Splenic Marginal Zone B Lymphocytes Regulate Cardiac Remodeling After Acute Myocardial Infarction in Mice
Abstract
Background. Mature B lymphocytes alter the recovery of cardiac function after acute myocardial infarction (MI) in mice. Follicular B cells and marginal zone B (MZB) cells are spatially distinct mature B cell populations in the spleen and exert specific functional properties. miR21/Hypoxia-inducible factor (HIF)α-related pathways have been shown to govern B cell functions. Objectives. We aimed to unravel the distinct role of MZB cells and that of endogenous activation of miR21/ HIFα signalling in MZB cells during post-ischemic injury. Methods. Acute MI was induced by permanent ligation of the left anterior descending coronary artery in mice. Cardiac function and remodeling were assessed using echocardiography and immunohistochemistry. To determine the specific role of MZB cells, we used mice with B cell lineage-specific conditional deletion of Notch signaling, which leads to selection deficiency of MZB cells. To evaluate the role of HIF-1α isoform, we generated mice with MZB cell lineage specific conditional deletion of Hif1a. Results. Acute MI prompted miR21-dependent increase of HIF-1α, particularly in splenic MZB cells. MZB cell deficiency and MZB cell-specific deletion of miR21 or Hif1a improved cardiac function after acute MI. miR21/HIF-1α signaling in MZB cells was required for Tolllike receptor dependent expression of the monocyte chemo-attractant protein CCL7, leading to increased mobilization of inflammatory monocytes to the ischemic myocardium and to adverse post-ischemic cardiac remodeling. Conclusions. This work reveals a novel function for miR21/HIF-1α pathway in splenic MZB cells with potential major implications for the modulation of cardiac function after acute MI.
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