Targeting pro-fibrotic neutrophil subsets for better healing of the infarcted heart

Erik Klapproth (Dresden)1, S. Grell (Dresden)1, G. Trimaglio (Dresden)2, K. Lorenz (Würzburg)3, P. Mirtschink (Dresden)2, P. Saftig (Kiel)4, M. Wagner (Dresden)5, A. El-Armouche (Dresden)1

1Medizinische Fakultät Carl Gustav Carus der TU Dresden Institut für Pharmakologie und Toxikologie Dresden, Deutschland; 2Universitätsklinikum Carl Gustav Carus an der TU Dresden Institut für klinische Chemie und Laboratoriumsmedizin Dresden, Deutschland; 3Universitätsklinikum Würzburg Institut für Pharmakologie und Toxikologie Würzburg, Deutschland; 4Christian-Albrechts-Universität Kiel Biochemisches Institut Kiel, Deutschland; 5Herzzentrum Dresden GmbH an der TU Dresden Rhythmologie Dresden, Deutschland


Background and Purpose. Neutrophils have long been considered short-lived effector cells of the innate immune system, with limited capacity for biosynthetic activity and a role primarily in acute inflammation before being replaced by more specialized cells. However, it is becoming increasingly clear that neutrophils are more versatile than originally thought and are not only involved in proinflammatory processes but also support cellular crosstalk, angiogenesis, extracellular matrix (ECM) remodeling, and resolution of inflammation. Here, we comprehensively characterize the diversity of neutrophils after myocardial infarction (MI) and identify a distinct pro-fibrotic neutrophil subset that relies on ADAM10/CX3CL1/CX3CR1 signaling.

Methods and Results. We show that upon MI, ADAM10-mediated shedding of CX3CL1 is specifically induced in cardiomyocytes, and cardiomyocyte-specific ADAM10 KO as well as pharmacological inhibition for only three days significantly improves overall survival and preserves cardiac function. Utilizing FACS analysis we identified reduced heart tissue infiltration of a CX3CR1-positive neutrophil population as underlying mechanism. FACS sorting and subsequent RNA sequencing of neutrophils revealed an increase of Cx3cr1 expression between three and seven days after MI, which correlated with the expression of pro-fibrotic genes such as Spp1, Arg1, Col1a1, Col3a1 and Fn1. Using decellularization, ECM enrichment and subsequent mass spectrometry of infarcted mouse hearts we substantiate that reducing CX3CR1-positive neutrophils through ADAM10 inhibition reduces scar size and decreases the abundance of Collagen type-I, Collagen type-III and Fibronectin in the infarcted heart.

Conclusion. Pharmacological and genetic targeting of the membrane sheddase ADAM10 is highly efficient in improving post-infarction cardiac function and survival by abrogating post-translational CX3CL1 processing, limiting infiltration of CX3CR1-positive neutrophils, and mitigating ECM remodeling. Thus, our findings uncover a novel therapeutic concept centered on pro-fibrotic neutrophil targeting, which may address a clinically significant therapeutic gap in the early stages following myocardial infarction.

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