Plenary 1 Monday 31 May – Session 3

The interface of immune and metabolic responses in atherosclerosis: Esther Lutgens, Amsterdam, The Netherlands

Atherosclerosis: metabolism dysfunction drives inflammation in the vessels

Esther Lutgens is Professor of Vascular Immunopathology at Amsterdam University Medical Centre and visiting Professor at the Ludwig Maximilian University, Munich, Germany. After completing her medical degree and PhD at the University of Maastricht, The Netherlands, she undertook post-doctoral training in the Department of Pathology, University of Maastricht, Harvard Medical School, Boston and Dartmouth Medical School, Hanover, USA. She was subsequently appointed Assistant Professor at the Cardiovascular Research Institute, Maastricht, before her current appointment. Her research interests focus on modulation of co-stimulatory pathways and the immune system in vascular inflammation, specifically the role of the CD40-CD40L signalling axis in atherosclerosis and how CD40-CD40L interactions in different cell-types and pathologies mediate the immune cell phenotype. More recently, her research has investigated the role of CD40L in obesity.

Inflammation is a key driver of atherosclerosis. The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) provided proof of the concept that targeted inhibition of residual inflammatory risk, in this case with the anti-interleukin-1β monoclonal antibody canakinumab, reduced cardiovascular events. These findings suggest that anti-inflammatory therapies have the potential to reduce (recurrent) atherosclerotic cardiovascular disease.

In the search for additional anti-inflammatory therapeutic strategies, attention has focused on the possibility of modulating inflammation by targeting immune checkpoint proteins, particularly at the interface of lipid metabolism and the immune response. These comprise co-stimulatory and co-inhibitory molecules and play a key role in the regulation of inflammation. One promising target is the immune checkpoint protein CD40 and its ligand CD40L (CD154), which is involved in regulating multiple immunological processes, including T cell activation, immunoglobulin isotype switching and cytokine production. Preclinical studies have shown that disrupting the CD40-CD40L pathway reduces atherosclerosis and induces a stable atherosclerotic plaque phenotype.  Directly targeting the CD40-CD40L dyad is, however, not feasible due to the risk for immunosuppression and thromboembolic events. Instead, modulating the downstream signalling pathway, as well as targeting the metabolism of immune cells, may offer potential to influence plaque progression and stabilization. Finally, as atherosclerosis results from the complex crosstalk between lipid metabolism and the immune response, targeting their interface may offer opportunities for novel therapeutic strategies in the future.

Recent references

Shami A, Atzler D, Bosmans LA, Winkels H, Meiler S, Lacy M, van Tiel C, Ta Megens R, Nitz K, Baardman J, Kusters P, Seijkens T, Buerger C, Janjic A, Riccardi C, Edsfeldt A, Monaco C, Daemen M, de Winther MPJ, Nilsson J, Weber C, Gerdes N, Gonçalves I, Lutgens E. Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans. Eur Heart J 2020;41:2938-2948.

Poels K, Vos WG, Lutgens E, Seijkens TTP. E3 Ubiquitin Ligases as immunotherapeutic target in atherosclerotic cardiovascular disease. Front Cardiovasc Med 2020;7:106.

Bosmans LA, Bosch L, Kusters PJH, Lutgens E, Seijkens TTP. The CD40-CD40L dyad as immunotherapeutic target in cardiovascular disease. J Cardiovasc Transl Res 2020; doi: 10.1007/s12265-020-09994-3.

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