Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02087-y
Inhibition of CX3CL1 ectodomain shedding abolishes neutrophil infiltration and improves survival and cardiac function after infarction
E. Klapproth1, P. Klose1, J. Wiedemann1, A. Witt2, S. Künzel1, S. Weber1, K. Guan3, I. Kopaliani2, K. Lorenz4, P. Saftig5, M. Wagner6, A. El-Armouche1
1Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus der TU Dresden, Dresden; 2Institut für Physiologie, Medizinische Fakultät Carl Gustav Carus der TU Dresden, Dresden; 3Institut für Pharmakologie und Toxikologie, Universitätsklinikum Carl Gustav Carus an der TU Dresden, Dresden; 4Institut für Pharmakologie und Toxikologie, Universitätsklinikum Würzburg, Würzburg; 5Institut für Biochemie, Christian-Albrechts-Universität Kiel, Kiel; 6Rhythmologie, Herzzentrum Dresden GmbH an der TU Dresden, Dresden;

Background and Purpose. CX3CL1 is unique among the family of chemokines as it functions as leukocyte adhesion molecule and as chemoattractant. Its function is controlled via ADAM10-mediated ectodomain shedding. Both, CX3CL1 and ADAM10 are upregulated in response to specific heart pathologies e.g. ischemic heart failure and elevated serum levels of the metalloprotease ADAM10 as well as CX3CL1 have been reported following myocardial infarction. The causal role of the ADAM10/CX3CL1 axis in cardiovascular diseases, however, is not known yet.

Methods and Results. In the heart, CX3CL1 and ADAM10 are most abundantly expressed in cardiomyocytes. We show that ADAM10 and CX3CL1 protein levels are elevated in patients with ischemic cardiomyopathy (2-fold) and ADAM10 mRNA expression correlates with expression of atrial (ANP) and brain natriuretic peptide (BNP) mRNA. Upon hypoxia, cardiomyocyte CX3CL1 is upregulated and its coprecipitation with ADAM10 is enhanced, which is resolved by ADAM10 inhibition. Moreover, we identify this novel cardiomyocyte-specific ADAM10/CX3CL1 signaling axis to regulate neutrophil migration following hypoxia. Upon MI, cardiomyocyte-specific ADAM10 knockout as well as pharmacological ADAM10 inhibition (GI254023X) result in significantly improved overall survival and preserved cardiac function. ADAM10 inhibition significantly reduces post-infarction CX3CL1 shedding which translates in abolished IL-1 beta-driven inflammation and neutrophil recruitment as evidenced by mRNA sequencing and FACS analysis.

Conclusion. Our data show that cardiomyocyte CX3CL1 is upregulated in response to hypoxia and infarction to control neutrophil recruitment. Pharmacological and genetic targeting of the CX3CL1-processing sheddase ADAM10 is highly efficient in diminishing CX3CL1-driven neutrophil bone marrow egress and heart tissue infiltration after infarction. Due to its potent effects on post-infarction cardiac function and survival, the upregulated ADAM10/CX3CL1 axis could be a potential molecular target to be blocked in patients after infarction.
https://dgk.org/kongress_programme/ht2022/aP352.html