Instytut Podstawowych Problemów Techniki
Polskiej Akademii Nauk


David Brough

Ostatnie publikacje
1.  Gregory Grace E., Jones Adam P., Haley Michael J., Hoyle C., Zeef Leo A. H., Lin I., Coope David J., King Andrew T., Evans D. G., Paszek P., Couper Kevin N., Brough D., Pathmanaban Omar N., The comparable tumour microenvironment in sporadic and NF2-related schwannomatosis vestibular schwannoma, Brain Communications, ISSN: 2632-1297, DOI: 10.1093/braincomms/fcad197, Vol.5, No.4, pp.1-15, 2023

Bilateral vestibular schwannoma is the hallmark of NF2-related schwannomatosis, a rare tumour predisposition syndrome associated with a lifetime of surgical interventions, radiotherapy and off-label use of the anti-angiogenic drug bevacizumab. Unilateral vestibular schwannoma develops sporadically in non-NF2-related schwannomatosis patients for which there are no drug treatment options available. Tumour-infiltrating immune cells such as macrophages and T-cells correlate with increased vestibular schwannoma growth, which is suggested to be similar in sporadic and NF2-related schwannomatosis tumours. However, differences between NF2-related schwannomatosis and the more common sporadic disease include NF2-related schwannomatosis patients presenting an increased number of tumours, multiple tumour types and younger age at diagnosis. A comparison of the tumour microenvironment in sporadic and NF2-related schwannomatosis tumours is therefore required to underpin the development of immunotherapeutic targets, identify the possibility of extrapolating ex vivo data from sporadic vestibular schwannoma to NF2-related schwannomatosis and help inform clinical trial design with the feasibility of co-recruiting sporadic and NF2-related schwannomatosis patients. This study drew together bulk transcriptomic data from three published Affymetrix microarray datasets to compare the gene expression profiles of sporadic and NF2-related schwannomatosis vestibular schwannoma and subsequently deconvolved to predict the abundances of distinct tumour immune microenvironment populations. Data were validated using quantitative PCR and Hyperion imaging mass cytometry. Comparative bioinformatic analyses revealed close similarities in NF2-related schwannomatosis and sporadic vestibular schwannoma tumours across the three datasets. Significant inflammatory markers and signalling pathways were closely matched in NF2-related schwannomatosis and sporadic vestibular schwannoma, relating to the proliferation of macrophages, angiogenesis and inflammation. Bulk transcriptomic and imaging mass cytometry data identified macrophages as the most abundant immune population in vestibular schwannoma, comprising one-third of the cell mass in both NF2-related schwannomatosis and sporadic tumours. Importantly, there were no robust significant differences in signalling pathways, gene expression, cell type abundance or imaging mass cytometry staining between NF2-related schwannomatosis and sporadic vestibular schwannoma. These data indicate strong similarities in the tumour immune microenvironment of NF2-related schwannomatosis and sporadic vestibular schwannoma.

Słowa kluczowe:
tumour microenvironment, vestibular schwannoma, tumour-associated macrophages, NF2, NF2-related schwannomatosis

Afiliacje autorów:
Gregory Grace E. - inna afiliacja
Jones Adam P. - inna afiliacja
Haley Michael J. - inna afiliacja
Hoyle C. - inna afiliacja
Zeef Leo A. H. - inna afiliacja
Lin I. - inna afiliacja
Coope David J. - inna afiliacja
King Andrew T. - inna afiliacja
Evans D. G. - inna afiliacja
Paszek P. - IPPT PAN
Couper Kevin N. - inna afiliacja
Brough D. - inna afiliacja
Pathmanaban Omar N. - inna afiliacja
2.  Daniels Michael J.D., Rivers-Auty J., Schilling T., Spencer Nicholas G., Watremez W., Fasolino V., Booth Sophie J., White Claire S., Baldwin Alex G., Freeman S., Wong R., Latta C., Yu S., Jackson J., Fischer N., Koziel V., Pillot T., Bagnall J., Allan Stuart M., Paszek P., Galea J., Harte Michael K., Eder C., Lawrence Catherine B., Brough D., Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models, Nature Communications, ISSN: 2041-1723, DOI: 10.1038/ncomms12504, Vol.7, pp.12504-1-10, 2016

Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes. The NLRP3 inflammasome is a multi-protein complex responsible for the processing of the proinflammatory cytokine interleukin-1β and is implicated in many inflammatory diseases. Here we show that several clinically approved and widely used NSAIDs of the fenamate class are effective and selective inhibitors of the NLRP3 inflammasome via inhibition of the volume-regulated anion channel in macrophages, independently of COX enzymes. Flufenamic acid and mefenamic acid are efficacious in NLRP3-dependent rodent models of inflammation in air pouch and peritoneum. We also show therapeutic effects of fenamates using a model of amyloid beta induced memory loss and a transgenic mouse model of Alzheimer’s disease. These data suggest that fenamate NSAIDs could be repurposed as NLRP3 inflammasome inhibitors and Alzheimer’s disease therapeutics.

Afiliacje autorów:
Daniels Michael J.D. - inna afiliacja
Rivers-Auty J. - inna afiliacja
Schilling T. - inna afiliacja
Spencer Nicholas G. - inna afiliacja
Watremez W. - inna afiliacja
Fasolino V. - inna afiliacja
Booth Sophie J. - inna afiliacja
White Claire S. - inna afiliacja
Baldwin Alex G. - inna afiliacja
Freeman S. - inna afiliacja
Wong R. - inna afiliacja
Latta C. - inna afiliacja
Yu S. - inna afiliacja
Jackson J. - inna afiliacja
Fischer N. - inna afiliacja
Koziel V. - inna afiliacja
Pillot T. - inna afiliacja
Bagnall J. - inna afiliacja
Allan Stuart M. - inna afiliacja
Paszek P. - inna afiliacja
Galea J. - inna afiliacja
Harte Michael K. - inna afiliacja
Eder C. - inna afiliacja
Lawrence Catherine B. - inna afiliacja
Brough D. - inna afiliacja
3.  Martín-Sánchez F., Diamond C., Zeitler M., Gomez A., Baroja-Mazo A., Bagnall J., Spiller David G., White M.R., Daniels Michael J.D., Mortellaro A., Peñalver M., Paszek P., Steringer J., Nickel W., Brough D., Pelegrín P., Inflammasome-dependent IL-1β release depends upon membrane permeabilisation, Cell Death & Differentiation, ISSN: 1350-9047, DOI: 10.1038/cdd.2015.176, Vol.23, pp.1219-1231, 2016

Interleukin-1β (IL-1β) is a critical regulator of the inflammatory response. IL-1β is not secreted through the conventional ER–Golgi route of protein secretion, and to date its mechanism of release has been unknown. Crucially, its secretion depends upon the processing of a precursor form following the activation of the multimolecular inflammasome complex. Using a novel and reversible pharmacological inhibitor of the IL-1β release process, in combination with biochemical, biophysical, and real-time single-cell confocal microscopy with macrophage cells expressing Venus-labelled IL-1β, we have discovered that the secretion of IL-1β after inflammasome activation requires membrane permeabilisation, and occurs in parallel with the death of the secreting cell. Thus, in macrophages the release of IL-1β in response to inflammasome activation appears to be a secretory process independent of nonspecific leakage of proteins during cell death. The mechanism of membrane permeabilisation leading to IL-1β release is distinct from the unconventional secretory mechanism employed by its structural homologues fibroblast growth factor 2 (FGF2) or IL-1α, a process that involves the formation of membrane pores but does not result in cell death. These discoveries reveal key processes at the initiation of an inflammatory response and deliver new insights into the mechanisms of protein release.

Afiliacje autorów:
Martín-Sánchez F. - inna afiliacja
Diamond C. - inna afiliacja
Zeitler M. - inna afiliacja
Gomez A. - inna afiliacja
Baroja-Mazo A. - inna afiliacja
Bagnall J. - inna afiliacja
Spiller David G. - inna afiliacja
White M.R. - University of Manchester (GB)
Daniels Michael J.D. - inna afiliacja
Mortellaro A. - inna afiliacja
Peñalver M. - inna afiliacja
Paszek P. - inna afiliacja
Steringer J. - inna afiliacja
Nickel W. - inna afiliacja
Brough D. - inna afiliacja
Pelegrín P. - inna afiliacja

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