ESPEYB20 8. Type 1 Diabetes New Mechanisms (3 abstracts)
8.11. Soluble RAGE prevents type 1 diabetes expanding functional regulatory T cells
Leung SS , Borg DJ , McCarthy DA , Boursalian TE , Cracraft J , Zhuang A , Fotheringham AK , Flemming N , Watkins T , Miles JJ , Groop PH , Scheijen JL , Schalkwijk CG , Steptoe RJ , Radford KJ , Knip M & Forbes JM
Diabetes 2022;71(9):1994–2008.PMID: 35713929
Brief summary: using a murine model of diabetes and ex vivo experiments in human T-cell cultures, this study showed that short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) modulates functional T regulatory cells (Treg) expansion and thus prevents diabetes.
This study provides further support for a role of the advanced glycation end-product (AGEs)-AGE receptor (RAGE) pathways in the pathogenesis of type 1 diabetes (T1D) (1). RAGE, a member of the immunoglobulin superfamily, is considered a proinflammatory receptor expressed in various cells, including T cells involved in the pathogenesis of T1D (2). Greater RAGE expression, leading to enhanced T-cell cytokine production and survival, has been reported on T cells from at risk individuals who progress to clinical T1D (3). Circulating RAGE isoforms, which lack the transmembrane domain, collectively termed soluble RAGE (sRAGE), are thought to have anti-inflammatory properties by competing with membrane bound RAGE for ligand binding (2). Low sRAGE concentrations are associated with higher risk for developing T1D (1), leading to proposals that sRAGE may be a potential novel therapeutic target to prevent T1D.
In this study, reduced circulating sRAGE concentrations in a murine model were targeted by short-term (2 weeks) administration of recombinant sRAGE. Treatment increased Tregs within the islets, pancreatic lymph nodes, and spleen, along with islet insulin expression and function. These beneficial effects were abrogated by Treg depletion and were shown to be dependent on antagonizing RAGE in a RAGE knockout mouse model. Ex vivo, human Tregs treated with a RAGE ligand downregulated several genes implicated in suppression, migration, and Treg homeostasis and these effects were reverted by sRAGE.
Although further confirmatory studies are needed, these results pinpoint a novel immunomodulatory role of sRAGE and suggest that treatment with sRAGE may be a promising T1D preventative therapy.
References: 1. Salonen KM, Ryhänen SJ, Forbes JM, et al. Decrease in circulating concentrations of soluble receptors for advanced glycation end products at the time of seroconversion to autoantibody positivity in children with prediabetes. Diabetes Care. 2015;38(4):665–670. 2. Du C, Whiddett RO, Buckle I, Chen C, Forbes JM, Fotheringham AK. Advanced glycation end products and inflammation in type 1 diabetes development. Cells. 2022;11(21):3503. 3. Durning SP, Preston-Hurlburt P, Clark PR, Xu D, Herold KC. The receptor for advanced glycation endproducts drives T cell survival and inflammation in type 1 diabetes mellitus. J Immunol. 2016;197(8):3076–3085.
Volume 20
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ESPE Yearbook of Paediatric Endocrinology
ISSN 1662-4009 (Online)
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