Metabolic remodelling across tissue compartments in psoriatic arthritis

PROJECT OVERVIEW

Global estimates of the prevalence of psoriatic arthritis (PsA) are between 0.3 and 1%. PsA causes pain, disability and systemic inflammation. There is a striking and profound association between systemic metabolic dysfunction and developing PsA, confirmed by mendelian randomisation studies. Elevated body mass index (BMI), type 2 diabetes, and dyslipidaemia are all increased in prevalence in individuals with PsA, and are linked to greater disease activity, reduced likelihood of remission, poorer treatment response and increased mortality. Yet, we do not understand the causal mechanisms linking obesity with development of psoriatic arthritis, or why it is associated with more severe disease.

Immune cell metabolism describes the reciprocal relationship between immune cell function and cellular metabolic pathways and is increasingly recognised as central to immune mediated inflammatory disease. Immune cell activation requires dynamic metabolic reprogramming: for example, effector T cells preferentially exhibit glycolysis, whereas memory immune states rely more on oxidative phosphorylation and fatty acid oxidation. Fatty acid species and their downstream mediators shape cytokine production, T cell differentiation and inflammation. Therefore, immune cell metabolism offers a framework to understand the mechanisms linking obesity and PsA.

It is probable that pathogenic metabolic reprogramming of immune cells occurs in tissue compartments, such as the liver or adipose tissue. Indeed, we have recently shown that treatment of PsA with IL-17 inhibitors improves liver fat, in association with significant changes in immunophenotype [DOI:10.64898/2026.07.06.26357384]. However, the immunometabolism of PsA is almost unknown.

One of the most attractive ways to uncover the mechanisms linking metabolic syndrome to PsA is restoration of homeostasis through weight loss. Until recently, mechanistic weight loss studies in inflammatory arthritis have been limited by the degree of weight loss achieved by diet and lifestyle. However, glucagon-like-peptide-1 receptor agonists (GLP-1RA), which reduce weight by 15-25% in one year, have emerged as a powerful new tool for experimental medicine.

Emerging data suggest that GLP1-RA may improve inflammatory arthritis in humans. It remains possible, based on animal and in vitro studies, that GLP1-RA may also act on immune cells in addition to their effects on systemic metabolism. However, there are no human in vivo studies which examine this, and so it is unknown. Given estimates suggest up to 15% of the UK population may be using a GLP1-RA in five years, exploration of their effects on the immune system in humans is of paramount importance.

In this project, you will use an experimental medicine approach to compare how systemic metabolism and immune cell metabolism interact across tissue compartments in PsA, with tirzepatide-induced weight loss as a clinically relevant metabolic perturbation. You will use stable, non-radioactive isotope tracers combined with mass spectrometry to quantify in vivo metabolic flux in humans. You will integrate whole-body metabolic kinetics with cellular immunometabolic phenotyping across tissue compartments. The findings will identify pathways that explain PsA disease biology, support rational use of GLP-1RA-therapies and reveal novel metabolic targets addressing both joint inflammation and obesity.

KEYWORDS

Immunometabolism

GLP-1 agonists

Psoriatic arthritis

Metabolism

TRAINING OPPORTUNITIES

Single cell RNA sequencing and spatial profiling

Flow cytometry

Stable isotope tracing resolved metabolomics

Metabolic modelling

Experimental medicine interventions

KEY PUBLICATIONS

Gunawardana et al. medRxiv 2026; DOI:10.64898/2026.07.06.26357384

Marjot et al. Cell Metabolism, 2026; 38, 474-492.e6

Subudhi et al. Immunity 2025; 57, 1665-1680.e7

Castillo et al. Science Immunology 2023; 8, eabq7991

Armstrong et al. Nature Reviews Disease Primers, 2025; 11, 45

THEMES

Experimental medicine

Inflammation and immunity

CONTACT INFORMATION OF ALL SUPERVISORS

Alexander Clarke

Laura Coates

Jeremy Tomlinson