Targeting immune-fibroblast cell communication in heart failure

Area of Science:

• Cardiovascular Biology
• Immunology
• Fibrosis Research

Background:

• Inflammation and tissue fibrosis are linked to organ dysfunction, particularly in cardiac disease.
• Molecular mechanisms of immune-fibroblast communication in human cardiac disease are poorly understood.
• Current treatments do not directly target cardiac fibrosis.

Purpose of the Study:

• To explore molecular mechanisms of immune-fibroblast communication in human cardiac disease.
• To identify therapeutic targets for cardiac fibrosis.

Main Methods:

• Multiomic single-cell gene expression, epitope mapping, and chromatin accessibility profiling in human hearts.
• Genetic lineage tracing in vivo.
• Assessment of mouse models for cardiac fibroblast modeling.
• Ligand-receptor analysis and spatial transcriptomics.
• In vivo manipulation of IL-1β signaling pathways.

Main Results:

• Identified a disease-associated fibroblast trajectory with distinct myofibroblast and FAP/POSTN+ matrifibrocyte populations.
• FAP+ fibroblasts contribute to the POSTN lineage.
• In vivo mouse models better recapitulate human cardiac fibrosis than cultured cells.
• IL-1β signaling between CCR2+ macrophages and fibroblasts drives FAP/POSTN+ fibroblast emergence.
• Inhibition of IL-1β signaling reduced FAP/POSTN+ fibroblasts, myocardial fibrosis, and improved cardiac function.

Conclusions:

• Interleukin-1β (IL-1β) signaling is a key mediator of immune-fibroblast communication driving cardiac fibrosis.
• Targeting IL-1β signaling in macrophages and fibroblasts offers a therapeutic strategy for cardiac fibrosis.
• Reducing inflammation can preserve organ function by mitigating tissue fibrosis.