iNKT cell activation exacerbates isoproterenol-induced cardiac injury through macrophage IFN-γ-STAT1 signaling.

AIMS: With the extensive application of immunotherapy in treating cancer, the immunotherapy-related cardiovascular toxicity (ITR-CVT) has gotten a rapid recognition due to its high mortality. Previously, we have found that potential cancer immunotherapies based on promoting iNKT cell activation exacerbate ISO-induced cardiac injury, but the underlying mechanism is unknown. The current study is to determine which specific cell type/s and the corresponding molecular pathways are responsible for such a cardiotoxicity.

MATERIALS AND

METHODS

Transcriptome sequencing and bioinformatic analysis were performed on heart tissues from an enhanced cardiac injury model following iNKT cell activation via α-Galactosylceramide (αGC). The role of IFN-γ-STAT1 signaling was validated using IFN-γ antibody blocking and JAK-STAT1 chemical inhibition. The experiments of Macrophage isolation and depletion were conducted to assess cell-specific contributions. In vitro co-culture experiments with αGC-primed macrophages and fibroblasts were conducted under STAT1 inhibition or silencing. Tumor-bearing mice were also examined.

KEY FINDINGS: Transcriptome analysis identified IFN-γ-STAT1 signaling as central to the enhanced cardiac injury, blocking IFN-γ or inhibiting STAT1 could attenuate the injury. Macrophages were identified as the main source of IFN-γ-STAT1 activation, and their depletion significantly reversed cardiac injury exacerbation. In vitro, STAT1 inhibition or silencing reduced fibroblast activation induced by αGC-primed macrophages. In tumor-bearing mice, αGC also further exacerbated cardiac injury.

SIGNIFICANCE: These findings revealed that the activation of STAT1 in cardiac macrophages via IFNγ critically contributes to cardiotoxicity induced by iNKT-immunotherapy, which provides a potential method to manage ITR-CVT in patients.