Abstract
Overactivated inflammatory responses contribute to adverse ventricular remodeling after myocardial infarction (MI). Regulatory B cells (Bregs) are a newly discovered subset of B cells with immunomodulatory roles in many immune and inflammation-related diseases. Our study aims to determine whether the expansion of Bregs exerts a beneficial effect on ventricular remodeling and explore the mechanisms involved. Here, we showed that adoptive transfer of Bregs ameliorated ventricular remodeling in a murine MI model, as demonstrated by improved cardiac function, decreased scar size and attenuated interstitial fibrosis without changing the survival rate. Reduced Ly6Chi monocyte infiltration was found in the hearts of the Breg-transferred mice, while the infiltration of Ly6Clo monocytes was not affected. In addition, the replenishment of Bregs had no effect on the myocardial accumulation of T cells or neutrophils. Mechanistically, Bregs reduced the expression of C–C motif chemokine receptor 2 (CCR2) in monocytes, which inhibited proinflammatory monocyte recruitment to the heart from the peripheral blood and mobilization from the bone marrow. Breg-mediated protection against MI was abrogated by treatment with an interleukin 10 (IL-10) antibody. Finally, IL-10 neutralization reversed the effect of Bregs on monocyte migration and CCR2 expression. The present study suggests a therapeutic value of Bregs in limiting ventricular remodeling after MI through decreasing CCR2-mediated monocyte recruitment and mobilization.
Highlights
Advances in the therapy of myocardial infarction (MI) by successful restoration of the occluded coronary artery profoundly decrease the mortality rate
Monocyte compartmentalization was differentially altered in Breg-treated mice on day 3 after MI, as revealed by enhanced retention in the bone marrow, but the numbers of monocytes in the blood and spleen were not changed (Fig. 5g–i). These results suggest that Bregs affect different processes of monocyte migration: Bregs inhibit monocyte recruitment to the heart from the peripheral blood with no influence on mobilization from the spleen or bone marrow on day 1, whereas monocyte mobilization from the bone marrow to the blood was impaired on day 3
We first demonstrated a beneficial effect of exogenous Bregs on MI mice, as confirmed by improved cardiac function, decreased scar size and attenuated interstitial fibrosis
Summary
Advances in the therapy of myocardial infarction (MI) by successful restoration of the occluded coronary artery profoundly decrease the mortality rate. Ischemic heart disease, which is the main cause of heart failure, is becoming a major public health concern all over the world [41]. Intensive efforts have been targeted at left ventricular pathological remodeling. Ventricular remodelling relates to the changes of cardiac function and structure in response to multifactorial stimuli, involving myocytes, interstitial cells and interstitial matrix [17]. Both clinical and experimental studies suggest that inflammatory responses participate in ventricular remodeling post-MI, attempting to clear up matrix debris and dead cells. Overactive inflammatory signaling exacerbates myocardial injury and causes adverse cardiac remodeling. Timely restraint of the excessive and pathological inflammatory responses is essential in promoting tissue repair and preserving cardiac function [11, 18]
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