High-throughput proteomics reveal alarmins as amplifiers of tissue pathology and inflammation after spinal cord injury.pdf (2.54 MB)
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High-throughput proteomics reveal alarmins as amplifiers of tissue pathology and inflammation after spinal cord injury.

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journal contribution
posted on 03.07.2019, 14:06 by A Didangelos, M Puglia, M Iberl, C Sanchez-Bellot, B Roschitzki, EJ Bradbury
Spinal cord injury is characterized by acute cellular and axonal damage followed by aggressive inflammation and pathological tissue remodelling. The biological mediators underlying these processes are still largely unknown. Here we apply an innovative proteomics approach targeting the enriched extracellular proteome after spinal cord injury for the first time. Proteomics revealed multiple matrix proteins not previously associated with injured spinal tissue, including small proteoglycans involved in cell-matrix adhesion and collagen fibrillogenesis. Network analysis of transcriptomics and proteomics datasets uncovered persistent overexpression of extracellular alarmins that can trigger inflammation via pattern recognition receptors. In mechanistic experiments, inhibition of toll-like receptor-4 (TLR4) and the receptor for advanced glycation end-products (RAGE) revealed the involvement of alarmins in inflammatory gene expression, which was found to be dominated by IL1 and NFκΒ signalling. Extracellular high-mobility group box-1 (HMGB1) was identified as the likely endogenous regulator of IL1 expression after injury. These data reveal a novel tissue remodelling signature and identify endogenous alarmins as amplifiers of the inflammatory response that promotes tissue pathology and impedes neuronal repair after spinal cord injury.

Funding

This work was supported by the UK Medical Research Council (SNCF award G1002055 to EJB), the RoseTrees Trust (JS16/M276 to EJB and AD) and proteomics experiments were funded by the European Union 7th framework program, PrimeXS, project 220 (AD, MP and BR).

History

Citation

Scientific Reports, 2016, 6, 21607

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Infection, Immunity and Inflammation

Version

VoR (Version of Record)

Published in

Scientific Reports

Publisher

Nature Research (part of Springer Nature)

eissn

2045-2322

Acceptance date

27/01/2016

Copyright date

2016

Available date

03/07/2019

Publisher version

https://www.nature.com/articles/srep21607

Notes

Supplementary information accompanies this paper at http://www.nature.com/srep

Language

en