Our Research

Our laboratory is dedicated to exploring the biology of specialized pro-resolving mediators (SPMs) to better understand mechanisms leading to disease. We aim to leverage the protective properties of SPMs as therapeutic targets and biomarkers for patient stratification. Below is an overview of our current research:

  1. Understanding the biology of SPM in maintaining host protection

Whilst much is known on the pharmacological activities of specialized pro-resolving mediators, less is known on the biological mechanisms that modulate their production. In our efforts to identify the mechanisms that regulate their production we have focused on the following:

Vagal regulation of SPM production – In published studies we observed that the vagus nerve is involved in the regulation of tissue SPM levels, whereby disruption in the activity of this nerve leads to a downregulation in the production of several SPM including the peptide-lipid conjugated mediator Protectin Conjugate in Tissue Regeneration (PCTR)1 (PMID: 24863066, PMID: 28065837). This loss in SPM production was linked with an alteration in macrophage phenotype and function leading to a dysregulation in the ability of the host response to limit bacterial infections (PMID: 28065837). In recent studies we observed that the vagus nerve also regulates the biological activities of monocytes via the activity of SPM and disruptions in this modulatory axis result in increased disease severity in chronic inflammatory settings. In separate studies we observed that vagal nerve stimulation upregulates the formation of SPM in peritoneal inflammatory exudates and these increases were linked with enhanced protection in experimental models of peritonitis (PMID: 35622894, PMID: 33859641). Regulation of splenic nerve activity was also found to regulate peripheral blood SPM concentrations and confer protection in models of inflammation (PMID: 33859641). Ongoing efforts are aimed at detailing the cellular and molecular mechanisms regulated by SPM in monocytes.

Diurnal mechanisms in the regulation of SPM. Diurnal mechanisms are central to our survival. We recently found that in healthy humans, peripheral blood levels of n-3 docosapentaenoic acid-derived resolvins (RvDn-3 DPA) are under diurnal regulation and dysregulation in the expression of these molecules were linked with cardiovascular disease and circulating phagocyte activation (PMID: 29437834). In ongoing studies, we are exploring the cellular and molecular mechanisms regulated by these molecules in phagocytes to limit inflammation in cardiovascular diseases.

Uncovering the GPCRs that mediate the activities of SPM. To date the know mode of action of SPM relies on the activation of receptors, primarily those of from the G-protein Coupled Receptor family, that mediate their biological activities. The identity of the cognate receptors for a number of SPM remains to be established. We recently found that the orphan receptor GPR101 mediates the biological actions of RvD5n-3 DPA on phagocytes and conditional deletion of this receptor on macrophages leads to an alteration in both their phenotype and function (PMID: 31793912; PMID: 36400250). In ongoing studies, we are exploring the molecular mechanisms elicited by RvD5n-3 DPA via GPR101 to regulate macrophage biology.

Evidence for the protective role of SPM and their receptors in humans. ITo further validate the protective effects of specialized pro-resolving mediators (SPMs) and their receptors in human immune responses, we are collaborating with colleagues from the East London Genes and Health study. Our focus is on the impact of loss-of-function mutations in genes responsible for SPM biosynthesis and receptor pathways on immune cell function. In a recent study, we identified a Single Nucleotide Polymorphism (SNP) in the gene encoding the Maresin 1 receptor, which leads to the selective deletion of the receptor in a subset of immune cells. This genetic variant was associated with an increased incidence of viral infections (PMID: 38718314).

2. Development of novel therapeutic modalities in rheumatoid arthritis.

Rheumatoid arthritis (RA) is characterized by uncontrolled joint inflammation that causes irreversible damage to bones and cartilage, significantly reducing quality of life. Patients with RA are also at increased risk of developing cardiovascular diseases, such as atherosclerosis. Current therapies primarily focus on controlling joint inflammation but have limited effects on repairing damaged joint tissues or preventing cardiovascular disease. Only a small proportion (~20%) of patients achieve low disease activity, and even fewer experience drug-free remission. As a result, most patients require lifelong treatment, exposing them to potential drug side effects. Additionally, around 40% of patients are refractory to available treatments.

MCTR3 in promotes joint repair: In Recent studies we observed that the peptide-conjugated pro-resolving mediator Maresin Conjugates in Tissue Regeneration (MCTR3) exhibits potent joint-protective activities by limiting joint inflammation. MCTR3 not only protects both joint and cartilage but also enhances the expression of joint reparative pathways, such as Arginase 1 and polyamines, while reducing the expression of molecules associated with joint damage. These anti-inflammatory and reparative effects were partly mediated by the epigenetic reprogramming of monocytes, which were induced to differentiate into synovial macrophages with reparative functions (PMID: 35430453). We are now focused on exploring the molecular mechanisms by which MCTR3 affects monocytes and other target cells to mediate these anti-inflammatory effects, as well as investigating its therapeutic potential for treating patients with RA.

RvT4 in cardiovascular protection: In other studies, we observed that resolvin T (RvT) 4, a lipid mediator produced from the essential fatty acid n-3 docosapentaenoic acid, reprograms lipid laden macrophages in the context of inflammatory arthritis exacerbated by metabolic dysfunction to reduce both atherosclerosis and joint inflammation (PMID: 38316794). We are now seeking to determine the molecular mechanisms regulated by this mediator to reprogram these cells and limit inflammation.

3. Exploring the utility of SPM as prognostic and diagnostic biomarkers

Disease processes vary significantly from patient to patient, underscoring the need for tools that facilitate personalized treatment and patient stratification in clinical practice. Currently, most biomarkers used in medicine are molecules involved in propagating inflammation, based on the idea that many diseases are caused by excessive production of inflammation-initiating signals. However, there are no biomarkers available today that predict a patient’s likelihood of responding to a specific treatment. Given that many treatments are not effective for all patients and can cause side effects, identifying prognostic biomarkers for treatment responsiveness is crucial. These biomarkers would enable clinicians to select the most effective treatment for each patient, reducing unnecessary drug exposure.

In collaboration with Prof. Costantino Pitzalis (QMUL), we explored the potential of specialized pro-resolving mediators (SPMs) as prognostic biomarkers. We evaluated peripheral blood levels of SPMs in patients who were naive to conventional synthetic disease-modifying anti-rheumatic drugs (cs-DMARDs). By using Artificial Intelligence-driven approaches with Prof. Conrad Bessant (QMUL), we linked these SPM levels to treatment responses. Our findings demonstrated that peripheral blood levels of specific SPMs could predict treatment responsiveness. Additionally, plasma lipid mediator concentrations were found to be diagnostic of joint disease pathotypes.

We also investigated the utility of lipid mediators in COVID-19, in collaboration with Dr. Paul Pfeffer (QMUL), where we observed that plasma lipid mediator concentrations could predict disease progression and response to dexamethasone treatment. Ongoing studies aim to further explore the prognostic utility of SPMs in predicting treatment responsiveness, particularly in rheumatoid arthritis (RA).

Omega-3 Supplements and SPM Regulation
Omega-3 supplements have long been recognized for their immunomodulatory properties. In recent studies, we observed that a specific omega-3 supplement dose-dependently modulated peripheral blood SPM levels in both healthy volunteers (in collaboration with Dr. David Collier – QMUL) and patients with peripheral artery disease (in collaboration with Prof. Mike Conte – UCSD). These SPM levels were linked to the regulation of circulating phagocyte and platelet functions. Interestingly, different omega-3 supplements were found to upregulate distinct SPMs, which correlated with varying abilities to modulate immune responses in experimental settings.

We are now focused on expanding these findings by linking the modulation of SPM levels by omega-3 supplements to their impact on immune regulation in different disease contexts.