Targeting macrophage-derived oncostatin M preserves cardiomyocyte mitochondrial bioenergetics and contractile function in fulminant myocarditis.

Background

Fulminant myocarditis (FM) is an acute inflammatory cardiomyopathy with high risk of cardiogenic shock. Current management relies largely on circulatory support, while mechanism-based pharmacological targets remain poorly defined.

Methods

Cardiac CD45+ single-cell RNA sequencing, whole-heart single-nucleus RNA sequencing, ligand-target inference, spatial validation, and human plasma/myocardial analyses were integrated to define disease-associated cellular interactions. CCR2+ macrophage sorting, macrophage depletion, CVB3-stimulated BMDMs, transcription-factor perturbation, ChIP-qPCR, and promoter assays defined the source and regulation of OSM. OSM signaling was examined using recombinant OSM, OSM-neutralizing antibody, macrophage Osm knockdown, cardiomyocyte Osmr silencing, and STAT3/ERK1/2 inhibition, followed by transcriptomic, mitochondrial, contractile, and in vivo analyses.

Results

FM featured expansion of CCR2+ inflammatory macrophages, cardiomyocyte inflammatory/stress remodeling, and enhanced macrophage-to-cardiomyocyte OSM-OSMR signaling. Circulating OSM was increased in patients with FM and correlated with higher NT-proBNP and cTnI and lower LVEF. OSM was produced predominantly by CCR2+ macrophages and transcriptionally induced by IRF1 after CVB3 stimulation. Recombinant OSM aggravated mortality, systolic dysfunction, myocardial inflammation, and cardiac injury. In cardiomyocytes, OSM activated OSMR-dependent STAT3/ERK1/2 signaling and impaired mitochondrial bioenergetics, contractility, and Ca²+ handling. OSM neutralization and macrophage Osm knockdown improved cardiomyocyte respiration and sarcomere shortening after exposure to CVB3-activated macrophage conditioned medium. In vivo, OSM neutralization improved survival, cardiac function, myocardial inflammation, mitochondrial integrity, and ATP content.

Conclusion

Macrophage OSM links inflammatory myeloid activation to cardiomyocyte mitochondrial and contractile failure in experimental FM. OSM-OSMR signaling is a candidate mechanism-based pharmacological target for acute inflammatory cardiac dysfunction.