Regulation of Inflammatory and anti-apoptotic responses through the IL-1RI/TILRR complex

Members of the toll-like and IL-1 receptor family (TIR) are central regulators of immune and inflammatory responses. Signal activation is induced through ligand binding and controlled by system specific co-receptors. The IL-1RI coreceptor TILRR is a splice variant of FREM1. TILRR association with the signaling receptor magnifies IL-1 induced activation of the canonical and non-canonical NF-kB network by enhancing signal amplification at the level of the receptor complex and potentiates recruitment of the MyD88 adapter and PI3 kinase. TILRRcontrolled MyD88 dependent activation of the canonical pathway is regulated in a Ras-dependent manner, reflected in alterations in cytoskeletal structure and cell adhesion. The changes induced provide a process for rapid control of NF-kB, involving sequestration and release of cytoskeletal bound IkBα through a mechanism controlled by TILRR signal amplification. In silico simulations using agent based modeling of the NFkB network predict cytoskeletal control of inhibitor levels to provide a mechanism for signal calibration and to enable activation-sensitive regulation of NFkB induced inflammatory responses. Our studies have identified two functional sites within the TILRR core protein, which selectively control inflammatory and anti-apoptotic responses. The mechanisms underlying distinct network amplification and the relevance of pathway-specific regulation of canonical and non-canonical NFkB activation will be discussed

Reducing complexity in an agent based reaction model-Benefits and limitations of simplifications in relation to run time and system level output.

Agent based modelling is a methodology for simulating a variety of systems across a broad spectrum of fields. However, due to the complexity of the systems it is often impossible or impractical to model them at a one to one scale. In this paper we use a simple reaction rate model implemented using the FLAME framework to test the impact of common methods for reducing model complexity such as reducing scale, increasing iteration duration and reducing message overheads. We demonstrate that such approaches can have significant impact on simulation runtime albeit with increasing risk of aberrant system behaviour and errors, as the complexity of the model is reduced

Distinct binding interactions of α5β1-integrin and proteoglycans with fibronectin

Dynamic single molecule force spectroscopy was performed to monitor the unbinding of fibronectin with the proteoglycans syndecan-4 and decorin, and to compare this with the unbinding characteristics of α5β1-integrin. A single energy barrier was sufficient to describe the unbinding of both syndecan-4 and decorin from fibronectin, while two barriers were observed for the dissociation of α5β1-integrin from fibronectin. The outer (high affinity) barrier in the interactions of fibronectin with α5β1-integrin and syndecan-4 are characterized by larger barrier heights and widths, and slower dissociation rates than those of the inner (low affinity) barrier in the interactions of fibronectin with α5β1-integrin and decorin. These results indicate that syndecan-4 and (ultimately) α5β1-integrin have the ability to withstand deformation in their interactions with fibronectin, while the decorin-fibronectin interaction is considerably more brittle

Bioinformatics Analysis of the FREM1 Gene—Evolutionary Development of the IL-1R1 Co-Receptor, TILRR

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

The IL-1RI co-receptor TILRR (FREM1 isoform 2) controls aberrant inflammatory responses and development of vascular disease

Summary Expression of the interleukin-1 receptor type I (IL-1RI) co-receptor Toll-like and interleukin-1 receptor regulator (TILRR) is significantly increased in blood monocytes following myocardial infarction and in the atherosclerotic plaque, whereas levels in healthy tissue are low. TILRR association with IL-1RI at these sites causes aberrant activation of inflammatory genes, which underlie progression of cardiovascular disease. The authors show that genetic deletion of TILRR or antibody blocking of TILRR function reduces development of atherosclerotic plaques. Lesions exhibit decreased levels of monocytes, with increases in collagen and smooth muscle cells, characteristic features of stable plaques. The results suggest that TILRR may constitute a rational target for site- and signal-specific inhibition of vascular disease

Investigating IKK dynamics in the NF-κB signalling pathway using X-Machines

The transcription factor NF-κB is a biological component that is central to the regulation of genes involved in the innate immune system. Dysregulation of the pathway is known to be involved in a large number of inflammatory diseases. Although considerable research has been performed since its discovery in 1986, we are still not in a position to control the signalling pathway, and thus limit the effects of NF-κB within promotion of inflammatory diseases. We have developed an agent-based model of the IL-1 stimulated NF-κB signalling pathway, which has been calibrated to wet-lab data at the single-cell level. Through rigorous software engineering, we believe our model provides an abstracted view of the underlying real-world system, and can be used in a predictive capacity through in silico experimentation. In this study, we have focused on the dynamics of the IKK complex and its activation of NF-κB. Our agent-based model suggests that the pathway is sensitive to: variations in the binding probability of IKK to the inhibited NF-κB-IκBα complex; and variations in the temporal rebinding delay of IKK