New insights into NLRP3 within inflammatory disease

Inflammation is our bodies' response to infection and injury. Characterised by redness, swelling, and heat, an inflammatory response involves the movement of cells from the bloodstream to an infected or injured tissue or organ. Typically inflammation is a beneficial response. However, a failure to switch off an inflammatory response, or for it to clear away fully (or resolve), can lead to chronic or inappropriate inflammation. This can result in the death of healthy cells and tissue. As we get older the bodies' control of how it regulates inflammation starts to decline. During disease our control of inflammation is also compromised. When inflammation is not regulated appropriately it starts to become a cause of disease, or makes disease outcomes worse. Thus we need to understand the mechanisms regulating inflammation, and then we need to develop ways of blocking it during disease. By combining the expertise of scientists from different fields I aim to make a leap forward in how we understand a particularly damaging inflammatory response. Working with experts on cell function and biology I will conduct a programme of research that aims to understand a) how damaging inflammation is switched on, and b) how damaging inflammation can be switched off. Only through an improved understanding of these processes can we then target inflammation in disease effectively.

Inflammation is an early and important response to tissue injury and infection. In the absence of pathogens, it is considered sterile and exacerbates the pathology of major non-communicable diseases. Furthermore, the impact of co- or multi-morbidities is through an exacerbated inflammatory response. Inflammatory cytokines associated with damaging inflammation are commonly members of the interleukin-1 (IL-1) family. The pro-inflammatory IL-1 cytokines are regulated by the inflammasomes. Inflammasomes are cytosolic multimeric protein complexes formed in inflammatory cells in response to pathogenic infection and tissue injury. Activated inflammasomes drive the processing of pro-IL-1b to its mature secreted form. The most commonly studied inflammasome, and inflammasome most associated with disease, is composed of the cytosolic pattern recognition receptor (PRR) NACHT, LRR and PYD domains-containing protein 3 (NLRP3). NLRP3-dependent inflammation is specifically associated with the worsening of non-communicable diseases including atherosclerosis, Alzheimer's disease, type-II diabetes, arthritis and many others, so a research priority has been to understand the mechanism of NLRP3 inflammasome activation. Despite this our understanding of the regulation of the NLRP3 inflammasome remains incomplete. In part this limitation has been because of the lack of specific high level cell biology expertise. I aim to address this here combining and harnessing leading cell biology and immunology expertise to answer the biggest open questions in the inflammasome field:
1. How and where in the cell is the NLRP3 inflammasome activated (specifically defining disrupted endosomal trafficking as the unifying trigger for NLRP3 inflammasome activation)?
2. How is the NLRP3 inflammasome deactivated and removed (specifically understanding the role of autophagy in NLRP3 dependent responses)?

- Who might 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 disease in general. Clinicians may be informed of new strategies or treatments for the management of inflammatory 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 might they benefit from this research?
Most immediately research from this proposal will help inform researchers in the respective fields of immunology and cell biology 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 models of 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.