Atrial fibrillation (AF) is associated with atrial dilatation, fibrotic remodelling and inflammation. It is well-established that stretch can trigger structural (and functional) remodelling, and that tissue fibrosis contributes to changes in cardiac tissue mechanics which is sensed and responded to by the various cardiac cell types. Atrial inflammation in response to dilatation is often regarded as an additional cause for the development of fibrosis in AF. How mechanical stimulation of fibroblasts affects inflammatory cells, and whether that may alter tissue mechanics is under-investigated.
The cation non-selective, stretch-activated channel Piezo1 is expressed at higher levels in atrial fibroblasts isolated from patients with AF, compared to patients in sinus rhythm.1 It is a functionally relevant mechanosensor in these cells and contributes to the control of interleukin (IL) 6 secretion. Using RNA sequencing, we showed that reducing the expression level of Piezo1 (siRNA-mediated) decreases the expression of pro-inflammatory cytokines, including CC-chemokine ligand 2 (CCL2) and IL-8. As soluble signalling molecules, these may contribute indirectly to mechanically-induced modulation of inflammatory processes, such as immune cell recruitment from the circulation.
To assess the capacity of human atrial fibroblasts to affect immunologically relevant processes in a paracrine Piezo1-dependent manner, we performed a series of in vitro co-culture experiments. Using transient knock-down or overexpression of Piezo1 in human atrial fibroblasts, we found that the expression level of Piezo1 correlates with the ability of fibroblasts to attract THP-1 monocytes in transwell migration assays. Higher Piezo1 expression led to 34% higher THP-1 migration toward fibroblasts, while Piezo1 down-regulation led to 33% lower THP-1 migration (N=3, p<0.0001 and p=0.0018 respectively, migration assessed by microscopy). Similar observations were made for primary human neutrophils (50% higher [N=1, p=0.010] and 47% lower [N=1, p=0.045] migration towards fibroblasts after Piezo1 up- and down-regulation, respectively). The migration of THP-1 monocytes was promoted by CCL2, while that of neutrophils – by IL-8.
Taken together, these data indicate that Piezo1 expression in human atrial fibroblasts may affect immune cell recruitment from the circulation by collectively acting on, monocytes and neutrophils via paracrine signalling. As Piezo1 is upregulated in AF, this might be a novel mechanism, potentially linking mechanical alterations in atrial tissue to enhanced atrial inflammation, and thereby contributing to disease progression.
1 Jakob D and Klesen A et al., Journal of Molecular and Cellular Cardiology 2021/158: 49-62.
