The interplay of different immune cells determines the progression of atherosclerosis and the propensity to cause clinical symptoms, such as a myocardial infarction or stroke. Immune checkpoint regulators, including co-stimulatory and co-inhibitory molecules, are important modulators of immune responses in atherogenesis. 

• Co-stimulatory molecules in Atherosclerosis

Previously, we have unraveled how co-stimulatory CD40L-CD40, CD27-CD70 and GITR-GITRL interactions drive atherosclerosis. We found that the CD40L-CD40-TRAF6 axis is crucial in atherosclerosis, and we could develop small molecule inhibitors targeting CD40-TRAF6 interactions, termed TRAF-STOPs. TRAF-STOP treatment successfully blocked (established) atherosclerosis and is currently being tested and optimized for human administration. Using conditional knock-out mice for CD40 and CD40L, we found that CD40 on dendritic cells and macrophages as well as CD40L on T cells are crucial for atherogenesis. Moreover, we discovered that the co-stimulatory molecule CD27 is a critical mediator for regulatory T cell (Treg) survival, which led to attenuated inflammation and retards atherosclerosis. Our latest data show that GITR drives myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability.

• Amino acid metabolism in atherosclerosis
  

Currently we extended our studies to investigate how aberrant T cell regulation emanating from changes in T cell metabolism may be pro- or anti-atherogenic. Our latest study unraveled a novel mechanism by which the amino acid homoarginine reduces atherosclerosis, establishing that homoarginine modulates the T cell cytoskeleton and thereby mitigates T cell functions important during atherogenesis.

Nitz K*, Lacy M*, Bianchini M, Wichapong K, Avcilar Kücükgöze I, Bonfiglio CA, Migheli R, Wu Y, Burger C, Li Y, Forné I, Ammar C, Janjic A, Mohanta S, Duchene J, Heemskerk JWM, Megens RTA, Schwedhelm E, Huveneers S, Lygate CA, Santovito D, Zimmer R, Imhof A, Weber C, Lutgens E, Atzler D. The amino acid homoarginine inhibits atherogenesis by modulating T-cell function. Circ Res. 2022

Lacy M*, Bürger C*, Shami A*, Ahmadsei M, Winkels H, Nitz K, van Tiel CM, Seijkens TTP, Kusters PJH, Karshovka E, Prange KHM, Wu Y, Brouns SLN, Unterlugauer S, Kuijpers MJE, Reiche ME, Steffens S, Edsfeldt A, Megens RTA, Heemskerk JWM, Goncalves I, Weber C, Gerdes N, Atzler D*, Lutgens E*. Cell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease.  Nat Commun. 2021

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

 Lutgens E, Atzler D, Döring Y, Duchene J, Steffens S, Weber C. Immunotherapy for cardiovascular disease. Eur Heart J. 2019

Faller KME*, Atzler D*, McAndrew DJ, Zervou S, Whittington HJ, Simon JN, Aksentijevic D, Ten Hove M, Choe CU, Isbrandt D, Casadei B, Schneider JE, Neubauer S, Lygate CA. Impaired cardiac contractile function in arginine:glycine amidinotransferase knockout mice devoid of creatine is rescued by homoarginine but not creatine. Cardiovasc Res. 2018;114(3):417-430.

 Seijkens TTP, van Tiel CM, Kusters PJH, Atzler D, Soehnlein O, Zarzycka B, Aarts SABM, Lameijer M, Gijbels MJ, Beckers L, den Toom M, Slütter B, Kuiper J, Duchene J, Aslani M, Megens RTA, van 't Veer C, Kooij G, Schrijver R, Hoeksema MA, Boon L, Fay F, Tang J, Baxter S, Jongejan A, Moerland PD, Vriend G, Bleijlevens B, Fisher EA, Duivenvoorden R, Gerdes N, de Winther MPJ, Nicolaes GA, Mulder WJM, Weber C, Lutgens E. Targeting CD40-Induced TRAF6 Signaling in Macrophages Reduces Atherosclerosis. J Am Coll Cardiol. 2018

 Atzler D, Schönhoff M, Cordts K, Ortland I, Hoppe J, Hummel FC, Gerloff C, Jaehde U, Jagodzinski A, Böger RH, Choe CU, Schwedhelm E. Oral supplementation with L-homoarginine in young volunteers. Br J Clin Pharmacol. 2016

 Lutgens, E., Gorelik, L., Daemen, M.J., de Muinck, E.D., Grewal, I.S., Koteliansky, V.E., Flavell, R.A. Requirement for CD154 in the progression of atherosclerosis. Nat Med. 1999