Key result
Post-MI RNA sequencing in mice reveals a long-lived proinflammatory neutrophil subset reaching ~50% by day 4.
Why the study?
Neutrophils are thought to be short-lived first responders to tissue injury such as myocardial infarction, but little is known about their diversification or dynamics.
Single-cell transcriptomics reveals a dynamic, late-emerging proinflammatory SiglecF HI neutrophil subset in the infarcted murine heart that expresses longevity-associated genes.
Answers are grounded in this paper and cite their sources.
Single-cell profiling reveals neutrophil heterogeneity after MI in mice; hypothesis-generating for immune-targeted therapies in humans.
Background Neutrophils are thought to be short‐lived first responders to tissue injuries such as myocardial infarction (MI), but little is known about their diversification or dynamics. Methods and Results We permanently ligated the left anterior descending coronary arteries of mice and performed single‐cell RNA sequencing and analysis of >28 000 neutrophil transcriptomes isolated from the heart, peripheral blood, and bone marrow of mice on days 1 to 4 after MI or at steady‐state. Unsupervised clustering of cardiac neutrophils revealed 5 major subsets, 3 of which originated in the bone marrow, including a late‐emerging granulocyte expressing SiglecF, a marker classically used to define eosinophils. SiglecF HI neutrophils represented ≈25% of neutrophils on day 1 and grew to account for >50% of neutrophils by day 4 post‐MI. Validation studies using quantitative polymerase chain reaction of fluorescent‐activated cell sorter sorted Ly6G + SiglecF HI and Ly6G + SiglecF LO neutrophils confirmed the distinct nature of these populations. To confirm that the cells were neutrophils rather than eosinophils, we infarcted GATA‐deficient mice (∆dblGATA) and observed similar quantities of infiltrating Ly6G + SiglecF HI cells despite marked reductions of conventional eosinophils. In contrast to other neutrophil subsets, Ly6G + SiglecF HI neutrophils expressed high levels of Myc‐regulated genes, which are associated with longevity and are consistent with the persistence of this population on day 4 after MI. Conclusions Overall, our data provide a spatial and temporal atlas of neutrophil specialization in response to MI and reveal a dynamic proinflammatory cardiac Ly6G + SigF + (Myc + NFϰB + ) neutrophil that has been overlooked because of negative selection.
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Calcagno et al. (2021) studied Myocardial infarction. Myocardial infarction (LAD ligation) vs. Steady-state was evaluated on Neutrophil subsets and transcriptomes. Following myocardial infarction in mice, single-cell RNA sequencing identified a late-emerging, long-lived proinflammatory Ly6G+SiglecF(HI) neutrophil subset accounting for >50% of neutrophils by day 4.
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