The healing myocardium mobilizes a distinct B-cell subset through a CXCL13-CXCR5-dependent mechanism

Recent studies have revealed that B-cells can influence post-myocardial infarction (MI) inflammation and repair, but the mechanisms controlling their mobilization and in situ activity remain poorly understood. Herein, we sought to dissect the mechanisms underlying B-cell cardiotropism and assess the B-cell antigen specificity profile in an experimental model of MI. Our study reveals that B-cells that are not antigen-specifically expanded readily infiltrate the infarcted myocardium via the CXCL13-CXCR5 axis. The restricted distribution of CXCR5 among hB cells could offer a suitable opportunity to selectively target this leukocyte subset therapeutically while minimally interfering with other local or systemic immunological processes. Histological, flow cytometry and single-cell RNA-sequencing (scRNAseq) analyses revealed the rapid accumulation of diverse B-cell subsets in the murine infarcted myocardium, including a distinct B-cell cluster exclusively found in the heart  (hB). The hB-cells exhibited upregulated expression of activation markers (e.g., Cd69) and expressed high levels of C-C-chemokine receptor type 7 (CCR7) and CXC-chemokine receptor type 5 (CXCR5). This distinct chemokine receptor signature was not shared with any other cell population in the healing myocardium. Moreover, we detected a myocardial gradient of CXC-motif chemokine ligand 13 (CXCL13, the ligand of CXCR5) in the early post-MI inflammatory (d1) and healing (d5) phases. Notably, mice treated with a neutralizing CXCL13-specific antibody showed reduced infiltration of myocardial B-cells after MI compared to control animals. Finally, global B-cell receptor (BCR) repertoire analyses revealed that the vast majority of B-cells infiltrating the infarcted myocardium were not clonally expanded and showed no sign of antigen specificity. In addition to the in situ B-cell responses, slight clonal expansion of a few germinal centre B-cells (GCs) was detected in the mediastinal lymph nodes (med-LNs).