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Title: Investigating the lactate/SLC5A12-induced metabolic signalling network in inflammation
Author: Pucino, V.
ISNI:       0000 0004 7971 825X
Awarding Body: Queen Mary, University of London
Current Institution: Queen Mary, University of London
Date of Award: 2019
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The tissue microenvironment is a key determinant of pathology in both inflammation and cancer. It is now understood that the tumour microenvironment is a niche that favours tumour growth over anti-tumour immune surveillance. Accumulation of lactate in the tumour microenvironment, largely due to the accelerated metabolism of cancer cells avidly consuming most of the scarcely available nutrients, has been shown to drive regulatory T cell responses favouring tumour growth. Immune cells that infiltrate the tissue microenvironments in inflammatory disorders find similarly harsh conditions, including scarce nutrients and high levels of lactate and other metabolites. Yet opposite to the tumour microenvironment, the inflamed tissue features high levels of inflammatory cytokines with impairment of Treg in favour of Th1 and Th17 immune responses, contributing to the perpetuation of the chronic inflammatory disease process. Indeed, in inflammatory disorders lactate is an amplifier of the inflammatory response. Here, I explored the response of CD4+ T cells to lactate in the context of inflammation. Specifically, the project aimed at characterizing whether the lactate/SLC5A12-induced metabolic signalling pathway modulates inflammatory immune responses. I employed a combination of immunology, mass spectrometry and biochemistry approaches on human peripheral blood mononuclear cells from healthy controls (HC) and rheumatoid arthritis (RA) subjects, as well as mononuclear cells from inflamed arthritic synovia and tonsils. I also used RNA-sequencing and clinical scores from a well-characterized early rheumatoid arthritis cohort and a murine model of CD4+ T cell-driven arthritis. I found that: 1. SLC5A12 is up-regulated by CD4+ but not CD8+ T cells upon T-cell-receptor (TCR) triggering. This expression is higher on CD4+ T cells isolated from RA synovial joints, where lactate is more abundant, as compared to peripheral RA and HC CD4+ T-cells. 2. Lactate-uptake by CD4+ T cells through SLC5A12 causes a reprogramming of intracellular metabolism, including reduced glycolysis and enhanced TCA cycle and fatty acid synthesis substrates. 3. SLC5A12-mediated lactate influx into human CD4+ T cells contributed to reshaping their effector phenotype, leading to increased IL- 4. 17 production via nuclear PKM2/Stat3 signalling and enhanced fatty acid synthesis. 5. SLC5A12-mediated lactate influx caused increased CD4+ T cell retention at the inflamed tissue as a consequence of impaired cell motility caused by reduced glycolysis and enhanced fatty acid synthesis. 6. Antibody-mediated blockade of SLC5A12 ameliorates the clinical course of CD4+ T cell-driven human glucose 6 phosphate isomerase (hG6PI)-induced arthritis. 7. Lactate/SLC5A12-induced metabolic reprogramming in CD4+ T cells is a distinctive mechanism of lymphoid RA pathogenesis. These findings establish lactate as an active signalling metabolite that contributes to the perpetuation of chronic inflammation and provide a novel therapeutic rationale to combat chronic inflammatory diseases.
Supervisor: Not available Sponsor: Versus Arthritis Clinical Research Fellowship
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Inflammation ; tissue microenvironment ; CD4+ T cell-driven arthritis. ; immune system