Resolution Pharmacology and Physiology of MCTR in Arthritis

Informations projet

MCTRinIA

N° de convention de subvention: 677542

DOI

10.3030/677542

Projet clôturé

Date de signature de la CE 4 Mars 2016

Date de début 1 Mars 2016

Date de fin 31 Août 2021

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 964 303,00

Contribution de l’UE

€ 1 964 303,00

Coordonné par

QUEEN MARY UNIVERSITY OF LONDON
United Kingdom

Periodic Reporting for period 4 - MCTRinIA (Resolution Pharmacology and Physiology of MCTR in Arthritis)

Période du rapport: 2020-09-01 au 2021-08-31

Résumé du contexte et des objectifs généraux du projet

Chronic inflammation may result from failure of the host response to engage pro-resolving pathways. The current treatment armamentarium for chronic inflammatory conditions may lead to immune suppression. Thus, identification of novel therapeutics that control inflammation without immune suppression will provide an attractive alternative approach. This is especially important since incidence of these conditions increases with an ageing global population. In planaria, mice, human peripheral blood and milk I recently uncovered a new family of endogenous molecules, named Maresin Conjugates in Tissue Regeneration (MCTR). These potently regulate white blood cell responses, promote the resolution of acute inflammation and accelerate tissue regeneration. The aim of this Starting Grant was to identify pathways that lead to failed resolution in inflammatory arthritis, as a prototypical chronic inflammatory condition. The hypothesis was that MCTR biosynthesis is dysregulated in inflammatory arthritis, leading to an unbridled host response, chronic inflammation and tissue destruction. This proposal was to employ a multipronged approach to test this hypothesis by 1) Determining MCTR regulation in self-resolving and delayed-resolving arthritis; 2) Investigating the host protective and tissue regenerative actions of MCTRs in inflammatory arthritis; 3) Establishing the MCTR biosynthetic pathway and 4) Determining the regulation if its components during self-limited and delayed-resolving arthritis.

The findings made during this grant demonstrate that MCTRs carry potent anti-inflammatory and tissue regenerative activities in experimental joint inflammation reducing both clinical signs of arthritis and promoting the repair or damaged tissues. These findings are significant since we also found that in patients with rheumatoid arthritis (RA) MCTR levels are reduced i with increasing with disease severity. Therefore these results suggest that MCTRs may be useful novel diagnostics and therapeutics in the management and treatment of patients with RA.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Results from experiments performed so far in MCTRinIA have identified the enzymes involved in the production of the three molecules that compose the MCTR family of mediators. These findings have also demonstrated the interrelationship of the three molecules as well as the dynamics in their regulation during joint disease. Assessment of patient derived peripheral blood also demonstrated that increased arthritic inflammation is linked with a loss in the circulating levels of these mediators, in particular MCTR3. We also have identified the mechanisms by which MCTRs up-regulate a key biological action in the resolution of inflammation, the clearance of apoptotic cells. We also demonstrated that upregulation of this process by MCTRs facilitates the repair and regeneration of damaged tissues identifying both signalling mechanisms and effector pathways that are regulated to promote this fundamental process in distinct model systems. Results from studies performed as part of this action also demonstrated the ability of MCTRs to both limit joint inflammation and to promote the repair of damaged tissues in arthritic inflammation and established that this occurs via the epigenetic reprogramming of monocytes.

These findings support a central role of MCTRs in regulating both inflammation and mechanisms central to the repair and regeneration of damaged joints in the context of rheumatoid arthritis and potentially other chronic inflammatory conditions characterised by persistent chronic inflammation. Given the potential implications of these findings in both patient management and treatment we are presently engaged in both identifying exploitation routes for these findings. As part of these efforts we have established a Spin Out company (Resolomics Ltd) that aims to develop diagnostics for patient stratification. We are also furthering the development of cell-based therapeutics for the treatment of patients with RA. As part of the dissemination efforts, in addition to publishing our work in highlight visible high quality journals and presenting our work at a range of national and international meetings, we have engaged with several online platforms to disseminate the findings from our studies to the general public, these included The Conversation and Health Europa.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

Results from the present findings identify a novel approach for the regulation of chronic inflammation utilizing MCTRs to actively reprogram the inflammatory instead instead of inhibiting inflammation, which is the paradigm currently used in treating patients with rheumatoid arthritis, thus potentially providing a potential step change in the treatment of these patients. We also found that circulating lipid mediator concentrations are predictive of treatment responsiveness in early RA patients, findings that have been submitted to IP protection and are licensed for clinical development. We also obtained proof of principle data demonstrating that MCTRs can be used to reprogram monocytes isolated from patients with RA towards an anti-inflammatory and tissue reparative phenotype and that these approach could represent a novel cell-therapy approach for treating of patients with RA. These findings were also submitted for IP protection and we are currently working of identifying the best route for development and exploitation.

Image of a healing knee joint from mice treated with MCTR3