Contribution of Neuro-inflammation to Cerebral Ischaemia

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences


Inflammation is our bodies' response to infection and injury. It is characterised by redness, swelling, and heat and requires recruitment of cells from the blood to an infected or injured area. Typically inflammation is a beneficial response. However, a failure to switch off an inflammatory response, or for it to resolve, can lead to chronic or inappropriate inflammation. This can result in the death of healthy cells and tissue. As we age the bodies control of how it regulates inflammation begins to diminish. Therefore when our bodies are challenged by an injury or an infection they fail to cope efficiently. Much research on mechanisms of inflammation has been carried out with respect to many types of infection and injury in many organs and great progress has been made. However, how inflammation is regulated in the brain is far less studied and we do not currently understand how the responses are coordinated. The main aim of this proposal is to understand the regulation of inflammation in the brain. We have access to mice in which specific parts of the inflammatory response have been removed, or knocked out. Using these mice we can examine the inflammatory response in the brain after an injury such as caused by stroke. This will give us information on the specific reactions that occur and their consequence. Brain inflammation has a significant impact on the health and wellbeing of the population, and particularly so for people of old age. Thus understanding how the brain regulates inflammation could lead to new strategies to treat brain injury and disease.

Technical Summary

Inflammation that occurs in response to tissue injury in the absence of pathogen is considered sterile, and can contribute to damage. The primary inflammatory cytokines associated with sterile inflammatory responses are members of the interleukin-1 (IL-1) family, IL-1a and IL-1b. IL-1 release from activated immune cells is regulated by a protein complex called the inflammasome. IL-1 is expressed in response to damage associated molecular patterns (DAMPs) that stimulate pattern recognition receptors (PRRs) on cells of the innate immune system. Once expressed, pro-IL-1 remains intracellular until an additional DAMP stimulation activates inflammasomes. Inflammasomes activate caspase-1 which in turn processes pro-IL-1 allowing release of the mature cytokine. We have discovered that brain inflammation after cerebral ischaemia is dependent upon the AIM2 and NLRC4 inflammasomes and also requires the inflammasome component ASC. However, we do not understand whether these inflammasomes are activated in the brain, whether they drive systemic inflammation, or indeed whether they contribute directly to cell death. We aim to identify the cell type and location driving the respective inflammasome-dependent responses, and to dissect the inflammasome-dependent neurotoxic and inflammatory responses activated by CI.

We will use a number of complimentary approaches to achieve the aims of this proposal. The middle cerebral artery occlusion (MCAo) model of stroke is a robust and clinically relevant model which we will use in mice in which components of different inflammasomes (e.g. AIM2, NLRP3, NLRC4, ASC) have been knocked out. Inflammatory, injury, and behavioural endpoints will provide a comprehensive view of the role of these proteins in the inflammatory response. We will also use functionalised carbon nanotubes (f-CNTs) to deliver RNAi to specific brain areas to uncouple the inflammatory response from cell death, and so fully interrogate mechanisms of inflammasome function.

Planned Impact

- Who will benefit from this research?
The immediate beneficiaries of this research will be the Faculty here at the University of Manchester. The development of methodologies, the training of students and of postdoctoral researchers will bring many benefits that will ultimately enrich the research environment. The potential identification of drug targets will benefit our local commercialisation team (UMIP) and may, in the longer term, provide economic benefits. Beyond this the presentation/publication of papers at conferences and in international high impact peer reviewed journals will benefit the wider scientific community and the University in general. The data generated through the course of this proposal may inform strategy boards of funding bodies (UK and overseas) on the growing recognition of the importance of inflammation to brain disorders and to disease in general. Clinicians may be informed of new strategies or treatments for the management of inflammatory brain disease that will ultimately lead to benefits for patients. The wider public will also benefit from increased understanding of and exposure to science through activities run by our labs. We also participate in careers fairs with local schools benefiting local school children to learn about future careers in science.

- How will they benefit from this research?
Most immediately research from this proposal will help inform researchers in the field and in the scientific community in general about key, up to now, unknown mechanisms of inflammation. The creative experiments we have designed, and the discoveries we make, will inspire other researchers to investigate similar mechanisms and thus our levels of knowledge on these process in general will increase substantially. The new areas of research that our discoveries will open will lead to the recruitment and training of students in this area which will spawn further developments. Many of these future developments will likely involve the identification of targets that may eventually lead to interventions that inhibit inflammation in animal models of brain disease. These will inform clinical studies and may lead to new treatments for disease. Due to the nature of this research there is scope for the commercialisation of the discoveries and potential economic benefits to the University and to the economy in general. Inflammatory disease has a massive impact on human suffering and thus research into the mechanisms of inflammation has potentially a direct impact on the health and wellbeing of people in the UK and worldwide.


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Abid KA (2018) Assessing Inflammation in Acute Intracerebral Hemorrhage with PK11195 PET and Dynamic Contrast-Enhanced MRI. in Journal of neuroimaging : official journal of the American Society of Neuroimaging

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Baldwin AG (2017) Boron-Based Inhibitors of the NLRP3 Inflammasome. in Cell chemical biology

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Barrington J (2017) A brain in flame; do inflammasomes and pyroptosis influence stroke pathology? in Brain pathology (Zurich, Switzerland)

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Haley MJ (2019) Acute high-fat feeding leads to disruptions in glucose homeostasis and worsens stroke outcome. in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

Description Brain Box 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The Brain Box was a large-scale public engagement spectacle that took place in Manchester Town Hall as part of ESOF and Manchester Day 2016, the aim of which was to inform and engage the public about all aspects of the brain and brain-related research. It achieved this with >5000 attendees. Aims of project or initiative:
• To create a unique and interactive public event engaging with a wide audience and showcasing the wonders of the brain, the breadth of brain research in Manchester and how it can be applied
• To establish new collaborations between scientists, artists and other creative practitioners
• To engender dialogue between scientists and the public
• To foster partnerships between the Universities, City Council, creative and charity organisations

Rationale/reasons for doing it:
To engage the broadest audience possible in a unique setting not typically associated with science, scientists and the brain
Year(s) Of Engagement Activity 2016
Description Stroke: Stories of the Self Through Art and Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Stroke survivors commonly talk about loss of the sense of self and social identity as one of their biggest emotional challenges and yet this phenomenon has received little attention to date. Our project, Stroke: Stories of the Self, was funded by the UoM Arts/Science fund in 2015 to explore this profound but invisible aspect of stroke through a series of interactive workshops that bring together a group of stroke survivors, the Stroke Association, clinicians, artists, researchers and students from across the UoM. Output from the workshops was displayed at a number of events, including the Stroke Association's Keynote Lecture in London, May 2017.
Year(s) Of Engagement Activity 2015,2016,2017