Abstract Body: Background: Myocardial infarction (MI) induces systemic inflammation characterized by emergency granulopoiesis and rapid mobilization of neutrophils. While early neutrophil responses contribute to tissue repair, sustained myelopoiesis can promote maladaptive cardiac remodeling and heart failure. Although circulating neutrophil counts strongly predict post-MI mortality, the mechanisms that terminate neutrophil-driven inflammation remain poorly understood. We hypothesized that persistent inflammasome priming reprograms neutrophils from IL-1β–driven pro-inflammatory cells into IL-10–producing regulatory cells that suppress excessive granulopoiesis during the resolution phase of MI.

Methods: MI was induced in C57BL/6 mice by permanent ligation of the left anterior descending coronary artery. Hematopoietic progenitor expansion, neutrophil phenotypes, and leukocyte dynamics were analyzed by flow cytometry and EdU incorporation assays. Cytokine levels in bone marrow (BM) extracellular fluid were measured following MI. Single-cell RNA sequencing was used to define transcriptional programs in BM neutrophil subsets. Mechanistic studies were performed in TLR4-stimulated neutrophils to examine temporal regulation of IL-1β and IL-10 production.

Results: MI induced rapid expansion of granulocyte–macrophage progenitors and marked neutrophil accumulation in the heart within 24 hours, consistent with emergency granulopoiesis. Single-cell RNA sequencing revealed transcriptional reprogramming of BM neutrophil subsets with enrichment of IL-10 signaling pathways. TLR4 activation triggered early IL-1β release, whereas sustained stimulation promoted an IL-10–dominant response. In vivo BM analyses showed a similar temporal pattern, with early IL-1β elevation followed by delayed IL-10 production. IL-10 signaling limited IL-1β–driven granulopoiesis through induction of anti-inflammatory mediators including SOCS3 and IL-1 receptor antagonist.

Conclusions: These findings identify an intrinsic neutrophil regulatory program in which persistent inflammasome priming induces an IL-10–dependent phenotypic switch that restrains IL-1β–driven granulopoiesis after MI. Targeting the IL-10–STAT3 axis may represent a therapeutic strategy to reduce harmful inflammation while preserving host defense during cardiac repair.