[R01] B cell-mediated antigen presentation drives sex-specific differences in the activation of the cardio-splenic axis of chronic heart failure

Ente: National Heart Lung and Blood Institute

Scadenza: 2031-06-30

Importo max: 763.036 EUR

Paese: US

Descrizione

Project Summary/Abstract Murine and human data indicate that cardiac damage initiates immunological changes in the spleen, which can subsequently trigger maladaptive changes in the heart. This phenomenon, which occurs along the “cardio- splenic axis” (CSA), shows promise for developing immunomodulatory-based treatments for heart failure. However, studies in this field have focused on male subjects, probably because the females did not provide a sufficiently strong signal. This has left the question of whether the CSA exhibits sex-specific features unanswered. Additionally, targeted therapies to modulate signaling along the CSA are lacking. We have recently shown that cardiac damage triggers the activation of “antigen processing and presentation” in splenic B cells, which recirculate between the spleen and the heart. We found that the transfer of splenic B cells from mice who had experienced heart damage to healthy animals was sufficient to produce cardiac dysfunction. Using genetic models, we have shown that this process depends on the B cell’s antigen- presenting function. We have gathered new preliminary data showing that splenic activation and B cell activation after a myocardial injury in mice and humans have strong sex-specific features. We have produced data suggesting that B cell- mediated, antigen presentation-dependent changes in cardiac function after acute cardiac damage might be restricted to males. Here, we request support to expand on these initial observations and test the hypothesis that the communication between the spleen and the heart in response to myocardial injury has sex-specific features driven by sex-related differences in B cell-mediated antigen presentation. To test this hypothesis, we propose combining analysis in rodent models and analysis of patients who experienced a myocardial infarction. Since the ultimate goal of our research is to develop novel therapeutic interventions, in our human studies, we will pay specific attention to the relationship between splenic/B cell activation and changes in adverse cardiac remodeling during the first year after myocardial infarction. The work proposed here will generate novel mechanistic insights into immune activation after myocardial infarction. It will be instrumental in developing targeted immunomodulatory treatments for heart failure that consider sex as a biological variable. Istituzione: JOHNS HOPKINS UNIVERSITY PI: Luigi Adamo Progetto: 1R01HL178615-01A1

Settori: National Heart Lung and Blood Institute

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