Neutrophils and NETs in Cardiovascular Disease
Principal Investigator: Dr. Lukas Heger
Once activated, platelets (A) form heterotypic, activating complexes with neutrophils and monocytes. The platelet-neutrophil interaction promotes extrusion of neutrophil extracellular traps (NETs; NETosis; B). NET production, in many cases, is preceded by neutrophil inflammasome assembly (C). Histones, as well as cytoplasmic and granular proteins entangled in NETs, have pleiotropic effects fueling pathological responses. Platelet-monocyte binding also induces inflammasome activation in monocytes (D). The inflammasome, through generation of active caspase 1, causes the release of the important vascular effector cytokine IL (interleukin)-1β. IL-1β in turn supports the endothelial expression of adhesion molecules such as E-selectin, propelling leukocyte recruitment. Activated platelets also stimulate TF (tissue factor) synthesis and its release in vesicles from monocytes (D). TF facilitates thrombin generation, fueling a systemic procoagulant state that with further platelet activation cumulates in the vicious cycle of thromboinflammation. Inhibition (┴) of PAD4, P-selectin/PSGL-1, inflammasome could potentially disrupt this process.
Our Mission:
To promote basic and applied discovery in the fields of neutrophil biology, heterocellular interactions and the thrombo-inflammatory response in cardiovascular disease and beyond.
What we are interested in:
To establish the activating interplay of neutrophil NLRP3 inflammasome and mechanisms that enable neutrophil extracellular traps release such as Protein Argini Deiminase 4 as targets for cardiovascular therapy in acute and chronic cardiovascular disease.
PI: Dr. med. Lukas A. Heger
Lukas is a MD and Clinical Scientist at the Department of Cardiology and Angiology, Faculty of Medicine, at University Hospital Freiburg in Germany. As a postdoctoral research fellow, funded by a grant from the German research foundation (DFG), he worked in the laboratory of Denisa Wagner at the Harvard Medical University investigating the role of peptidylarginine deiminase 4 (PAD4) and neutrophil extracellular traps (NETs) in adverse myocardial remodeling in chronic inflammation.
Lab manager: Daniela Stallmann
MD candidate Jonathan Häßner
Jonathan is in his 9th semester of medical school and investigating the temporal dynamics of neutrophil NLRP3 expression and NET release following ST-segment elevation myocardial infarction and ischemia/reperfusion injury.
MD candidate Lara Schönig
Lara is investigating the role of neutrophil preactivation and NET release in Transthyretin amyloid cardiomyopathy
Current Projects:
- IRIS Study
- NETs in Amyloidose
- The platelet C5a-C5aR-axis and NET release
- Right Ventricular strain as predictive factor in transjugular intrahepatic portosystemic shunt (TIPS) outcome
- Heger, L. A., N. Schommer, S. Van Bruggen, C. E. Sheehy, W. Chan and D. D. Wagner (2024). "Neutrophil NLRP3 promotes cardiac injury following acute myocardial infarction through IL-1beta production, VWF release and NET deposition in the myocardium." Sci Rep 14(1): 14524.
- Heger, L. A., N. Schommer, S. Fukui, S. Van Bruggen, C. E. Sheehy, L. Chu, S. Rajagopal, D. Sivanandhan, B. Ewenstein and D. D. Wagner (2023). "Inhibition of protein arginine deiminase 4 prevents inflammation-mediated heart failure in arthritis." Life Sci Alliance 6(10).
- Wagner, D. D. and L. A. Heger (2022). "Thromboinflammation: From Atherosclerosis to COVID-19." Arterioscler Thromb Vasc Biol 42(9): 1103-1112.