Brain inflammation

Inflammation is generally a protective process in response to an infection or an injury. However, if there is disease in the brain, inflammation can often make the disease worse.

For this reason, we need to understand the mechanisms of inflammation occurring in a diseased brain. When we understand these mechanisms, we will then work to find a way to block and prevent inflammatory damage.

Our research

The aim of our research is to understand fundamental mechanisms of inflammation and how they contribute to brain disease and pathology.

To address this, we investigate inflammation in a number of clinically important disease contexts, spanning acute brain injury and chronic neurodegeneration.

We also employ translationally-relevant approaches where mechanisms of inflammation are dissected in models of disease with validation in patient tissues and cohorts.

The overall objective of our research is to identify how immune pathways can be targeted as new treatments for brain disease.

Example ongoing projects in this area include:

• Dissecting the immunological landscape in brain tumours to understand how cancer cells and immune cells communicate, and how the nature of this communication controls the trajectory of disease.
• Identifying how the potent inflammatory cytokine interleukin-1 can be targeted in different diseases, such as neurodegeneration, stroke, cerebral malaria and brain tumours.
• Understanding how the brain communicates with other organs in the body (for example, the gut) and how this interaction influences brain inflammation and injury after stroke.
• Defining how inflammation at the border of the brain (the meninges) influences the development and progression of brain disease, and after traumatic brain injury.

Examples of our research

Lawrence Lab

Intracerebral haemorrhage is a life-threatening type of stroke with no current treatment options. This type of stroke occurs when a blood vessel suddenly ruptures and begins bleeding into the brain.

Blood that is now in the brain contains various cells (including red blood cells) that start to release ‘toxic factors’ that can cause further damage to brain cells. Therefore, it is important to try and get rid of the blood as quickly as possible, to reduce the chances of it causing any harm. Blood will also cause an inflammatory response, which can damage brain cells.

Our tissues/organs contain a group of cells called phagocytes whose job is to eat any harmful cells and smaller particles to try to protect our bodies from any of their harmful effects. In haemorrhagic stroke, these phagocytes try to eat up the red blood cells and toxic factors that can cause inflammation.

However, this job can take time, and trying to find a way to help the phagocytes get rid of the blood quicker and more efficiently would help to prevent further damage to the brain.

The Lawrence lab, along with researchers in the Kasher lab and others, are now trying to find treatments to help the phagocytes do their job better and clear away the blood more efficiently. The group is a unique team of scientists who are using different animal models of brain haemorrhage, as well as tissue from patients who died from this condition.

The overall aim is to lead to the identification of a new way to help patients with intracerebral haemorrhage.

Greenhalgh lab

One arm of research in the Greenhalgh Lab is to understand how concussion affects the brain, and whether we can use neuroimaging to measure it people. We combine advanced MRI in elite athletes following head injury with a range of laboratory investigations in preclinical models.

Using cutting-edge techniques such as high-dimensional flow cytometry, single-cell RNA sequencing, imaging, and behavioural analysis, we are beginning to understand how the immune response drives concussion-related injury and symptoms.

NLRP3 endosome paper

Inflammation is how the immune system protects our bodies against infection and damage. However, when inflammation is not controlled, it can contribute to many diseases including Alzheimer’s disease, stroke, and cancer. Learning more about how inflammation occurs at the microscopic level will allow us to gain a greater understanding of how we can target treatments for disease.

Inside immune cells there is a structure called the inflammasome that monitors its surrounding environment and remains inactive when the cell is functioning normally. For a cell to function normally, proteins and essential cargo are trafficked around the cell in carriers called endosomes. When traffic is disrupted, endosomes are stopped in their tracks and the cell undergoes a stress response.

We have shown here that the inflammasome can respond to this cell stress and become activated, triggering the release of harmful proteins, and causing an uncontrolled inflammatory response.

The research carried out in this paper allows us to understand more about how the inflammasome is activated. Further research into inflammasomes in this way will increase our current understanding of inflammation and how we can target inflammasomes in disease.

• Learn more in the publication: Disruptions in endocytic traffic contribute to the activation of the NLRP3 inflammasome (Science Signaling)

Investigators