Ling; Lynch, Marina A.; Monie, Tom P.; Murphy, Caroline; Seidl, Katherine J.; Wells, Christine A.; Dunne, Aisling; O’Neill, Luke A. J.

doi:10.4049/jimmunol.0901518

Cited by 49 publications

(57 citation statements)

References 30 publications

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“…We identified TRIL (TLR4 interactor with leucine rich repeats) as a novel modulator of TLR4 signaling showing high expression in the brain (1). We now show that TRIL also plays a role in TLR3 signaling.…”

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confidence: 61%

“…L. A. J. O'Neill is a cofounder, minority shareholder, and member of the scientific advisory board of Opsona Therapeutics Ltd., a University Start-up company involved in the development of anti-inflammatory therapeutics. 1 Both authors contributed equally to this work. 2 (1).…”

Section: Methodsmentioning

confidence: 99%

“…1 Both authors contributed equally to this work. 2 (1). Cells were cultured in DMEM for 10 days prior to treatment.…”

Section: Methodsmentioning

confidence: 99%

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Toll-like Receptor 3 (TLR3) Signaling Requires TLR4 Interactor with Leucine-rich Repeats (TRIL)

Carpenter¹,

Wochal²,

Dunne

et al. 2011

Journal of Biological Chemistry

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Toll-like receptors (TLRs) are a family of proteins that act as the primary sensors of microbial products. Many TLRs require accessory molecules in order to recognize these microbial products and initiate signal transduction cascades. We have identified TRIL (TLR4 interactor with leucine-rich repeats) as a novel modulator of TLR4 signaling showing high expression in the brain. We now show that TRIL also plays a role in TLR3 signaling. TRIL is expressed intracellularly in the astrocytoma cell line U373 and in the monocytic cell line THP1. TRIL co-localizes with the endosomal compartment. These data are consistent with a role for TRIL in TLR3 signaling and endosomal TLR4 signaling. TRIL was induced by the TLR3 ligand poly(I:C). Overexpression of TRIL enhanced cytokine production and interferon-stimulated response element (ISRE) luciferase activity following poly(I:C) stimulation in U373. TRIL interacted with TLR3, and this interaction was enhanced following poly(I:C) stimulation. Transient knockdown of TRIL with siRNA or stable knockdown using shRNA in U373 cells inhibited TLR3 signaling, reducing ISRE luciferase, RANTES, and type I interferon production. Knockdown of TRIL did not affect TLR2 signaling. Most accessory molecules identified to date, such as CD14, gp96, PRAT4a, and Unc93B, all play roles in multiple TLR signaling pathways, and we now show that this is also the case for TRIL. Toll-like receptors (TLRs)3 are pattern recognition receptors essential for the recognition of a wide range of microbial products (2). TLR4, -1, -2, and -6 are expressed on the surface of cells and recognize microbial products, such as LPS and lipopeptides, whereas TLR3, -7, -8, and -9 are expressed intracellularly and are involved in the recognition of nucleic acids (3). The subcellular localization of TLRs is optimized for recognition of microbial products and results in the activation of a specific type of transcriptional response. TLRs activated at the plasma membrane engage MyD88, leading to the activation of NFB, resulting in the production of proinflammatory cytokines. In contrast, the intracellular TLRs (TLR7, -8, and -9) all associate with MyD88 and lead to the activation of IRF7, resulting in the production of type I interferons. TLR3 engages the adaptor molecule TRIF in order to activate the production of type I interferons (4). In addition, TLR4 has been found to traffic to the early endosome. At the plasma membrane, TLR4 engages with MyD88 and signals to activate NFB. When TLR4 is endocytosed, it binds TRIF, resulting in the production of type 1 interferons (5).In order for the TLR signaling complexes to function, they require a number of accessory molecules (6). Some accessory proteins function at the level of regulation at the cell surface, such as MD-2. Both MD-2 and TLR4 bind to LPS and initiate signaling (7). MD-2 knock-out mice fail to respond to LPS, further emphasizing the important role MD-2 plays in this response (8). RP-105 also functions at the cell surface, where it appears to have contrasting roles, whi...

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confidence: 61%

Section: Methodsmentioning

confidence: 99%

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Toll-like Receptor 3 (TLR3) Signaling Requires TLR4 Interactor with Leucine-rich Repeats (TRIL)

Carpenter¹,

Wochal²,

Dunne

et al. 2011

Journal of Biological Chemistry

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“…1A). Tril is a transmembrane protein that functions as a coreceptor for Toll-like receptor (Tlr)3 and Tlr4 to mediate innate immune responses in the brain of adult mammals (Carpenter et al, 2009(Carpenter et al, , 2011Wochal et al, 2014). The extracellular domain contains multiple leucine-rich repeats (LRRs) and a fibronectin type III domain (FN), while the intracellular domain (ICD) contains no known signaling motifs (Fig.…”

Section: Results Tril Is a Downstream Target Of Gata2 That Is Expressmentioning

confidence: 99%

“…Tril was originally identified as a co-receptor that interacts with Tlr3 and Tlr4 to activate the NF-κB transcription complex during innate immunity (Carpenter et al, 2009(Carpenter et al, , 2011), but it is not known whether it functions in concert with Tlrs in all contexts. In Drosophila, Toll-mediated activation of NF-κB plays an essential role in dorsoventral patterning by inducing expression of Bmp antagonists and repressing expression of decapentaplegic, the fly ortholog of bmp2/4 (Hong et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Tril targets Smad7 for degradation to allow hematopoietic specification in Xenopus embryos

et al. 2016

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In Xenopus laevis, Bone morphogenetic proteins induce expression of the transcription factor Gata2 during gastrulation, and Gata2 is required in both ectodermal and mesodermal cells to enable mesoderm to commit to a hematopoietic fate. In the current studies, we identify tril as a Gata2 target gene that is required in both ectoderm and mesoderm for primitive hematopoiesis to occur. Tril is a transmembrane protein that functions as a co-receptor for Toll like receptors to mediate innate immune responses in the adult brain, but developmental roles for this molecule have not been identified. We show that Tril function is required both upstream and downstream of Bmp receptor mediated Smad1 phosphorylation for induction of Bmp target genes. Mechanistically, Tril triggers degradation of the Bmp inhibitor, Smad7. Tril-dependent down regulation of Smad7 relieves repression of endogenous Bmp signaling during gastrulation and this enables mesodermal progenitors to commit to a blood fate. Thus, Tril is a novel component of a Bmp-Gata2 positive feedback loop that plays an essential role in hematopoietic specification.

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An inhaled dose of budesonide induces genes involved in transcription and signaling in the human airways: enhancement of anti‐ and proinflammatory effector genes

Leigh

Mostafa

King

et al. 2016

Pharmacology Res & Perspec

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Although inhaled glucocorticoids, or corticosteroids (ICS), are generally effective in asthma, understanding their anti‐inflammatory actions in vivo remains incomplete. To characterize glucocorticoid‐induced modulation of gene expression in the human airways, we performed a randomized placebo‐controlled crossover study in healthy male volunteers. Six hours after placebo or budesonide inhalation, whole blood, bronchial brushings, and endobronchial biopsies were collected. Microarray analysis of biopsy RNA, using stringent (≥2‐fold, 5% false discovery rate) or less stringent (≥1.25‐fold, P ≤ 0.05) criteria, identified 46 and 588 budesonide‐induced genes, respectively. Approximately two third of these genes are transcriptional regulators (KLF9, PER1, TSC22D3, ZBTB16), receptors (CD163, CNR1, CXCR4, LIFR, TLR2), or signaling genes (DUSP1, NFKBIA, RGS1, RGS2, ZFP36). Listed genes were qPCR verified. Expression of anti‐inflammatory and other potentially beneficial genes is therefore confirmed and consistent with gene ontology (GO) terms for negative regulation of transcription and gene expression. However, GO terms for transcription, signaling, metabolism, proliferation, inflammatory responses, and cell movement were also associated with the budesonide‐induced genes. The most enriched functional cluster indicates positive regulation of proliferation, locomotion, movement, and migration. Moreover, comparison with the budesonide‐induced expression profile in primary human airway epithelial cells shows considerable cell type specificity. In conclusion, increased expression of multiple genes, including the transcriptional repressor, ZBTB16, that reduce inflammatory signaling and gene expression, occurs in the airways and blood and may contribute to the therapeutic efficacy of ICS. This provides a previously lacking insight into the in vivo effects of ICS and should promote strategies to improve glucocorticoid efficacy in inflammatory diseases.

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TRIL, a Functional Component of the TLR4 Signaling Complex, Highly Expressed in Brain

Cited by 49 publications

References 30 publications

Toll-like Receptor 3 (TLR3) Signaling Requires TLR4 Interactor with Leucine-rich Repeats (TRIL)

Toll-like Receptor 3 (TLR3) Signaling Requires TLR4 Interactor with Leucine-rich Repeats (TRIL)

Tril targets Smad7 for degradation to allow hematopoietic specification in Xenopus embryos

An inhaled dose of budesonide induces genes involved in transcription and signaling in the human airways: enhancement of anti‐ and proinflammatory effector genes

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