Professor Jesmond Dalli

Profile

Jesmond Dalli is a Professor of Molecular Pharmacology at the Barts and The London School of Medicine and Dentistry and Queen Mary College. He is also the director of the Lipid Mediator Unit at the William Harvey Research Institute. He received a B.Sc (Hons) in chemistry and biology and an M.Sc in biology from the University of Malta. He then read for and completed a PhD at the William Harvey Research Institute, Queen Mary University of London with Prof. Mauro Perretti. Professor Dalli then moved to Prof. Charles N. Serhan’s laboratory at Harvard Medical school and the Brigham and Women’s Hospital where he held the position of Instructor. He was also the co-director with Prof. Serhan of two NIH funded lipid mediator metabololipidomics cores. He published over 170 peer-reviewed publications including publications in Nature Medicine, Immunity and Science Translation Medicine. 

Awards

•    Eicosanoid Research Foundation Young Investigator Prize
•    Sir Henry Dale Fellowship
•    William Harvey Young Investigator Award 
•    IADR/AADR William J. Gies Award

Membership

•    British Pharmacological Society
•    British Society of Immunology
•    American Society for Investigative Pathology
•    British Society for Mass Spectrometry
•    Society for Leukocyte Biology
•    International Lipidomic Society
•    European Macrophage and Dendritic Cell Society

Research

Group members

Summary 

Our laboratory is interested in exploring the biology of specialized pro-resolving mediators (SPM) with the aim of gaining insights into mechanisms that lead to disease. We also want to leverage the protective properties of these molecules and their pathways as therapeutic leads/targets and biomarkers for patient stratification. Below is an overview of ongoing research efforts:

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. In order to further substantiate the protective activities of SPM and their receptors in the regulation of human immune responses in collaboration with colleagues from the East London Genes and Health study we are exploring the impact of loss of function mutations in genes encoding for SPM biosynthetic pathways and receptors on immune cell function.

2. Development of novel therapeutic modalities in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by uncontrolled joint inflammation resulting in non-reversable damaged of bones and cartilage resulting in a reduction of quality of life. Patients with RA are at an increased risk of developing cardiovascular diseases, including atherosclerosis. Therapies used to treat this condition are primarily aimed at controlling joint inflammation with limited known effects on both repairing damaged joint tissues and protecting from cardiovascular disease. Only a very small proportion (~20%) of patients achieve low joint disease activity and even fewer go into drug free remission. Therefore, patients are treated for their entire life exposing them to the side effects of the drugs. Furthermore, a marked proportion of patients (~40%) 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) displays potent joint protective activities limiting joint inflammation. Whereby we observed that MCTR3 protected both joint and cartilage, upregulating the expression of joint reparative pathways including Arginase 1 and polyamines and downregulating the expression of molecules linked with joint damage. We also observed that these anti-inflammatory and joint reparative activities of MCTR3, were mediated at least in part, via the epigenetic reprogramming of monocytes which conferred on to these cells the ability to differentiate into synovial macrophages with reparative activities (PMID: 35430453). We are now interested in exploring the molecular mechanisms engaged by MCTR3 in monocytes and other target cells that mediate the observed anti-inflammatory activities as well as determining therapeutic utility of this molecules in 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. 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 from patient-to-patient highlighting the need for 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. Furthermore, to date there are no biomarkers that are prognostic of the likelihood that an individual will respond to a give treatment. Since available treatments are not effective in all patients, and many of these drugs carry a wide range of side effects it is imperative that we identify prognostic biomarkers for treatment responsiveness. This is because such biomarkers will enable clinicians to identify the most effective treatment for a given patient and limit the unnecessary exposure of the patients to the side effects of drugs that will not yield them any benefit. To explore whether SPM may be useful as prognostic biomarkers in collaboration with Prof Costantino Pitzalis (QMUL) we evaluated peripheral blood levels of these molecules in conventional synthetic disease modifying anti-rheumatic drug naive (cs-DMARD) patients and using Artificial Intelligence-driven approaches, in collaboration with Prof Conrad Bessant (QMUL), linked these to their responses to cs-DMARDs. Results from these studies demonstrated that peripheral blood levels of a subset of SPM were prognostic of treatment responsiveness. We also observed that plasma lipid mediator concentrations were diagnostic of joint disease pathotype. The diagnostic utility of lipid mediators was also explored in the context of COVID-19, in collaboration with Dr Paul Pfeffer (QMUL) where we observed that plasma lipid mediator concentrations were prognostic of disease course in patients with COVID-19 and diagnostic of dexamethasone treatment. In ongoing studies, we are seeking to expand of these initial observations to determine both the prognostic utility of SPM in establishing treatment responsiveness in patients with RA.

Omega-3 supplements have long been held to exert immunomodulatory activities. In recent studies we observed a dose dependent modulation of peripheral blood SPM levels by a specific omega-3 supplement in both healthy volunteers (in collaboration with Dr David Collier – QMUL) and patients with periphery artery disease (in collaboration with Prof Mike Conte – UCSD). We also observed that peripheral blood SPM concentrations were linked with the regulation of circulating phagocyte and platelet functions in these volunteers. Intriguingly we found that different omega-3 supplements upregulate the formation of distinct SPM, and this was linked with a differential ability to regulate innate immune responses in experimental settings. We are now interested in further expanding on these initial findings by linking the modulation of SPM levels by omega-3 supplements to their abilities at regulating host immune responses in distinct disease settings.

Key Publications

1. Pistorius K, Ly L, Souza PR, Gomez EA, Koenis DS, Rodriguez AR, Foster J, Sosabowski J, Hopkinson M, Rajeeve V, Spur BW, Pitsillides A, Pitzalis C, Dalli J. MCTR3 reprograms arthritic monocytes to upregulate Arginase-1 and exert pro-resolving and tissue-protective functions in experimental arthritis. EBioMedicine. 2022 May;79:103974. doi: 10.1016/j.ebiom.2022.103974.
2. De Matteis R, Flak MB, Gonzalez-Nunez M, Austin-Williams S, Palmas F, Colas RA, Dalli J. Aspirin activates resolution pathways to reprogram T cell and macrophage responses in colitis-associated colorectal cancer. Sci Adv. 2022 Feb 4;8(5):eabl5420. doi: 10.1126/sciadv.abl5420.
3. Koenis DS, Beegun I, Jouvene CC, Aguirre GA, Souza PR, Gonzalez-Nunez M, Ly L, Pistorius K, Kocher HM, Ricketts W, Thomas G, Perretti M, Alusi G, Pfeffer P, Dalli J. Disrupted Resolution Mechanisms Favor Altered Phagocyte Responses in COVID-19. Circ Res. 2021 Aug 6;129(4):e54-e71. doi: 10.1161/CIRCRESAHA.121.319142.
4. Souza PR, Marques RM, Gomez EA, Colas RA, De Matteis R, Zak A, Patel M, Collier DJ and Dalli J. Enriched marine oil supplements increase peripheral blood specialized pro-resolving mediator concentrations and reprogram host immune responses: A randomized double-blind placebo-controlled study. Circ Res. 2020 Jan 3;126(1):75-90. doi: 10.1161/CIRCRESAHA.119.315506
5. Flak MB, Koenis DS, Sobrino A, Smith J, Pistorius K, Palmas F, Dalli J. GPR101 mediates the pro-resolving actions of RvD5n-3 DPA in arthritis and infections. J Clin Invest. 2019 Dec 3. pii: 131609. doi: 10.1172/JCI131609.
6. Gomez EA, Colas RA, Souza PR, Hands R, Lewis M J, Bessant C, Pitzalis C & Dalli J. Blood pro-resolving mediators are linked with synovial pathology and predictive of DMARD responsiveness in rheumatoid arthritis. Nat Comms. doi.org/10.1038/s41467-020-19176-z
7. Colas RA, Souza PR, Walker ME, Burton M, Marques RM, Zasłona Z, Curtis AM, Dalli J. Impaired Production and Diurnal Regulation of Vascular RvDn-3 DPA Increases Systemic Inflammation and Cardiovascular Disease. Circ Res. 2018 Feb 5. pii: CIRCRESAHA.117.312472. PMID: 29437834
8. Dalli J, Colas RA, Arnardottir HH, and Serhan CN Group-3 Innate lymphoid cells and PCTR1 govern phagocyte response and infectious resolution via neuronal control. Immunity 2017 Jan 17;46(1):92-105.
9. Dalli J, Vlasakov I, Riley IR, Rodriguez AR, Spur BW, Petasis NA, Chiang N, Serhan CN. Maresin conjugates in tissue regeneration biosynthesis enzymes in human macrophages. Proc Natl Acad Sci U S A. 2016 Oct 25;113(43):12232-12237.
10. Dalli J, Chiang N, Serhan CN. Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. Nat Med. 2015 Sep;21(9):1071-5.
11. Dalli J, Ramon S, Norris PC, Colas RC and Serhan CN. Novel Proresolving and Tissue Regenerative Resolvin and Protectin Sulfido-Conjugated Pathways. The FASEB Journal. 2015 Feb 20. pii: fj.14-268441. 
12. Dalli J, Chiang N, Serhan CN. Identification of 14-Series Sulfido-Conjugated Mediators That Promote Resolution of Infection and Organ Protection. Proc Natl Acad Sci U S A. 2014 Nov 4;111(44):E4753-61
13. Dalli J, Colas RA, Serhan CN. Novel n-3 immunoresolvents: structures and actions. Sci Rep. 2013;3:1940.
14. Dalli J, Consalvo AP, Ray V, Di Filippo C, D'Amico M, Mehta N, Perretti M. Proresolving and tissue-protective actions of annexin A1-based cleavage-resistant peptides are mediated by formyl peptide receptor 2/lipoxin A4 receptor. J Immunol. 2013 Jun 15;190(12):6478-87.
15. Dalli J, Montero-Melendez T, Norling LV, Yin X, Hinds C, Haskard D, Mayr M, Perretti M. Heterogeneity in neutrophil microparticles reveals distinct proteome and functional properties. Mol Cell Proteomics. 2013 Aug;12(8):2205-19.
16. Dalli J and Serhan CN. Specific lipid mediator signatures of human phagocytes: Microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood. Blood. 2012 Oct11;120(15):e60-72.
17. Dalli J, Norling LV, Renshaw D, Cooper D, Leung KY, Perretti M. Annexin 1 mediates the rapid anti-inflammatory effects of neutrophil-derived microparticles. Blood. 2008 Sep 15;112(6):2512-9. 

Collaborators

Internal

Prof Mauro Perretti; Prof Costantino Pitzalis; Dr Lucy Norling; Prof Patricia Munroe; Prof Hemant Kocher; Dr David Collier 

External

Prof Trond V Hansen; Prof Justin Perkins; Prof Vincenzo Brancaleone

News

• Super Human Radio interview - 2021
• News Wise – July 2021
• American Heart Association – December 2019
• Science Daily – March 2018
• The Conversation – January 2017 

Disclosures

Consultancy fees

• Metagenics Inc
• Standard Process
• Willian Harvey Research Limited
• Nestle
• Fresenius Kabi

Funding

• GSK/Galvani
• Bayer AG
• Metagenics Inc
• Standard Process
• European Research Council
• Wellcome Trust
• Versus Arthritis
• Barts Charity

Intellectual Property

Jesmond Dalli is an inventor on patents related to the composition of matter and/or use of pro-resolving mediators and their analogues or mimetics, some of which are licensed by Brigham and Women's Hospital or Queen Mary University of London for clinical development.