TREM-2, inflammation resolution and the transition from brain injury to repair after stroke

Stroke is one of the most common causes of death and disability and is normally caused by a blockage in an artery carrying blood to the brain. Blockage of the artery triggers many processes that cause brain tissue to die and this leads to disability. Long term outcome after stroke and related brain disorders is influenced by the amount of initial brain damage and the capacity for surviving brain tissue to promote regeneration and repair. This is why understanding the factors that influence this balance between brain damage and repair after stroke is so important. Currently we have a poor understanding of this but recent research suggests that the immune system might be a crucial balancing influence.

The immune system produces an inflammatory response when the body is infected or injured, including when the brain is injured after a stroke. Research we and others have carried out previously in stroke patients and animal models of stroke has shown that inflammation can worsen brain damage and cause more disability. However, not all inflammation is bad because some brain repair processes are boosted by inflammation. These contrasting effects of inflammation mean that we need to find out how the bad, injury-causing effects of inflammation can be switched off without compromising the good effects of inflammation on brain repair and recovery.

Our recent research has identified a chemical made by inflammatory cells that we believe could help control the balance between good and bad inflammation in the brain after stroke. This chemical is called TREM-2. The most exciting thing about TREM-2 is that it seems to affect this balance by limiting the injury-promoting affects of inflammation but at the same time still supporting responses of brain cells needed for repair. To potentially take advantage of these properties of TREM-2 in future we need to find out a lot more about how TREM-2 works under the conditions that occur in the brain after stroke.

The overall aim of our research project is to build on our recent results and firmly establish how TREM-2 influences the balance of inflammation, injury and repair in the brain after stroke. To do this, we will address four key questions:
1. When and where is TREM-2 produced in the brain after stroke?
2. How does TREM-2 function affect the behaviour of inflammatory cells in the brain?
3. What effect does genetic deletion of TREM-2 have on inflammation, injury and repair?
4. What affect does boosting production of TREM-2 have on inflammation, injury and repair?

We expect that the answers to these questions will firmly show us if TREM-2 does limit injury-causing inflammation without compromising repair in the brain after stroke. More generally, the work will help us understand how the delicate balance of inflammation in the injured brain is controlled. Ultimately, we hope our findings can be used to help set up patient trials that will test if new treatments based on manipulating TREM-2 and more generally the balance of inflammation have potential to reduce death and disability in stroke patients.

Inflammation may have both damaging and protective influences during acute and chronic neurodegeneration including after acute cerebral ischaemia/stroke. This duality of inflammation underlines the need to understand how toxic and beneficial inflammation is balanced in the injured brain. In particular, establishing how pro-injurious inflammation can be contained or resolved without compromising the capacity for endogenous or exogenously-triggered brain repair is essential.

Our recent data supporting this proposal show that Triggering Receptor Expressed on Myeloid cells-2 (TREM-2) may act as a critical molecular regulator restraining injurious inflammation and supporting repair e.g. we have shown that TREM-2 signalling in microglia and macrophages connects the removal of neurotoxic neutrophils with proliferation of neuronal precursors. However, the role of TREM-2 under the unique conditions of the ischaemic brain has not been studied previously.

The overriding aim of this proposal is to test the hypothesis that Triggering Receptor Expressed on Myeloid cells-2 (TREM-2) drives resolution of injurious inflammation and the transition from injury to repair in the brain after acute cerebral ischaemia. We will use a multi-modal approach including an experimental model of stroke, in vitro co-culture systems combining myeloid and neural cells and post-mortem brain tissue from stroke patients. We will exploit and generate novel tools that enable targeted deletion or augmentation of TREM-2 activity. These approaches will be used to determine expression patterns of TREM-2, the effects of TREM-2 on inflammatory cell phenotypes and the impact of TREM-2 deletion or overexpression on inflammatory profile and markers of injury and repair after stroke.

We expect our findings will provide a rational basis for developing effective immunomodulatory approaches for the treatment of stroke and other neurological conditions.

Academic research - as described in the academic beneficiaries section, we expect multiple groups will benefit including those in the neurobiology/degeneration, stroke, immunology and bone disorder fields. This reflects the position of TREM-2 as a molecule that functions at the interface of basic neurobiology, neurodegeneration and immunology. These groups include those in the UK and internationally and include our collaborators. These groups will benefit through the increased knowledge and understanding our research will bring that will impact on their own ability to make advances in understanding related biological mechanisms and disease processes. The general biomedical community will also benefit through a major new resource we will create (TREM-2 overexpressing mouse) and our training of researchers in highly skilled and sought-after techniques, notably whole animal physiology.

University teaching and education - our research findings will inform teaching content and practices by providing up-to-date information on scientific advances leading to a more relevant teaching experience equipping students with better knowledge and skills

Clinical/healthcare - our project will benefit clinicians and healthcare providers through advancing knowledge on potential new strategies for treatment and management of stroke and related neurological disorders. These groups would be able to use the data we generate to inform decisions on testing agents in clinical trials in patients. Our project may also impact on general policy and practice in the long-term through generating new concepts on how stroke patients can be treated and managed e.g. by targeting mechanisms in the sub-acute phase.

Industry - a key aim of our proposal is to generate an evidence base for new therapeutic strategies and targets for stroke and related conditions. This information will benefit biotech and pharmaceutical companies by informing their drug discovery and development pathways. Reciprocal benefits are possible through partnerships with industry and investment by companies in academia

Schools - through our research projects and engagement activities we are able to promote the awareness of how scientific research contributes to addressing important issues related to health and wellbeing. This can benefit schools through enriching the science curriculum and providing opinion and advice to pupils and teachers on careers in biomedical research

General public - although our proposed research is at the discovery stage it has the potential to impact on the health and well-being of the general population through identifying new ways to treat many more individuals affected by stroke and related neurological conditions. The benefit may take years to realise however our research has the potential to contribute a vital step in this process. Our research will also generate opportunities to increase public awareness of science and its role in reducing suffering associated with injury and disease

Policy makers - our work involves considerable use of in vivo approaches so has potential to generate new information influencing policy and practice relating to the use of animals in research