Cardiac fibroblast participates as an immune modulator in IL-17A-driven post-injury cardiac inflammation and remodeling

Heart diseases are the leading causes of mortality and morbidity worldwide. The post-injury cardiac inflammation and remodeling process determined the severity of cardiac damage and the likelihood of developing heart failure. We have adapted both experimental autoimmune myocarditis (EAM) and myocardial infarction (MI) mouse model to investigate the mechanism behind cardiac inflammation and remodeling. We showed that Interleukin 17 (IL-17A) signaling is required for adverse cardiac remodeling and fibrosis in both EAM and MI models. IL-17A induces cardiac fibroblast (CF) to produce granulocyte-macrophage colony stimulating factor (GM-CSF). GM-CSF in turn drives the development of adverse cardiac remodeling and fibrosis. Despite the heterogeneity of CF population, we successfully identified a specific subset of cardiac fibroblast to be the main recipient of IL-17A signal to produce GM-CSF, CCL2 and other cytokines/chemokines. The same CF subset was detected in heart failure patient biopsies from various etiologies including myocarditis, ischemia patients, etc. Further investigation also revealed that this subset is plastic in cytokine production. Lastly, both complete knockout of IL-17A receptor (R) and specific ablation of IL-17RA in this subset significantly reduced ventricular dilation and infarct scar size. Our findings provide an excellent opportunity to develop specific treatment for post-injury cardiac remodeling and fibrosis through specific targeting the IL-17A signaling to this CF subset or the downstream cytokine production by these cells.