Inflammation presides early after
myocardial infarction (MI) as a key event in cardiac wound healing. Ischemic cardiomyocytes secrete inflammatory cues to stimulate infiltration of leukocytes, predominantly macrophages and neutrophils. Infiltrating neutrophils degranulate to release a series of
proteases including
matrix metalloproteinase (MMP)-9 to break down extracellular matrix and remove necrotic myocytes to create space for the
infarct scar to form. While neutrophil to macrophage communication has been explored, the reverse has been understudied. We used a proteomics approach to catalogue the macrophage secretome at MI day 1. Murinoglobulin-1 (MUG1) was the highest-ranked secreted
protein (4.1-fold upregulated at MI day 1 vs. day 0 pre-MI cardiac macrophages, p = 0.004). By transcriptomics evaluation,
galectin-3 (
Lgals3) was 2.2-fold upregulated (p = 0.008) in MI day 1 macrophages. We explored the direct roles of MUG1 and
Lgals3 on neutrophil degranulation. MUG1 blunted while
Lgals3 amplified neutrophil degranulation in response to
phorbol 12-myristate 13-acetate or interleukin-1β, as measured by MMP-9 secretion.
Lgals3 itself also stimulated MMP-9 secretion. To determine if MUG1 regulated
Lgals3, we co-stimulated neutrophils with MUG1 and
Lgals3. MUG1 limited degranulation stimulated by
Lgals3 by 64% (p < 0.001). In vivo, MUG1 was elevated in the
infarct region at MI days 1 and 3, while
Lgals3 increased at MI day 7. The ratio of MUG1 to
Lgals3 positively correlated with
infarct wall thickness, revealing that MUG1 attenuated
infarct wall thinning. In conclusion, macrophages at MI day 1 secrete MUG1 to limit and
Lgals3 to accentuate neutrophil degranulation to regulate
infarct wall thinning.