Professor Jesmond Dalli

Accelerating the resolution of joint inflammation and the regeneration of damaged tissues

Inflammatory arthritis is characterised by uncontrolled joint inflammation resulting in damaged bones and cartilage. Current therapies are aimed at controlling the inflammatory component, however they do not promote the repair and regeneration of damaged tissues. We have recently identified two novel families of endogenous mediators produced by leukocytes during self-limited inflammation and coined thriteen series resolvins (RvT_{n-3 DPA}) and maresin conjugates in tissue regeneration (MCTR). These mediators activate the host response to clear damaged cells, counter-regulate the production of pro-inflammatory mediators and they protect organs during ongoing inflammation. Therefore, we are interested in identifying the mechanisms that RvT_{n-3 DPA} and MCTR activate to promote the resolution of joint inflammation and joint regeneration.

Mechanisms in promoting the clearance of bacterial infections

When inflammation is self-contained it leads to efficient disposal of the invading pathogen and the reestablishment of tissue and organ function. Recent evidence demonstrates that termination (or resolution) of acute inflammation is an active process that is orchestrated by a novel genus of essential fatty acid-derived mediators, termed specialised pro-resolving mediators. Disruption in these pro-resolving pathways leads to delayed termination of infectious inflammation, failed resolution and is associated with poor prognosis in humans. We recently uncovered a novel family of pro-resolving mediators, produced during acute self-limited infections that promote bacterial clearance by phagocytes and tissue repair and regeneration. The formation of these mediators in human leukocytes is initiated by 17-lipoxygenation of docosahexaenoic acid and thus they were coined protectin conjugates in tissue regeneration (PCTR). PCTR1 is also central in regulating tissue resolution tone and host responses to infections promoting the uptake and killing of bacteria by phagocytes as well as regulating cellular trafficking. Tissue PCTR1 biosynthesis is regulated by the vagus nerve that via the neurotransmitter acetylcholine that upregulates the PCTR1 pathway in leukocytes. Of note, disruption of this pathway impairs the host innate immune response and bacterial clearance.

Using lipid mediator Profiling in dissecting disease mechanisms and patient stratification.

Disease processes vary from patient-to-patient this highlighting the need for the development of tools to facilitate patient identification and stratification in clinical medicine. Most of the biomarkers employed in clinical medicine today are molecules that are involved in the propagation of inflammation. This stems from the notion that inflammatory diseases, which form by-and-large the majority of diseases afflicting modern society, occur due to over production of inflammation-initiating molecules. Recent evidence demonstrates that inflammation is not always detrimental and that the body produces molecules, identified by our group and others and termed specialised pro-resolving mediators [SPM], which actively promote its termination. Failure by the body to produce these molecules is now thought to contribute to disease. Therefore we are using lipid mediator profiles to obtain an understanding of mechanisms that may lead to disease by as well as  patient’s disease status. Together these may then be useful for identifying more effective therapeutic strategies and monitor treatment effectiveness.