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IL-1 Signaling Blockade in Human Lymphocytic Myocarditis

ABSTRACT: Lymphocytic myocarditis is characterized by infiltration of lymphocytes and macrophages. Current treatment for lymphocytic myocarditis is limited to corticosteroids and a proportion of patients progress to require heart transplantation or durable mechanical circulatory support within a year. Increasing attention is directed toward targeting pro-inflammatory mediators in myocarditis. One promising candidate is IL-1. Here, we investigated a patient with underlying autoimmune disease and biopsy confirmed lymphocytic myocarditis who was initially treated with corticosteroids and experienced clinical deterioration requiring temporary mechanical circulatory support. Rilonacept was consequently administered as a salvage therapy. Pathologically, rilonacept reduced inflammation and fibrosis. We performed spatial transcriptomics (ST) on formalin-fixed paraffin-embedded endomyocardial biopsy samples to further investigate how the cardiac immune landscape is modulated by rilonacept.

ORGANISM(S): Homo sapiens

PROVIDER: GSE296452 | GEO | 2025/07/09

REPOSITORIES: GEO

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Project description:Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1/PD-L1 or CTLA4 have revolutionized cancer management but are associated with devastating immune-related adverse events (irAEs) including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI-myocarditis is often fulminant and is pathophysiologically characterized by myocardial infiltration of T lymphocytes and macrophages. While much has been learned regarding the role of T-cells in ICI-myocarditis, little is understood regarding the identity, transcriptional diversity, and functions of infiltrating macrophages. We employed an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, and molecular imaging. We observed marked increases in CCR2+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation expressing Cxcl9, Cxcl10, Gbp2b, and Fcgr4 that originated from CCR2+ monocytes. Importantly, a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) were found selectively in patients with ICI myocarditis compared to other forms of heart failure and myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-γ and CXCR3 signaling pathways. Depleting CD8+T-cells and blockade of IFN-γ signaling blunted the emergence of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis suggesting that this interaction was necessary for disease pathogenesis. Collectively, these data demonstrate that ICI-myocarditis is associated with the emergence of a specific population of inflammatory macrophages and suggest the possibility that IFN-γ blockade may serve as an effective treatment for this devastating condition.

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IL-1 Signaling Blockade in Human Lymphocytic Myocarditis

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