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

Abstract

Aims Recent studies have revealed that B-cells and antibodies can influence inflammation and remodelling following a myocardial infarction (MI) and culminating in heart failure—but the mechanisms underlying these observations remain elusive. We therefore conducted in mice a deep phenotyping of the post-MI B-cell responses in infarcted hearts and mediastinal lymph nodes, which drain the myocardium. Thereby, we sought to dissect the mechanisms controlling B-cell mobilisation and activity in situ. Methods and Results Histological, flow cytometry and single-cell RNA-sequencing (scRNA-seq) analyses revealed a rapid accumulation of diverse B-cell subsets in infarcted murine hearts, paralleled by mild clonal expansion of germinal centre B-cells in the mediastinal lymph nodes. The repertoire of cardiac B-cells was largely polyclonal and showed no sign of antigen-driven clonal expansion. Instead, it included a distinct subset exclusively found in the heart, herein termed “heart-associated B-cells” (hB) that expressed high levels of Cd69 as an activation marker, C-C-chemokine receptor type 7 (Ccr7), CXC-chemokine receptor type 5 (Cxcr5) and transforming growth factor beta 1 (Tgfb1). This distinct 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) on days 1 and 5 post-MI. When compared to wild type controls, mice treated with a neutralising CXCL13-specific antibody as well as CXCR5-deficient mice showed reduced post-MI infiltration of B-cells and reduced local Tgfb1 expression but no differences in contractile function nor myocardial morphology were observed between groups. Conclusions Our study reveals that polyclonal B-cells showing no sign of antigen-specificity readily infiltrate the heart after MI via the CXCL13-CXCR5 axis and contribute to local TGF-ß1 production. The local B-cell responses are paralleled by mild antigen-driven germinal centre reactions in the mediastinal lymph nodes that might ultimately lead to the production of specific antibodies.

Leukocyte-Mediated Cardiac Repair after Myocardial Infarction in Non-Regenerative vs. Regenerative Systems

“…In contrast to the above-mentioned studies demonstrating a detrimental or beneficial role of B cells after cardiac injury, a recent study, which identified a novel population of heart-associated B (hB) cells, showed that depletion of hB cells through CXCR5 deficiency or with CXCL13 antibodies had no effect on heart function after injury [237]. Most likely, the differences observed in beneficial and detrimental effects on cardiac repair are due to the examination of different B-cell subtypes.…”

Cellular Heterogeneity of the Heart

“…However, interferon gamma ( IFNG ), tumor necrosis factor ( TNF ), IL3 and IL17 genes, related to classically polarized Th cells were not differentially expressed after MI in mice ( 87 ). In the same model, B cells presented with upregulation of activation markers such as CD69 , CCR7 , CXC-chemokine receptor type 5 ( CXCR5 ), and transforming growth factor beta 1 ( TGFB1 ) ( 88 ).…”

Progress of Single-Cell RNA Sequencing Technology in Myocardial Infarction Research

“…Another study showed that lymphocytes readily infiltrate the heart after MI, and single-cell sequencing revealed that lympho B cells promote TGF-1β production in locally damaged hearts ( 25 ). Xia et al monitored the dynamic recruitment of regulatory T cells (Tregs) in the damaged heart of a mouse MI model ( 49 ).…”