The IL-1RI Co-Receptor TILRR (FREM1 Isoform 2) Controls Aberrant Inflammatory Responses and Development of Vascular Disease.
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ABSTRACT:
SUBMITTER: Smith SA
PROVIDER: S-EPMC5582195 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The TLRs and IL-1 receptors have evolved to coordinate the innate immune response following pathogen invasion. Receptors and signalling intermediates of these systems are generally characterised by a high level of evolutionary conservation. The recently described IL-1R1 co-receptor TILRR is a transcriptional variant of the FREM1 gene. Here we investigate whether innate co-receptor differences between teleosts and mammals extend to the expression of the TILRR isoform of FREM1. Bioinformatic and phylogenetic approaches were used to analyse the genome sequences of FREM1 from eukaryotic organisms including 37 tetrapods and five teleost fish. The TILRR consensus peptide sequence was present in the FREM1 gene of the tetrapods, but not in fish orthologs of FREM1, and neither FREM1 nor TILRR were present in invertebrates. The TILRR gene appears to have arisen via incorporation of adjacent non-coding DNA with a contiguous exonic sequence after the teleost divergence. Comparing co-receptors in other systems, points to their origin during the same stages of evolution. Our results show that modern teleost fish do not possess the IL-1RI co-receptor TILRR, but that this is maintained in tetrapods as early as amphibians. Further, they are consistent with data showing that co-receptors are recent additions to these regulatory systems and suggest this may underlie differences in innate immune responses between mammals and fish.
| S-EPMC4009816 | biostudies-literature
Project description:Host defense against infection is induced by Toll-like and interleukin (IL)-1 receptors, and controlled by the transcription factor NF-kappaB. Our earlier studies have shown that IL-1 activation impacts cytoskeletal structure and that IL-1 receptor (IL-1RI) function is substrate-dependent. Here we identify a novel regulatory component, TILRR, which amplifies activation of IL-1RI and coordinates IL-1-induced control with mechanotransduction. We show that TILRR is a highly conserved and widely expressed enhancer of IL-1-regulated inflammatory responses and, further, that it is a membrane-bound glycosylated protein with sequence homology to members of the FRAS-1 family. We demonstrate that TILRR is recruited to the IL-1 receptor complex and magnifies signal amplification by increasing receptor expression and ligand binding. In addition, we show that the consequent potentiation of NF-kappaB is controlled through IL-1RI-associated signaling components in coordination with activation of the Ras GTPase. Using mutagenesis, we demonstrate that TILRR function is dependent on association with its signaling partner and, further, that formation of the TILRR-containing IL-1RI complex imparts enhanced association of the MyD88 adapter during ligand-induced activation of NF-kappaB. We conclude that TILRR is an IL-1RI co-receptor, which associates with the signaling receptor complex to enhance recruitment of MyD88 and control Ras-dependent amplification of NF-kappaB and inflammatory responses.
| S-EPMC2844171 | biostudies-literature
Project description:Inflammatory responses are controlled through members of the interleukin-1 receptor (IL-1R)/Toll-like receptor superfamily. Our earlier work demonstrates that the IL-1 receptor type 1 (IL-1RI) co-receptor, Toll-like and IL-1 receptor regulator (TILRR), amplifies IL-1 activation of NF-?B and inflammatory genes. Here we show that TILRR similarly promotes IL-1-induced anti-apoptotic signals and reduces caspase-3 activity. Further, the TILRR-induced effects on cell survival and inflammatory responses are controlled through distinct parts of the IL-1RI regulatory Toll IL-1 receptor (TIR) domain. Alanine-scanning mutagenesis identified a functional TILRR mutant (R425A), which blocked increases in cell survival and upstream activation of Akt but had no effect on amplification of MyD88-dependent inflammatory responses. A second mutant (D448A) blocked TILRR potentiation of MyD88-dependent signals and inflammatory activation but had no impact on cell survival. Secondary structure predictions suggested that the mutations induce distinct alterations in the ?-helical structure of the TILRR core protein. The results indicate a role for TILRR in selective amplification of NF-?B responses through IL-1RI and suggest that the specificity is determined by changes in receptor conformation and adapter protein recruitment.
| S-EPMC3320984 | biostudies-literature
Project description:The transcription factor NF-κB (nuclear factor kappa B) is activated by Toll-like receptors and controlled by mechanotransduction and changes in the cytoskeleton. In this study we combine 3-D predictive protein modelling and in vitro experiments with in silico simulations to determine the role of the cytoskeleton in regulation of NF-κB. Simulations used a comprehensive agent-based model of the NF-κB pathway, which includes the type 1 IL-1 receptor (IL-1R1) complex and signalling intermediates, as well as cytoskeletal components. Agent based modelling relies on in silico reproductions of systems through the interactions of its components, and provides a reliable tool in investigations of biological processes, which require spatial considerations and involve complex formation and translocation of regulatory components. We show that our model faithfully reproduces the multiple steps comprising the NF-κB pathway, and provides a framework from which we can explore novel aspects of the system. The analysis, using 3-D predictive protein modelling and in vitro assays, demonstrated that the NF-κB inhibitor, IκBα is sequestered to the actin/spectrin complex within the cytoskeleton of the resting cell, and released during IL-1 stimulation, through a process controlled by the IL-1RI co-receptor TILRR (Toll-like and IL-1 receptor regulator). In silico simulations using the agent-based model predict that the cytoskeletal pool of IκBα is released to adjust signal amplification in relation to input levels. The results suggest that the process provides a mechanism for signal calibration and enables efficient, activation-sensitive regulation of NF-κB and inflammatory responses.
| S-EPMC4482363 | biostudies-literature
Project description:In atherosclerosis, upregulated TILRR (FREM1 isoform 2) expression increases immune cell infiltration. We hypothesized that TILRR expression is also correlated with cancer progression. By analyzing data from Oncomine and the Tumor Immune Estimation Resource, we found that TILRR mRNA expression was significantly lower in breast cancer tissue than adjacent normal tissue. Kaplan-Meier survival analysis and immunohistochemical staining revealed shortened overall survival and disease-free survival in patients with low TILRR expression. TILRR transcript expression was positively correlated with immune score, immune cell biomarkers and the expression of CXCL10 and CXCL11. TILRR expression was also positively correlated with CD8+ and CD4+ T-cell infiltration. These correlations were verified using the ESTIMATE algorithm, gene set enrichment analysis and Q-PCR. We concluded that impaired TILRR expression is correlated with breast cancer prognosis and immune cell infiltration.
| S-EPMC7732299 | biostudies-literature
Project description:FREM1 (Fras-related extracellular matrix 1) and its splice variant TILRR (Toll-like interleukin-1 receptor regulator) have been identified as integral components of innate immune systems. The potential involvement of FREM1 in HIV-1 (human immunodeficiency virus 1) acquisition was suggested by a genome-wide SNP (single nucleotide polymorphism) analysis of HIV-1 resistant and susceptible sex workers enrolled in the Pumwani sex worker cohort (PSWC) in Nairobi, Kenya. The studies showed that the minor allele of a FREM1 SNP rs1552896 is highly enriched in the HIV-1 resistant female sex workers. Subsequent studies showed that FREM1 mRNA is highly expressed in tissues relevant to mucosal HIV-1 infection, including cervical epithelial tissues, and TILRR is a major modulator of many genes in the NF-κB signal transduction pathway. In this article, we review the role of FREM1 and TILRR in modulating inflammatory responses and inflammation, and how their influence on inflammatory responses of cervicovaginal tissue could enhance the risk of vaginal HIV-1 acquisition.
| S-EPMC8346017 | biostudies-literature
Project description:Vascular cells are continuously exposed to mechanical stress that may wreak havoc if exceeding physiological levels. Consequently, mechanisms facing such a challenge are indispensable and contribute to the adaptation of the cellular phenotype. To this end, vascular smooth muscle cells (VSMCs) activate mechanoresponsive transcription factors promoting their proliferation and migration to initiate remodeling the arterial wall. In mechanostimulated VSMCs, we identified nuclear factor of activated T-cells 5 (NFAT5) as transcriptional regulator protein and intended to unravel mechanisms controlling its expression and nuclear translocation. In cultured human VSMCs, blocking RNA synthesis diminished both baseline and stretch-induced NFAT5 mRNA expression while inhibition of the proteasome promoted accumulation of the NFAT5 protein. Detailed PCR analyses indicated a decrease in expression of NFAT5 isoform A and an increase in isoform C in mechanoactivated VSMCs. Upon overexpression, only NFAT5c was capable to enter the nucleus in control- and stretch-stimulated VSMCs. As evidenced by analyses of NFAT5c mutants, nuclear translocation required palmitoylation, phosphorylation at Y143 and was inhibited by phosphorylation at S1197. On the functional level, overexpression of NFAT5c forces its accumulation in the nucleus as well as transcriptional activity and stimulated VSMC proliferation and migration. These findings suggest that NFAT5 is continuously expressed and degraded in resting VSMCs while expression and accumulation of isoform C in the nucleus is facilitated during biomechanical stress to promote an activated VSMC phenotype.
| S-EPMC6115610 | biostudies-literature
Project description:1. Interleukin-1 (IL-1) has been implicated in neurodegeneration and in central nervous system (CNS)-mediated host defence responses to inflammation. All actions of IL-1 identified to date appear to be mediated through its only known functional type I receptor (IL-1RI). However, our recent evidence suggests that some actions of IL-1 in the brain may be IL-1RI independent, suggesting the involvement of a new, hitherto unknown functional receptor for IL-1. 2. The objective of the present study was to determine if primary mixed glial cells express additional functional IL-1 receptors by studying the signalling mechanisms responsible for the pro-inflammatory actions of IL-1beta in cultures derived from IL-1RI-/- and wildtype mice, and to characterize the functional importance of IL-1 signalling pathways in glia. 3. IL-1beta induced marked release of IL-6 and prostaglandin-E(2) (PGE(2)) in the culture medium, and activated nuclear factor-kappa B (NFkappaB) and the mitogen-activated protein kinases (MAPK) p38, c-Jun N-terminal kinase (JNK) and the extracellular signal-regulated protein kinase (ERK1/2) in cells from wildtype mice. These responses were dependent on IL-1RI, since cells isolated from IL-1R1-/- mice did not demonstrate any of these responses. 4. In wildtype mice, inhibition of p38 or ERK1/2 MAPKs significantly reduced IL-1beta induced IL-6 release, whilst the NFkappaB inhibitor caffeic acid phenethyl ester (CAPE) modulated IL-1 induced IL-6 release by action on NFkappaB and MAPKs pathways. 5. These data demonstrate that IL-1RI is essential for IL-1beta signalling in cultured mixed glial cells. Thus IL-1 actions observed in IL-1RI-/- mice in vivo may occur via an alternative pathway and/or via different CNS cells.
| S-EPMC1573350 | biostudies-other
Project description:TILRR has been identified as an important modulator of inflammatory responses. It is associated with NF-κB activation, and inflammation. Our previous study showed that TILRR significantly increased the expression of many innate immune responsive genes and increased the production of several pro-inflammatory cytokines/chemokines by cervical epithelial cells. In this study, we evaluated the effect of TILRR-induced pro-inflammatory cytokines/chemokines on the migration of immune cells. The effect of culture supernatants of TILRR-overexpressed cervical epithelial cells on the migration of THP-1 monocytes and MOLT-4 T-lymphocytes was evaluated using Transwell assay and a novel microfluidic device. We showed that the culture supernatants of TILRR-overexpressed HeLa cells attracted significantly more THP-1 cells (11-40%, p = 0.0004-0.0373) and MOLT-4 cells (14-17%, p = 0.0010-0.0225) than that of controls. The microfluidic device-recorded image analysis showed that significantly higher amount with longer mean cell migration distance of THP-1 (p < 0.0001-0.0180) and MOLT-4 (p < 0.0001-0.0025) cells was observed toward the supernatants of TILRR-overexpressed cervical epithelial cells compared to that of the controls. Thus, the cytokines/chemokines secreted by the TILRR-overexpressed cervical epithelial cells attracted immune cells, such as monocytes and T cells, and may potentially influence immune cell infiltration in tissues.
| S-EPMC7348050 | biostudies-literature
Project description:The proinflammatory cytokine IL-1β plays critical roles in inflammatory and autoimmune diseases. IL-1β signaling is tightly regulated to avoid excessive inflammatory response. In this study, we identified the E3 ubiquitin ligase membrane-associated RING-CH-type finger 3 (MARCH3) as a critical negative regulator of IL-1β-triggered signaling. Overexpression of MARCH3 inhibited IL-1β-triggered activation of NF-κB as well as expression of inflammatory genes, whereas MARCH3 deficiency had the opposite effects. MARCH3-deficient mice produced higher levels of serum inflammatory cytokines and were more sensitive to inflammatory death upon IL-1β injection or Listeria monocytogenes infection. Mechanistically, MARCH3 was associated with IL-1 receptor I (IL-1RI) and mediated its K48-linked polyubiquitination at K409 and lysosomal-dependent degradation. Furthermore, IL-1β stimulation triggered dephosphorylation of MARCH3 by CDC25A and activation of its E3 ligase activity. Our findings suggest that MARCH3-mediated IL-1RI degradation is an important mechanism for attenuating IL-1β-triggered inflammatory response.
| S-EPMC6298087 | biostudies-other