Biology subjects

Rastrick, J.

Publications and source records attributed to Rastrick, J..

3 recordsLinked to original sources

bioRxiv2025

The inflammatory skin disease map (ISD map): an interactive computational resource focused on psoriasis and atopic dermatitis molecular mechanisms

BackgroundInflammatory skin diseases (ISD), including atopic dermatitis (AD) and psoriasis (PsO), emerge from a complex network of inter- and intracellular biochemical interactions under the influence of genetic and environmental factors. The complexity of ISD mechanisms hinders translation of research findings into effective treatments and may explain the low remission rates despite the availability of modern targeted therapies. ObjectiveTo model AD- and PsO-associated mechanisms as networks of context-specific molecular interactions, the so-called ISD map, and to check the usefulness of this map as a graphically guided review of AD and PsO mechanisms and as a mechanistic hypothesis-generating platform. MethodsThe ISD map was built by assembling mechanistically resolved causal interactions obtained from relevant biomedical literature via manual curation. ResultsWe demonstrate that the ISD map (https://imi-biomap.elixir-luxembourg.org/) serves as an interactive, graphical review of AD and PsO molecular mechanisms and as a mechanistic hypothesis-generating platform. By analysing the map structure itself or the map integrated with genetics and functional genomics data, we could generate the following mechanistic hypotheses: (i) AD poor response to dupilumab is associated with a potential upregulation of IFNG, IL22, TSLP, IL-17A and IL25 signalling pathways in keratinocytes and/or single nucleotide polymorphisms (SNPs) in genes encoding regulators of IFNG expression in Th1 cells and (ii) PsO resistance to cytokine-induced apoptosis is associated with SNPs in IFNG signalling genes regulating SOCS1 in keratinocytes. Finally, the IL4/IL13 pathway in the AD submap of the ISD map was converted into a probabilistic Boolean model to simulate the effects of IFNG in sensory perception of itching after treatment with dupilumab. Our findings suggest that inhibiting both IFNG and IL4R may improve the therapeutic management of itching. ConclusionThe ISD map provides a significant interactive, computationally accessible resource of molecular knowledge on AD and PsO that can be used to graphically review known AD and PsO mechanisms and generate mechanistic hypotheses.

bioinformatics↗

bioRxiv2022

Extracellular matrix educates a tumor macrophage phenotype found in ovarian cancer metastasis

Recent studies have shown the tumor extracellular matrix (ECM) associates with immunosuppression, and that targeting the ECM can improve immune infiltration and immunotherapy response. A question that remains is whether the ECM is directly educating the immune phenotypes seen in cancer. We identified a tumor-associated macrophage (TAM) population correlated with poor prognosis, interruption of the cancer immunity cycle, and tumor ECM composition. To investigate whether ECM was capable of generating the TAM phenotype seen, we developed a decellularized tissue model that retains the native ECM architecture and composition. Macrophages cultured on decellularized ovarian metastasis shared transcriptional profiles with the TAMs found in human tissues. ECM educated macrophages have a tissue remodeling and immunoregulatory phenotype, inducing altered T cell function. We conclude that the tumor ECM is directly educating this macrophage population found in cancer tissues. Therefore, current and emerging cancer therapies that target the tumor ECM may be tailored to improve macrophage phenotype and their downstream regulation of immunity.

cancer biology↗

bioRxiv2020

Type-1 IFN primed monocytes in pathogenesis of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most severe form of lung fibrosis. It is progressive, and has an extremely poor outcome and limited treatment options. The disease exclusively affects the lungs, and thus less attention has been focused on blood-borne immune cells. which could be a more effective therapeutic target than lung-based cells. Here, we questioned if circulating monocytes, which has been shown to be increased in IPF, bore abnormalities that might contribute to its pathogenesis. We found that levels of circulating monocytes correlated directly with the extent of fibrosis in the lungs, and increased further during acute clinical deterioration. Monocytes in IPF were phenotypically distinct, displaying increased expression of CD64, a type 1 IFN gene expression signature and a greater magnitude of type 1 IFN response when stimulated. These abnormalities were accompanied by markedly raised CSF-1 levels in the serum, prolonged survival of monocytes ex vivo, and increased numbers of monocytes in lung tissue. Our study defines the key monocytic abnormalities in IPF, proposing type 1 IFN-primed monocytes as a potential driver of an aberrant repair response and fibrosis. It provides a rationale for targeting monocytes and identifies monocytic CD64 as a potential specific therapeutic target for IPF.

immunology↗