Clin Res Cardiol (2021). 10.1007/s00392-021-01933-9

ADAM10-mediated cleavage of CX3CL1 impacts on the inflammatory response after myocardial infarction
P. Klose1, J. Wiedemann1, K. Guan1, E. Klapproth1, A. El-Armouche1
1Institut für Pharmakologie und Toxikologie, Medizinische Fakultät Carl Gustav Carus der TU Dresden, Dresden;

Background and Purpose. A disintegrin and metalloproteinase 10 (ADAM10) proteolytically cleaves cell surface and membrane bound proteins and thereby actively regulates intra- and intercellular communication. ADAM10 is upregulated in patients with dilated cardiomyopathy as well as atrial fibrillation indicating a potential role in heart pathologies. Additionally, heart failure (HF) patients show elevated serum levels of the ADAM10 substrates CX3CL1, CXCL16 and Fas-L. We could already show that ADAM10 expression is induced specifically after myocardial infarction (MI) and that genetic and pharmacological ablation of ADAM10 improves post-infarction cardiac function and survival. Here, we address the mechanism by which cardiomyocyte-specific ADAM10 regulates intercellular communication for cardioprotection after MI.

Methods and Results. Upon MI via LAD ligation and pharmacological ADAM10 inhibition (GI254023X) we found significantly reduced levels of components of the NLRP3 inflammasome including IL1-β as well as reduced macrophage counts in the infarct border zone as compared to DMSO treated controls. Additionally, serum levels of soluble CX3CL1 (ELISA) and protein expression of cleaved membrane bound CX3CL1 were significantly reduced in response to ADAM10 inhibition while CXCL16 and Fas-L remained unchanged. Using immunoprecipitation and immunofluorescence analysis, we further identify direct interaction of ADAM10 and CX3CL1 in cultured cardiomyocytes (HL-1) which was increased after hypoxia and decreased to basal levels upon parallel ADAM10 inhibition. Compared to DMSO-treated controls, we show significantly reduced macrophage migration capacity (transwell migration) of RAW264.7 mouse macrophages attracted with supernatants of hypoxic, GI254023X-treated HL-1 cells which was comparable to attraction with normoxic, untreated supernatants.

Conclusion. Here we identify the ADAM10/CX3CL1/IL1-β axis as novel mechanism driving sterile inflammation after MI. Pharmacological inactivation of ADAM10 inhibits a pro-inflammatory cardiomyocyte-macrophage crosstalk mediated by ADAM10-cleaved CX3CL1 for improvement of post-infarction cardiac function. Due to its overexpression in heart tissue of HF patients, ADAM10 could be an attractive molecular target after MI.