In our project, we delve into the intricate world of CD40/CD40L signaling and its pivotal connection with inflammatory processes in the context of myocardial infarction (MI). Our collaborative efforts are concentrated on the exploration of small molecule inhibitors as potential tools for modulating various inflammatory phases that occur during acute myocardial infarction (AMI).

One compelling avenue of our investigation involves delving into the interplay between CD40 signaling and the complex landscape of diabetes-associated hyperinflammation within the context of MI. This investigation aims to elucidate the role of CD40 signaling in driving and intensifying hyperinflammatory responses seen in MI patients with diabetes. By uncovering the molecular intricacies of this interplay, we seek to shed light on potential therapeutic targets that could be harnessed to mitigate excessive inflammation in such high-risk patients.

As we navigate through the realms of CD40/CD40L signaling and its association with myocardial infarction, our mission is to contribute to a comprehensive understanding of the inflammatory mechanisms at play. By pinpointing the key players and unraveling the dynamics of this intricate signaling pathway, we hope to pave the way for innovative strategies that hold the promise of ameliorating the impact of inflammation in the aftermath of AMI, particularly in the context of diabetes-related complications.

Associated Scientists:

Dr. Alexander Lang

M.Sc. Camila Zöhner

Dr. med. cand. Antonia Arnold

Dr. med. cand. Chiara Wernet

Previous work has identified a novel macrophage subpopulation termed interferon-inducible cells (IFNICs) in murine abdominal aortic aneurysm (AAA) that exhibits high CD40 expression and an interferon gene signature. The function of IFNICs in the genesis of AAA and the role of the pro-inflammatory CD40/CD40L axis and other immunomodulatory signalling cascades (TAMs, IFNAR) remains unknown. We aim to define the phenotype, localisation and function of CD40+ IFNICs in AAA and to investigate the CD40-mediated modulation of AAA-relevant type I interferon responses. In addition, predictors for life-threatening ruptures in patients in late stages of AAA and new therapeutic approaches for therapy will be identified.

This project is fundet by the DFG: www.trr259.uni-bonn.de/en/projects/a05

Associated Scientists:

Dr. Susanne Pfeiler

M.Sc Christin Elster

B.Sc. Noura Kharrat

Kea Mara Toennissen

Myocardial infarction triggers a cascade of complex inflammatory responses, which play a critical role in tissue repair and cardiac recovery. Our research focuses on understanding and modulating these immunological processes to promote better outcomes for patients. A central aspect of our work involves studying the mechanistic role of mTOR, a key regulator in cellular and immune function. We are particularly investigating the effects of Everolimus, an mTOR inhibitor, on immune activation and cell migration. By exploring how Everolimus influences these processes, we aim to shed light on its potential as a therapeutic agent to regulate inflammation and improve post-infarction recovery. Our ultimate goal is to contribute to the development of innovative, targeted therapies that enhance cardiac repair and long-term heart health.

Associated Scientists:

Dr. Madlen Kaldirim

Dr. med. cand. Justus Matthey

Cellular senescence, a natural process of irreversible cell cycle arrest, plays a significant role in aging and age-related diseases. This phenomenon is marked by distinct molecular and physiological changes, contributing to a decline in tissue function. In our research, we center our attention on unraveling the intricate relationship between cellular senescence and systemic factors such as diabetes.

We are dedicated to understanding how diabetes-associated systemic factors accelerate the accumulation of senescent cells, a process further exacerbated by conditions like hyperglycemia and chronic inflammation.

Specifically, we are delving into the role of the senescence-associated secretory phenotype (SASP), a unique profile of secreted factors by senescent cells. By deciphering the influence of SASP on cardiac, vascular, and systemic functions, we aim to pinpoint the mechanisms through which cellular senescence contributes to the deterioration of these critical physiological systems in diabetes.

Our approach involves the utilization of senolytics, compounds designed to selectively eliminate senescent cells. By targeting these cells, we aspire to uncover the effects of senescence elimination on mitigating the adverse consequences of diabetes-related organ dysfunction. Ultimately, our research strives to provide valuable insights into the intricate web of cellular senescence, diabetes, and their collective impact on organ function, paving the way for potential therapeutic interventions to improve the lives of individuals affected by these conditions.

Associated Scientist:

M.Sc. Camila Zöhner

M.Sc. Ashley-Jane Duplessis

Dr. Alexander Lang

The goal of our project is to merge advanced technologies and artificial intelligence to unravel the connection between gene expression, metabolomics, and immune responses post myocardial infarction (MI).

We combine single cell RNA sequencing, bulk RNA sequencing, and metabolomics to paint a comprehensive picture of the molecular landscape during post-MI immune responses.

Our AI model learns from this integrated data, revealing intricate links between gene activity and metabolic changes. This predictive approach identifies key molecules and pathways that steer post-MI immune responses, uncovering potential therapeutic targets.

By bridging RNA sequencing insights and metabolic signaling, our project paves the way for personalized treatments. This promises tailored interventions that modulate immune responses after MI, leading to improved patient outcomes and advancing cardiovascular research.

This project is funded by MODS https://www.mods.hhu.de/

Associated Scientists:

Dr. Tin Yau Pang

Dr. Alexander Lang

Pubmed-Link to all Publications of AG Gerdes

• Lang, A.; Oehler, D.; Benkhoff, M.; Reinders, Y.; Barcik, M.; Shahrjerdi, K.; Kaldirim, M.; Sickmann, A.; Dannenberg, L.; Polzin, A.;  Pfeiler, S.; Kelm, M.; Grandoch, M.; Jung, C.; Gerdes, N. Mitochondrial Creatine Kinase 2 (Ckmt2) as a Plasma-Based Biomarker for Evaluating Reperfusion Injury in Acute Myocardial Infarction. Biomedicines 2024, 12, 2368. https://doi.org/10.3390/biomedicines12102368 

• Duplessis, A.*; Elster, C.*; Becher, S.; Engel, C.; Lang, A.; Kaldirim, M.; Jung, C.; Grandoch, M.; Kelm, M.; Pfeiler, S. Gerdes, N. Novel Fluorescence-Based Methods to Determine Infarct and Scar Size in Murine Models of Reperfused Myocardial Infarction. Cells 2024, 13, 1633. https://doi.org/10.3390/cells13191633 

• Gerdes N, Klingenberg R. Mini-Review: Immunogenic epitopes in apolipoprotein B-100 for atheroprotective immunization. Front Cardiovasc Med. 2024 Aug 15;11:1448664. doi: 10.3389/fcvm.2024.1448664. PMID: 39211769; PMCID: PMC11357920. https://pubmed.ncbi.nlm.nih.gov/39211769/

• Elster C, Ommer-Bläsius M, Lang A, Vajen T, Pfeiler S, Feige M, Yau Pang T, Böttenberg M, Verheyen S, Lê Quý K, Chernigovskaya M, Kelm M, Winkels H, Schmidt SV, Greiff V, Gerdes N. Application and challenges of TCR and BCR sequencing to investigate T- and B-cell clonality in elastase-induced experimental murine abdominal aortic aneurysm. Front Cardiovasc Med. 2023 Nov 14;10:1221620. doi: 10.3389/fcvm.2023.1221620. PMID: 38034381; PMCID: PMC10686233. https://pubmed.ncbi.nlm.nih.gov/38034381/

• Lang A*, Binneboessel S*, Nienhaus F, Bruno RR, Wolff G, Piayda K, Pfeiler S, Ezzahoini H, Oehler D, Kelm M, Winkels H, Gerdes N, Jung C. Acute and short-term fluctuations in gravity are associated with changes in circulatory plasma protein levels. NPJ Microgravity. 2024 Mar 4;10(1):25. doi: 10.1038/s41526-024-00370-y. PMID: 38438462; PMCID: PMC10912449. https://pubmed.ncbi.nlm.nih.gov/38438462/ 
   
• Kaldirim M, Lang A, Pfeiler S, Fiegenbaum P, Kelm M, Bönner F, Gerdes N. Modulation of mTOR Signaling in Cardiovascular Disease to Target Acute and Chronic Inflammation. Front Cardiovasc Med. 2022 Jun 29;9:907348. doi: 10.3389/fcvm.2022.907348. PMID: 35845058; PMCID: PMC9280721. https://pubmed.ncbi.nlm.nih.gov/35845058/ 

• Reiche, M. E., den Toom, M., Willemsen, L., van Os, B., Gijbels, M., Gerdes, N., Aarts, S., & Lutgens, E. Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction. BMJ open diabetes research & care, 2023 7(1), e000829. doi.org/10.1136/bmjdrc-2019-000829
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936585/

• Bianchini M, Duchêne J, Santovito D, Schloss MJ, Evrard M, Winkels H, Aslani M, Mohanta SK, Horckmans M, Blanchet X, Lacy M, von Hundelshausen P, Atzler D, Habenicht A, Gerdes N, Pelisek J, Ng LG, Steffens S, Weber C, Megens RTA. PD-L1 expression on nonclassical monocytes reveals their origin and immunoregulatory function. Sci Immunol. 2019;4(36):eaar3054. doi:10.1126/sciimmunol.aar3054
  https://immunology.sciencemag.org/content/4/36/eaar3054

• Winkels H, Meiler S, Lievens D, Engel D, Spitz C, Burger C, Beckers L, Dandl A, Reim S, Ahmadsei M, Hartwig H, Holdt LM, Hristov M, Megens RT, Schmitt M, Biessen EA, Borst J, Faussner A, Weber C, Lutgens E, Gerdes N. CD27 co-stimulation increases the abundance of regulatory t cells and reduces atherosclerosis in hyperlipidemic mice. Eur Heart J. 2017, 38(48):3590-3599. (PMID: 29045618)
  https://academic.oup.com/eurheartj/article/38/48/3590/4554905

• Winkels H, Meiler S, Smeets E, Lievens D, Engel D, Spitz C, Bürger C, Rinne P, Beckers L, Dandl A, Reim S, Ahmadsei M, Van den Bossche J, Holdt LM, Megens RT, Schmitt M, de Winther M, Biessen EA, Borst J, Faussner A, Weber C, Lutgens E, Gerdes N. CD70 limits atherosclerosis and promotes macrophage function. Thromb Haemost. 2017, 117(1):164-175. (PMID: 27786334)
  https://www.thieme-connect.de/products/ejournals/abstract/10.1160/TH16-04-0318

• Gerdes N, Seijkens T, Lievens D, Kuijpers MJ, Winkels H, Projahn D, Hartwig H, Beckers L, Megens RT, Boon L, Noelle RJ, Soehnlein O, Heemskerk JW, Weber C, Lutgens E. Platelet CD40 Exacerbates Atherosclerosis by Transcellular Activation of Endothelial Cells and Leukocytes. Arterioscler Thromb Vasc Biol. 2016, 36(3):482-90. (PMID: 26821950)
  https://www.ncbi.nlm.nih.gov/pubmed/26821950

• Wang J, Sun C, Gerdes N, Liu C, Liao M, Liu J, Shi MA, He A, Zhou Y, Sukhova GK, Chen H, Cheng M, Kuzuya M, Murohara T, Zhang J, Cheng X, Jiang M, Shull GE, Rogers S, Yang CL, Ke Q, Jelen S, Bindels R, Ellison DH, Jarolim P, Libby P, Shi GP. Interleukin 18 function in atherosclerosis requires both the interleukin 18 receptor and the Na-Cl co-transporter. Nat Med. 2015, 21(7):820-6. (PMID: 26099046)
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554539/

• Strodthoff D, Lundberg AM, Agardh HE, Ketelhuth DF, Paulsson-Berne G, Arner P, Hansson GK, Gerdes N. Lack of Invariant Natural Killer T Cells Affects Lipid Metabolism in Adipose Tissue of Diet-Induced Obese Mice. Arterioscler Thromb Vasc Biol. 2013, 33(6):1189-96. (PMID: 23520162)
  https://www.ahajournals.org/doi/10.1161/ATVBAHA.112.301105

• Klingenberg R*, Gerdes N*, Badeau RM, Gisterå A, Strodthoff D, Ketelhuth DF, Lundberg AM, Rudling M, Nilsson SK, Olivecrona G, Zoller S, Lohmann C, Lüscher TF, Jauhiainen M, Sparwasser T, Hansson GK. Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J Clin Invest. 2013, 123(3):1323-34. (PMID: 23426179) (* indicates equal contribution)
  https://www.jci.org/articles/view/63891

• Gerdes N, Zhu L, Ersoy M, Hermansson A, Hjemdahl P, Hu H, Hansson GK, Li N. Platelets regulate CD4⁺ T-cell differentiation via multiple chemokines in humans. Thromb Haemost. 2011, 106(2):353-62. (PMID: 21655676)
  https://www.ncbi.nlm.nih.gov/pubmed/21655676

• Zirlik A, Maier C, Gerdes N, MacFarlane LA, Soosairajah J,  Bavendiek U, Arens I, Ernst S, Bassler N, Missiou A, Patko Z, Aikawa M, Schönbeck U, Bode C, Libby P, Peter K. CD40L mediates inflammation independently of CD40 by interaction with Mac-1. Circulation. 2007, 115(12):1571-1580. (PMID: 17372166)
  https://www.ncbi.nlm.nih.gov/pubmed/17372166

• Schönbeck U, Gerdes N, Varo N, Reynolds RS, Horton DB, Bavendiek U, Robbie LA, Ganz P, Kinlay S, Libby P. Oxidized low-density lipoprotein augments and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors limit CD40 and CD40L expression in human vascular cells. Circulation 2002, 106(23):2888-2893. (PMID: 12460867)
  https://www.ncbi.nlm.nih.gov/pubmed/12460867

• Gerdes N, Sukhova GK, Libby P, Young JL, Reynolds RS, Schönbeck U. Expression of interleukin (IL)-18 and functional IL-18 receptor on human vascular endothelial cells, smooth muscle cells, and macrophages: implications for atherogenesis. J Exp Med. 2002, 195(2):245-257. (PMID: 11805151)
  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2193607/