ADAM10 sheddase-mediated myeloid bias after acute myocardial infarction

• Applicants: Professor Dr. Ali El-Armouche; Dr. Erik Klapproth
• Subject Area: Pharmacology ; Cardiology, Angiology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 544115600

After myocardial infarction (MI) the most effective method to preserve the viability of the ischemic myocardium is to limit infarct size by early reperfusion of the occluded vessel. However, adjunctive therapies for reperfusion that further protect the ischemic tissue, limit scar size, and thus prevent progression to terminal heart failure are still lacking. Following infarction, the innate immune response is pivotal in clearing of tissue debris as well as scar formation, but exaggerated cytokine and chemokine secretion with subsequent immune cell infiltration also leads to further myocardial damage. It is well established that sterile inflammation, as it occurs after MI, triggers emergency myelopoiesis, which has an acute but transient effect on hematopoietic stem and progenitor cells (HSPCs) to provide a constant supply of immune cells. However, recent research indicates that sterile inflammation can induce not only acute but also long-term changes in HSPCs that are passed on to their progeny, contributing to a more aggressive immune cell phenotype. This largely interleukin (IL)-1ß-dependent process is referred to as myeloid bias. While periodontal disease, for example, has been shown to induce myeloid bias that is associated with the occurrence of comorbidities such as arthritis, it is as yet unclear whether changes in HSPCs and differentiated immune cells characteristic of permanent myeloid bias occur after MI and how these affect the outcome of possible secondary cardiovascular events. We have recently shown that a novel ADAM10 / CX3CL1 axis is critical in the regulation of neutrophil recruitment and IL-1ß secretion after MI. Short-term pharmacological ADAM10 inhibition early after MI improved survival, enhanced heart function and reduced scar size. Mechanistically, this was driven by abolished ADAM10-mediated CX3CL1 ectodomain shedding and diminished IL-1ß-dependent inflammation, neutrophil bone marrow egress and myocardial tissue infiltration. Based on the central role of IL-1ß in inducing myeloid bias and our preliminary findings, we here hypothesize that MI triggers myeloid bias, leading to the development of a persistent pro-inflammatory immune cell phenotype which is critical for outcome and prognosis of recurrent cardiovascular events. We expect that short-term inhibition of the ADAM10 / neutrophil / IL-10ß axis after acute MI abrogates infarct-induced myeloid bias, resulting in improved outcome after recurrence.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Peter Mirtschink