Margarete Heinrichs1,2, DiyaaElDin Ashour1,2, Johanna Siegel1,2, Lotte Büchner1,2, Georg Wedekind1, Katrin G Heinze3, Panagiota Arampatzi4, Antoine-Emmanuel Saliba5, Clement Cochain2,6, Ulrich Hofmann1,2, Stefan Frantz1,2, Gustavo Campos Ramos1,2. 1. Department of Internal Medicine I, University Hospital Würzburg, Am Schwarzenberg 15, 97078 Würzburg, Germany. 2. Comprehensive Heart Failure Centre, University Hospital Würzburg, Am Schwarzenberg 15, 97078, Würzburg, Germany. 3. Rudolf Virchow Centre for Integrative and Translational Bioimaging, University of Würzburg, Am Schwarzenberg 15, 97078, Würzburg, Germany. 4. Core Unit Systems Medicine, University of Würzburg, Am Schwarzenberg 15, 97078, Würzburg, Germany. 5. Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Centre for Infection Research (HZI), Am Schwarzenberg 15, 97078, Würzburg, Germany. 6. Institute of Experimental Biomedicine, University Hospital Würzburg, Am Schwarzenberg 15, 97078, Würzburg, Germany.
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 mobilization 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 with wild-type controls, mice treated with a neutralizing 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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 mobilization 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 with wild-type controls, mice treated with a neutralizing 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Gabriele G Schiattarella; Pilar Alcaide; Gianluigi Condorelli; Thomas G Gillette; Stephane Heymans; Elizabeth A V Jones; Marinos Kallikourdis; Andrew Lichtman; Federica Marelli-Berg; Sanjiv Shah; Edward B Thorp; Joseph A Hill Journal: Nat Cardiovasc Res Date: 2022-03-14