Human pericardial macrophages suppress cardiac fibrosis through cystatin C signaling after myocardial infarction

The pericardium plays an important homeostatic function for the neighbouring heart providing both lubricating and structural support. In vivo models have further identified a protective role for the pericardium in modulating cardiac remodelling following myocardial infarction possibly through the actions of tissue-resident pericardial macrophages. Using patient derived pericardial samples, we establish that human pericardial immune cells directly inhibit cardiac fibroblast fibrotic activity and this action is dampened following myocardial infarction. Performing single-cell RNA sequencing of patient pericardial fluid cells, we identify two pericardial macrophage subsets that are uniquely altered in response to myocardial infarction, which contributes to a shift in their effector molecule expression profiles. We confirm that fibronectin-expressing human pericardial macrophages are the primary driver of the pericardial anti-fibrotic actions through the release of cystatin C. Finally, we establish cystatin C as a macrophage-derived cardioprotective effector molecule in an in vivo model of myocardial infarction. Collectively, we uncover a new molecular mechanism of the local immune environment that regulates cardiac remodelling post myocardial infarction.