Mechanisms of interleukin-1 action in neuronal injury

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

The blood supply to the brain provides essential oxygen and nutrients to support brain function. During stroke, haemorrhage (bleeding), head injury and certain types of dementia, the blood supply to the brain may be partially reduced or blocked, with fatal consequences for the patient. Our work focuses on understanding what happens in the brain and the rest of the body when the blood supply is reduced, in order to develop safer and more effective treatments for stroke. We have discovered that, in animal brains, a molecule normally associated with inflammation and infection (called interleukin-1 or IL-1 for short) increases when the blood supply is blocked. IL-1 can then kill brain cells, most importantly the nerve cells (neurones), which are essential for the brain to work properly. Our work in animals has already led to the testing of a drug that blocks the effects of IL-1 in stroke patients. However, to develop successful treatments for stroke and other conditions, we need to better understand how IL-1 kills brain cells either directly or by releasing killer molecules from other brain cells. We will test our discoveries in relevant animal models of disease and are well placed to take these findings into patients. This work may lead to new ways of blocking IL-1 and possible new treatments for stroke and related diseases.

Technical Summary

Cerebral ischaemia is one of the leading causes of death and disability worldwide. It occurs in stroke, sub-arachnoid and intra-cerebral haemorrhage, brain trauma, surgery and tumours, birth asphyxia and vascular dementia. Despite its devastating consequences there are few, if any, effective treatments, and a history of hundreds of failed trials. These failures may be for a number of reasons, including the choice of targets, animal models (which fail to replicate human pathology), and poor recognition that cerebral ischaemia is heavily dependent on processes occurring within the vasculature. The programme addresses these concerns and builds on our record of discovery in cerebral ischaemia. We have demonstrated the importance of central nervous system inflammation and the contribution of the pro-inflammatory cytokine interleukin-1 (IL-1) to experimental brain injury, and conducted a Phase II trial of IL-1 receptor antagonist in acute stroke.
Our overall objective is to fully elucidate the mechanisms of IL-1 action in neuronal injury and to optimise new targets for the treatment of cerebral ischaemia. More specifically, within this programme of work we will:
I. Identify how IL-1 acts on astrocytes and endothelial cells to cause neuronal injury
II. Determine how IL-1 modifies neuronal susceptibility to injury
III. Translate findings to identify and validate new targets and interventions in CI
The proposed studies will use a combination of molecular, cellular and in vivo approaches, to not only identify the downstream mediators of IL-1 action, but also the interplay between the multiple cellular effects of IL-1 that we have identified to date. All in vitro findings will be validated in vivo in animal models of ischaemic brain injury. We will then take forward identified interventions, which show significant neuroprotection, for further validation as potential treatments.
This programme of translational research will relate closely to our ongoing clinical studies. We have extensive published and preliminary data supporting our hypotheses, established techniques and very experienced research staff.

Publications

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Denes A (2015) AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3. in Proceedings of the National Academy of Sciences of the United States of America

 
Description Project grant
Amount £113,000 (GBP)
Funding ID PG/13/55/30365 
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2013 
End 10/2016
 
Description Research Grant
Amount £275,000 (GBP)
Organisation British Heart Foundation (BHF) 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2013 
End 04/2016
 
Title Generation of IL-1R1 and IL-1R2 floxed mice 
Description Transgenic mice generated for conditional deletion of interleukin-1 type1 and type2 receptors, to study the role of IL-1 in inflammation. These mice are currently named as key tools in current grant applications. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2011 
Provided To Others? Yes  
Impact None as yet 
 
Description Frontiers of Science talk, Uni of Manchester 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Frontiers of Science talk delivered to ~150 undergraduate students from 1st year to 3rd year, followed by questions and discussion.
Title: "Flaming brains - new discoveries about brain disease"


No specific impact known.
Year(s) Of Engagement Activity 2011
 
Description Keynote lecture to Schools Science Conference 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Schools
Results and Impact Talk followed by Q&A session. Title: "A stroke of bad luck - new discoveries in the treatment of brain disease". Session: Science is the Future.
Venue : Royal College of Pathologists, London
Audience : 50 secondary year students from years 10-13 and their teachers

No specific impact known.
Year(s) Of Engagement Activity 2011
 
Description Keynote talk at Stroke Assembly 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact An annual event that enables stroke survivors and their families to express their opinions and hopes in a UK-wide forum. This was held in 2013 at Nottingham University. Around 200 people attended and participated in discussions around our research.

Not yet known
Year(s) Of Engagement Activity 2013
URL http://www.strokeassembly.org.uk/content/brains-fire
 
Description Lecture at the University of Birmingham 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Talk title: "A stroke of bad luck: mechanisms and treatments for brain disease". For ~200 Uni staff and students. Followed by questions and discussion.

No specific impact known.
Year(s) Of Engagement Activity 2011
 
Description Numerous scientific, public and policy talks - too many to detail 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Numerous scientific, public and policy talks - too many to detail.

Significant press coverage
Year(s) Of Engagement Activity 2006,2007,2008
 
Description World Stroke Day 2011 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Primary Audience Participants in your research and patient groups
Results and Impact Had several interactive stands/displays showing different aspects of our preclinical research, at World Stroke Day event in Oct. 2011 organised by our clinical colleagues. The audience comprised ~180 stroke patients and their carers, healthcare professionals and associated charities/organisations.

Not known.
Year(s) Of Engagement Activity 2011
 
Description World Stroke Day 2011 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Primary Audience Participants in your research and patient groups
Results and Impact World Stroke Day event in Oct. 2011 organised by our clinical colleagues. The clinical investigator Dr Tyrrell presented the results of the clinical study funded by this grant. The audience comprised ~180 stroke patients and their carers, healthcare professionals and associated charities/organisations.

Not known.
Year(s) Of Engagement Activity 2011