A cardiomyocyte-intrinsic RXRγ–SOCS3 axis governs macrophage-driven inflammation in viral myocarditis
Z Zhou, W He, D WangAbstract
Background/Introduction
Myocarditis is a challenging inflammatory disease of the heart, and better understanding of its aetiology is needed to develop specific drug therapies. At present, the pathogenesis of myocarditis remains incompletely defined, and disease-specific interventions are lacking. Based on prior single-cell transcriptomic profiling of myocarditis hearts, we observed profound remodelling of transcriptional regulators in inflammation-affected cardiomyocytes. Notably, retinoid X receptor gamma (RXRγ), a member of the nuclear receptor superfamily, is highly and specifically expressed in homeostatic cardiomyocytes but is rapidly suppressed in response to viral infection and inflammatory stress.
Purpose
We hypothesized that RXRγ functions as a transcriptional activator to sustain the expression of its downstream target, suppressor of cytokine signalling 3 (SOCS3), thereby restraining excessive amplification of inflammatory signalling cascades.
Methods
To dissect the functional role of RXRγ, we generated cardiomyocyte-specific RXRγ overexpression and knockout mouse models. Viral myocarditis was induced using coxsackievirus B3 (CVB3). We further integrated single-cell multi-omics profiling (scRNA-seq combined with scATAC-seq) of murine hearts to delineate the mechanistic basis of RXRγ-mediated cardiomyocyte–macrophage crosstalk during inflammatory signalling.
Results
RXRγ was selectively enriched in cardiomyocytes under physiological conditions but rapidly downregulated upon viral and inflammatory challenge. Following CVB3 infection, cardiomyocyte-specific RXRγ knockout mice exhibited precipitous cardiac dysfunction, exacerbated myocardial inflammatory infiltration, and markedly elevated circulating inflammatory cytokines. In contrast, cardiomyocyte-specific overexpression of RXRγ significantly attenuated both cardiac and systemic inflammatory responses. Mechanistically, integrative single-cell multi-omics analyses (RNA-seq + ATAC-seq), together with genome-wide RXRγ occupancy profiling, revealed that RXRγ directly promotes transcription of intracellular SOCS3. SOCS3, in turn, suppressed macrophage JAK2–STAT3 signalling, thereby limiting CVB3-induced cardiac cytokine storm and inflammatory amplification. These findings establish a cardiomyocyte-intrinsic nuclear receptor program that non-cell autonomously constrains macrophage-driven inflammation.
Conclusion(s)
The RXRγ–SOCS3 axis represents a pivotal regulatory node in cardiomyocyte–macrophage inflammatory communication and constitutes a central checkpoint in the orchestration of cardiac cytokine storm. Targeting this pathway offers novel mechanistic insight into myocarditis pathogenesis and provides a promising conceptual framework for precision therapeutic intervention.