Key result
Anti-Ly6G targeting shifts neutrophils to a SiglecF+ phenotype and increases post-MI border zone fibrosis.
Why the study?
The mechanisms governing cardiac neutrophil heterogeneity and the subsequent functional impact of this diversity on tissue repair following myocardial infarction remain to be elucidated.
Does in vivo Ly6G targeting shift cardiac neutrophils towards a SiglecF+ state and increase infarct border zone fibrosis in mice following myocardial infarction?
Does in vivo Ly6G targeting shift cardiac neutrophils towards a SiglecF+ state and increase infarct border zone fibrosis in mice following myocardial infarction?
This preclinical study demonstrates that peripheral priming and terminal programming of neutrophils into a SiglecF+ state in the ischemic heart directly drives post-myocardial infarction cardiac fibrosis and immune landscape remodeling.
Answers are grounded in this paper and cite their sources.
Ly6G targeting increases murine post-MI fibrosis; leaves open whether SiglecF+ neutrophil modulation could limit adverse remodeling in patients.
Following myocardial infarction (MI), the heart undergoes massive neutrophil infiltration characterized by the emergence of distinct subsets, notably a SiglecF + population that accumulates according to specific temporal dynamics. The mechanisms governing cardiac neutrophil heterogeneity and the subsequent functional impact of this diversity on tissue repair following myocardial infarction remain to be elucidated. Using single-cell RNA-sequencing of neutrophils in the heart and peripheral organs of infarcted mice, we here show that while acquisition of the SiglecF + state only fully occurs in the ischemic heart tissue, MI primes neutrophils in the periphery to acquire Siglecf and to upregulate receptors for TGFβ and GM-CSF that drive acquisition of the SiglecF + state. Ly6G targeting in vivo shifted cardiac neutrophils towards the SiglecF + state at day 3 post-MI, induced the emergence of reprogrammed SiglecF + Ly6G lo and Retnlg hi neutrophil states at day 5, and was associated with increased fibrosis of the infarct border zone. Mechanistically, Ly6G targeting reshaped the cardiac immune landscape with increased recruitment of pro-fibrotic γδ T cells and monocytes, and SiglecF + neutrophils exerted direct pro-fibrotic effects on fibroblasts in a co-culture system. Altogether, our results indicate that peripheral neutrophil priming combined with their terminal programming towards a SiglecF + state in the ischemic heart drives cardiac fibrosis after MI.
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Piollet et al. (2026) studied Myocardial infarction (preclinical mouse model). Anti-Ly6G antibody targeting vs. 25 µg rat IgG2aκ isotype control + 50 µg mouse anti-rat IgG2aκ was evaluated on Cardiac neutrophil reprogramming toward a SiglecF+ state and infarct border zone fibrosis. Anti-Ly6G targeting in infarcted mice shifted cardiac neutrophils toward a SiglecF+ state and increased infarct border zone fibrosis via direct fibroblast activation and pro-fibrotic immune cell recruitment.
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