Coagulation proteases in vascular disease and sterile inflammation

A major research focus is the thrombomodulin-protein C pathway and its role in regulating cellular signaling. When thrombin binds to thrombomodulin on the endothelial surface, it activates protein C, which subsequently limits further thrombin generation. In addition to its anticoagulant function, activated protein C (aPC) exerts important cytoprotective and anti-inflammatory signaling effects. Many of these effects are mediated through PAR-dependent signaling pathways, particularly PAR1. In contrast to pro-inflammatory signaling induced by thrombin, aPC largely promotes protective PAR1 signaling that stabilizes endothelial barrier function and limits inflammation. We study molecular structures of PAR1 mediating biased thrombin versus aPC signaling and of PAR homo- and heterodimers. These pathways link activation of the coagulation cascade to inflammatory and innate immune responses, including interferon-associated signaling programs, ER-stress and inflammasome in vascular and immune cells. Our work aims to understand how these pathways regulate cellular responses during vascular and organ injury and regeneration. These projects are funded by the DFG under individual grants or are a part of the SFB1423. Berend Isermann is on advisory boards of start-up companies developing drugs harnessing cytoprotective signaling of aPC (function therapeutics, Novapep). 

Regulation of cellular function by thrombin (IIa) and activated protein C (aPC)-mediated PAR-signaling. The complex of thrombin and thrombomodulin (TM) generates activated protein C (aPC). aPC and IIa induce biased PAR1 signaling and regulate cellular function (e.g., mitochondrial or endoplasmic reticulum function), with the effects being mostly opposite (cytoprotective versus cytodisruptive for aPC versus IIa, respectively).​​

Our ERC-funded research evaluates how tissue factor modulates immune signaling by interacting with the interferon-receptor IFNAR1. Tissue factor is the main initiator of the coagulation cascade and is strongly induced during vascular injury and inflammation. We discovered an interaction of TF with IFNAR1: In this heterodimer, both TF and IFNAR1 are inactive. Upon cellular stimulation, this heteromer dissociates, activating simultaneously TF and IFNAR1. Thus, the TF – IFNAR1 heteromer is a singular molecular switch controlling directly thrombo-inflammation. We aim to understand how this heteromer is regulated, on which cells and in which disease conditions the TF – IFNAR1 thrombo-inflammatory switch is relevant, and aim to identify therapeutic approaches to modulate the TF – IFNAR1 heteromer.

A novel thrombo-inflammatory switch: the TF-IFNAR heterodimer. On resting cells, TF and IFNAR1 form a heterodimer and both are inactive (green). Upon cellular activation, this heterodimer breaks up, IFNAR1 forms a heterodimer with IFNAR2, inducing IFN type 1 signaling upon lingand binding, and TF binds to fVII, initiating blood clotting via the extrinsic coagulation pathway and TF-dependent signaling.

​Within the framework of the Leipzig Center of Metabolism (LeiCeM), part of the German excellence initiative, we study how vascular aging and associated molecular changes such as hypercoagulability or inflammation drive metabolic alterations, obesity and organ dysfunction. We aim to understand how vascular aging drives metabolism driven diseases, such as obesity or kidney disease. In addition, in collaboration with the endocrinology clinic and other clinics and institute, we evaluate strategies to defeat weight re-gain post weight loss.

https://www.uni-leipzig.de/leipzig-center-of-metabolism​

Early Mechanisms of Lifestyle-Associated Vasculo-Metabolic Disease​

As part of EMILIA – Early Medical Training in Lifestyle-Associated Chronic Vasculo-Metabolic Diseases, we are promoting funding opportunities for medical students to conduct their research work. Within the EMILIA consortium, we investigate the early mechanisms that initiate lifestyle-related diseases, including obesity, diabetes, and cardiovascular disorders. Our focus is on the initial stages of disease development, where physiological adaptation begins to shift toward pathological processes. A key objective is to identify critical “switch points" at which vascular and metabolic homeostasis transitions into disease. By studying these early events at the molecular and cellular level, we aim to better understand how metabolic stress, inflammatory signaling, and vascular dysfunction interact at the onset of disease. Identifying such transition points may enable the development of early diagnostic markers and precision medicine approaches to prevent disease onset or slow disease progression at early disease stages.

https://www.uniklinikum-leipzig.de/wissenschaft-forschung/schwerpunkte-forschung/forschungsprojekte/emilia

Within the above listed projects, we combine advanced molecular and systems-level technologies. These include single-nucleus RNA sequencing (snRNA-seq) to resolve cell type-specific responses in vascular tissues, OLINK based proteomics and FRET/BRET-based biosensors to study protease and receptor signaling dynamics in living cells. We further apply epigenetic analyses, genetically modified mouse models, and studies in human cohorts to investigate these pathways in vivo and in clinically relevant contexts. In addition, Seahorse-based metabolic profiling allows us to examine how cellular metabolism influences endothelial activation and vascular inflammation. We interact with other national and international laboratories to supplement our know-how and methodological approaches.

Together, these approaches enable us to investigate how protease-driven signaling networks regulate vascular biology in health and disease.​

1. ​Elwakiel A, Gupta D, Rana R, Manoharan J, Al-Dabet MM, Ambreen S, Fatima S, Zimmermann S, Mathew A, Li Z, Singh K, Gupta A, Pal S, Sulaj A, Kopf S, Schwab C, Baber R, Geffers R, Götze T, Alo B, Lamers C, Kluge P, Kuenze G, Kohli S, Renné T, Shahzad K, Isermann B. Factor XII signaling via uPAR-integrin β1 axis promotes tubular senescence in diabetic kidney disease. Nat Commun. 2024 Sep 11;15(1):7963.
2. Zimmermann S, Mathew A, Bondareva O, Elwakiel A, Waldmann K, Jiang S, Rana R, Singh K, Kohli S, Shahzad K, Biemann R, Roskoden T, Storsberg SD, Mawrin C, Krügel U, Bechmann I, Goldschmidt J, Sheikh BN, Isermann B. Chronic kidney disease leads to microglial potassium efflux and inflammasome activation in the brain. Kidney Int. 2024 Dec;106(6):1101-1116. 
3. Manoharan J, Rana R, Kuenze G, Gupta D, Elwakiel A, Ambreen S, Wang H, Banerjee K, Zimmermann S, Singh K, Gupta A, Fatima S, Kretschmer S, Schaefer L, Zeng-Brouwers J, Schwab C, Al-Dabet MM, Gadi I, Altmann H, Koch T, Poitz DM, Baber R, Kohli S, Shahzad K, Geffers R, Lee-Kirsch MA, Kalinke U, Meiler J, Mackman N, Isermann B. Tissue factor binds to and inhibits interferon-α receptor 1 signaling. Immunity. 2024 Jan 9;57(1):68-85.e11. 
4. Rana R, Manoharan J, Elwakiel A, Zimmermann S, Lindquist JA, Gupta D, Al-Dabet MM, Gadi I, Fallmann J, Singh K, Gupta A, Biemann R, Brandt S, Alo B, Kluge P, Garde R, Lamers C, Shahzad K, Künze G, Kohli S, Mertens PR, Isermann B. Glomerular-tubular crosstalk via cold shock Y-box binding protein-1 in the kidney. Kidney Int. 2024 Jan;105(1):65-83.
5. Gupta D, Elwakiel A, Ranjan S, Pandey MK, Krishnan S, Ambreen S, Henschler R, Rana R, Keller M, Ceglarek U, Shahzad K, Kohli S, Isermann B. Activated protein C modulates T-cell metabolism and epigenetic FOXP3 induction via α-ketoglutarate. Blood Adv. 2023 Sep 12;7(17):5055-5068.

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Current members:
Vascular aging and endothelial dysfunction
	Dr. Ahmed Elwakiel Post-doc  Send Email
	Dr. Rajiv Rana Post-doc  Send Email ​
	Dr. Julia Buchold Clinican Scientist  Send Email
	Zhiyang Li PhD student  Send Email
	Pan Hu PhD student  Send Email
	Antonia Pfeiffer MD student  Send Email
	Jasper Lieckfeldt MD student  Send Email
Diabetic vascular complications
	Dr. Kathleen Biemann Clinician Scientist  Send Email
	Hailong Kong PhD student  Send Email
Intracellular signaling
	Akash Mathew PhD Student  Send Email ​
	Elias Pogander MD student  Send Email
	Fides Möbus MD student  Send Email
PAR signaling
	Dr. Hamzah Khawaja PhD student  Send Email
	Shihai Jiang PhD student  Send Email
	Dr. Josephine Jacoby Clinician Scientist  Send Email
	Julian Sun PhD student  Send Email
	Surinder Pal PhD student  Send Email
TF driven interferon signaling
	Yuvrajsinh Gohil PhD student  Send Email
	Eylül Akyildiz PhD student  Send Email
	Yashwini Dewan PhD student  Send Email
	Dr. Felix Förster Clinician Scientist  Send Email
Former members:
	Jayakumar Manoharan PhD student
	Dheerendra Gupta PhD student
	Shruthi Krishnan PhD student
	Ishan Gadi PhD student
	Lukas Breitenstein MD student
	Thati Madhsudhan PhD student, Post-doc
	Sanchita Ghosh PhD student
	Satish Ranjan PhD student
	Juliane Wolter PhD student
	Hongjie Wang PhD/ MD student
	Moh'd Al-Dabet PhD student​​