TRIL Is Involved in Cytokine Production in the Brain following <i>Escherichia coli</i> Infection

Wochal, Paulina; Rathinam, Vijay; Dunne, Aisling; Carlson, Thaddeus; Kuang, Wenjun; Seidl, Katherine J.; Hall, J. Perry; Lin, Lih-Ling; Collins, Mary; Schattgen, Stefan A.; MacKay, Christopher R.; Fagundes, Caio T.; Carpenter, Susan; Fitzgerald, Katherine A.; O’Neill, Luke A. J.

doi:10.4049/jimmunol.1302392

Cited by 18 publications

(23 citation statements)

References 49 publications

(50 reference statements)

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“…In contrast to the hematopoietic defects observed in Xenopus Tril morphants, mice lacking tril show impaired cytokine production in the brain in response to infection, but do not show gross developmental defects (Wochal et al, 2014). Tril may have subtle functions during mammalian development that have not yet been examined or other molecules present in mice, but not in Xenopus, may compensate for loss of Tril.…”

Section: Discussionmentioning

confidence: 66%

“…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%

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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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Section: Discussionmentioning

confidence: 66%

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

confidence: 99%

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

et al. 2016

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“…In vitro studies showed that the extracellular domain of Tril interacts directly with Tlr4, and with its ligand, LPS, suggesting that it functions primarily to enhance ligand/receptor affinity (7). Subsequent in vitro studies showed that Tril plays a similar role in regulating Tlr3 signaling, and in vivo studies confirmed that Tril is essential for maximal Tlr3-and Tlr4-dependent cytokine production in the brain in response to bacterial infection (8,9).…”

Section: Discussionmentioning

confidence: 97%

“…While Tlrs are known to play non-immune roles in developmental patterning and morphogenesis in insects, evidence that vertebrate Tlr signaling is required for early development is lacking (12). Recent studies, however, have shown that Tlr signaling is required for normal neurogenesis, axonal growth and structural plasticity in the developing and adult brain (11), where Tril is highly expressed (9). Very little is known about the signaling pathways that are initiated by Tlrs to mediate these non-immune effects.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism by which Tril signals to degrade Smad7 is unknown. Tril was initially characterized as a co-receptor for Tlr3 and Tlr4 and is required to mediate innate immune responses in the brain of adult mammals (7)(8)(9). Tlrs bind microbial products or nucleic acids, initiating a signaling cascade involving cytoplasmic adaptors, kinases and ubiquitin ligases that generally culminates in activation of transcriptional regulators such as NF-κB, AP-1 and interferon regulatory factors (10).…”

Section: Introductionmentioning

confidence: 99%

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Fibronectin type III and intracellular domains of Toll-like receptor 4 interactor with leucine-rich repeats (Tril) are required for developmental signaling

Kim

McKnite

Xie

et al. 2017

Preprint

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Biased signalling is an essential feature of TLR4 in glioma cells

Zeuner

Krüger

Volk

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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A distinct feature of the Toll-like receptor 4 (TLR4) is its ability to trigger both MyD88-dependent and MyD88-independent signalling, culminating in activation of pro-inflammatory NF-κB and/or the antiviral IRF3. Although TLR4 agonists (lipopolysaccharides; LPSs) derived from different bacterial species have different endotoxic activity, the impact of LPS chemotype on the downstream signalling is not fully understood. Notably, different TLR4 agonists exhibit antitumoural activity in animal models of glioma, but the underlying molecular mechanisms are largely unknown. Thus, we investigated the impact of LPS chemotype on the signalling events in the human glioma cell line U251. We found that LPS of Escherichia coli origin (LPSEC) leads to NF-κBbiased downstream signalling compared to Salmonella minnesota-derived LPS (LPSSM).Exposure of U251 cells to LPSEC resulted in faster nuclear translocation of the NF-κB subunit p65, higher NF-κB-activity and expression of its targets genes, and higher amount of secreted IL-6 compared to LPSSM. Using super-resolution microscopy we showed that the biased agonism of TLR4 in glioma cells is neither a result of differential regulation of receptor density nor of formation of higher order oligomers. Consistent with previous reports, LPSEC-mediated NF-κB activation led to significantly increased U251 proliferation, whereas LPSSM-induced IRF3 activity negatively influenced their invasiveness. Finally, treatment with methyl-βcyclodextrin (MCD) selectively increased LPSSM-induced nuclear translocation of p65 and NF-κB activity without affecting IRF3.Our data may explain how TLR4 agonists differently affect glioma cell proliferation and migration.

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TRIL Is Involved in Cytokine Production in the Brain following Escherichia coli Infection

Cited by 18 publications

References 49 publications

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

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

Fibronectin type III and intracellular domains of Toll-like receptor 4 interactor with leucine-rich repeats (Tril) are required for developmental signaling

Biased signalling is an essential feature of TLR4 in glioma cells

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