Intercellular model predicts mechanisms of inflammation-fibrosis coupling after myocardial infarction

After myocardial infarction (MI), cardiac cells work together to regulate wound healing of the infarct. The pathological response to MI yields cardiac remodelling comprising inflammatory and fibrosis phases, and the interplay of cellular dynamics that underlies these phases has not been elucidated. This study developed a computational model to identify cylokine and cellular dynamics post-MI to predict mechanisms driving post-MI inflammation, resolution of inflammation, and scar formation. Additionally, this study evaluated the interdependence between inflammation and fibrosis. Our model bypassed limitations of in vivo approaches in achieving cellular specificity and performing specific perturbations such as global knockouts of chemical factors. The model predicted that inflammation is a graded response to initial infarct size that is amplified by a positive feedback loop between neutrophils and interleukin 1 beta (IL-1 beta). Resolution of inflammation was driven by degradation of IL-1 beta, matrix metalloproteinase 9, and transforming growth factor beta (TGF-1 beta), as well as apoptusis of neutrophils. Inflammation regulated TGF beta secretion directly through immune cell recruitment and indirectly through upregulation of macrophage phagocytosis. Lastly, we found that mature collagen deposition was an ultrasensitive switch in response to inflammation, which was amplified primarily by cardiac fibroblast proliferation. These findings describe the relationship between inflammation and fibrosis and highlight how the two responses work together post-MI. This model revealed that post-MI inflammation and fibrosis are dynamically coupled, which provides rationale for designing novel anti-inflammatory, pro-resolving or anti-fibrotic therapies that may improve the response to MI.

Automated summary

After myocardial infarction, the inflammatory response and fibrosis are dynamically coupled. Inflammation is a graded response to initial infarct size, amplified by a positive feedback loop between neutrophils and interleukin 1 beta (IL-1 beta). The resolution of inflammation is driven by degradation of IL-1 beta, matrix metalloproteinase 9, and transforming growth factor beta (TGF-1 beta), as well as neutrophil apoptosis. Inflammation regulates TGF beta secretion directly through immune cell recruitment and indirectly through upregulation of macrophage phagocytosis. Mature collagen deposition acts as an ultrasensitive switch in response to inflammation, mainly amplified by cardiac fibroblast proliferation.