Age-Related Changes in Macrophage Composition Impact Cardiac Remodeling Following Myocardial Infarction

Tobias Weinberger (München)1, C. Garcia-Rodriguez (Paris)2, D. Messerer (München)1, M. Fischer (München)1, M. Joppich (München)3, R. Zimmer (München)3, E. Gomez-Perdiguero (Paris)2, C. Schulz (München)1

1LMU Klinikum der Universität München Medizinische Klinik und Poliklinik I München, Deutschland; 2Insitut Pasteur Unité Macrophages et Développement de l'Immunité, Département de Biologie du Développement et Cellules Souches Paris, Frankreich; 3Ludwig-Maximilians-Universität Bioinformatik München, Deutschland


Aging is characterized by chronic inflammatory stress which leads to distinct alterations in the tissue environment and inflammatory responses, a process termed inflammaging. While the inflammatory response to myocardial infarction has been studied extensively in young mice, we are lacking data regarding the influence of aging on cardiac healing and the role of the immune system in this context. This is particularly relevant as the majority of myocardial infarctions occur in the elderly population.

We applied multiple lineage-tracing and pulse-labeling models combined with single cell sequencing to analyse the change in immune cell composition and transcriptome in baseline conditions and their dynamic response to myocardial infarction in aging. Macrophages remain the most abundant cardiac immune cell population in aged animals. The origin of cardiac macrophages exhibited age-dependent changes, with an increased recruitment of proinflammatory macrophages and a reduction in embryo-derived homeostatic macrophages during aging. This induced a proinflammatory phenotype in cardiac immune cells, which was paralleled by elevated fibrosis and increased presence of senescent cells in baseline conditions.

In response to myocardial infarction, the recruitment of macrophages to the remote area was significantly increased in aged mice, which was associated with an increased infarct size. To specifically address the changes in immune cell composition in the heart, we phenocopied the increased contribution of recruited macrophages seen in aging into young mice by depletion and recovery of macrophages. This resulted in an increased contribution of bone-marrow derived proinflammatory macrophages to the resident macrophage pool and was associated with a similar cardiac outcome after myocardial infarction in young mice (e.g. increased infarct size).

In conclusion, our findings suggest that altered immune cell composition in aging may play a pivotal role in the poor cardiac outcomes following myocardial infarction in aging.

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