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. We can then aim to identify new ways to treat brain disease.

To address and understand inflammation, we have a number of ongoing projects in this area.

• Dissecting the immunological landscape of brain tumours, using the Hyperion imaging system to survey a high number of protein markers in a single scan.
• Targeting the immune pathway for the production of IL-1, a potent inflammatory cytokine, using new and existing anti-inflammatory drugs in preclinical models and clinical disease.

Understanding the gut-brain axis and how it influences brain inflammation and injury after stroke.

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)

The NLRP3 inflammasome as a target for sensorineural hearing loss

About 12 million people in the UK live with hearing loss. For many people, hearing loss is associated with communication difficulties, poor social interaction, unemployment, anxiety and depression.

Hearing loss resulting from damage to the inner ear is known as sensorineural hearing loss (SNHL), which is generally regarded as permanent. Currently, the management of SNHL is limited to hearing aids because there are no approved drugs for its treatment.

At the centre of many conditions that lead to SNHL lies inflammation. Inflammation is an immune system response vital for protecting the body against infection and injury although it can also lead to tissue damage, such as in areas involved in hearing.

For example, the inflammatory cells called macrophages that are usually responsible for clearing infections can become active in the inner ear, causing damage to the auditory nerve and inner ear hair cells.

This activation relies on a sensor of inflammation inside macrophages being stimulated, known as the NLRP3 inflammasome. Once the inflammasome is active, the macrophages release a signalling particle called IL1B into the inner ear that leads to further inflammation and damage in a vicious cycle that can result in SNHL.

Interestingly, there is evidence to suggest drugs that inhibit the inflammatory signal IL1B can reduce the hearing loss experienced in patients with conditions that lead to SNHL.

However, these drugs are yet to be tested as treatments for people with auto-inflammatory diseases and SNHL resulting from tumour growth such as vestibular schwannomas.

The identification of the inflammasome in these cases of SNHL provides evidence that IL1B targeted drugs could be repurposed as a wider treatment of SNHL to benefit a larger number of people with hearing loss.

• Learn more in the publication: The NLRP3 inflammasome as a target for sensorineural hearing loss (Clinical Immunology)

Investigators