Short communicationB cells modulate the expression of MHC-II on cardiac CCR2− macrophages
Introduction
Current models of B cell biology posit that naïve B cells merely recirculate between primary and secondary lymphoid stations until meeting their cognate antigen [1,2]. However, recent studies have highlighted that: 1) the naïve myocardium contains a sizeable population of naïve circulating B cells that pause on the myocardial microvascular endothelium; 2) B cell–deficient and B cell–depleted mice have alterations in myocardial mass, myocardial contractility and number of myocardial T cells [3,4]. These studies pointed to an unexpected biological relationship between B cells and the heart but did not investigate whether B cells exhibit any local effects in the myocardium [3]. The demonstration of a local B cell effect within the myocardium would broaden our understanding of the relationship between circulating immune cells and the myocardium and challenge current paradigms of B cell biology.
The murine myocardium contains four distinct subsets of CD64+ macrophages defined by different expression levels of CC chemokine receptor 2 (CCR2) and major histocompatibility complex class II (MHC-II) [5]. The vast majority of macrophages in the naïve heart are CCR2− resident macrophages (MHC-IIhigh or MHC-IIlow) of embryonic origin. CCR2+ cells are bone marrow–derived monocytic cells that acquire higher levels of MHC-II expression as they fully differentiate into tissue macrophages [[5], [6], [7]]. These macrophage subsets have several important roles in the context of myocardial physiology and pathology [6,[8], [9], [10], [11]]. Recently, a population of intra parenchymal myocardial macrophages has been identified in close association with the vasculature [8]. The factors that modulate the myocardial macrophage pool composition in the naïve heart have not been completely understood.
Here, we used histology, flow cytometric analysis of myocardial macrophages from B cell–deficient mice and B cell–depleted mice, and primary cardiac macrophage cultures to investigate the hypothesis that B cells modulate the phenotype of myocardial macrophages through a paracrine effect.
Section snippets
Mice
To investigate the effects of B cell deficiency, we used 4–5 week-old male and female wild-type (WT) (background C57BL/6 J; Stock No. 000664) and μMT mice (B cell deficient) (background C57BL/6 J; B6.129S2-Ighmtm1Cgn/J; Stock No. 002288) age and sex matched. These strains were purchased from The Jackson Laboratory and bred in house. The CD19 reporter model was generated as previously reported [3]. Mice were bred and maintained at the Washington University School of Medicine Animal Care Facility
Results and discussion
We began investigating the relationship between B cells and myocardial macrophages by immunostaining cryosections of naïve murine hearts and analyzing the relative positions of B cells and CD68+ macrophages. We found that myocardial-associated B cells were almost exclusively intravascular and myocardial macrophages were frequently perivascular (Fig. 1A and Supplementary movies S1 and S2). Intravascular myocardial associated B cells and perivascular myocardial macrophages were typically in close
Contribution to the field statement
The naïve myocardium hosts a heterogeneous pool of resident macrophages with disparate ontogeny and function. The biological cues that regulate the composition of the myocardial macrophage pool in the naïve heart remain mostly unexplored. Studying both B cell-deficient and B cell-depleted animals, we found that B cells modulate the composition of the myocardial macrophage pool in the naïve murine heart. We performed histological analysis and in vitro studies that support the notion that
Declaration of Competing Interest
LA is cofounder of i-Cordis LLC, which is focused on the development of B cell–modulating therapies for the treatment of heart failure, and coinventor on patent WO2019028062, “Pirfenidone derivatives for modulation of B lymphocyte activity and organ protection,” owned by Washington University in St Louis. CRR and FP have no conflict of interest to disclose.
Acknowledgments
This study was supported by NIH grant 1K08HL145108-01A1 and institutional funds from the Washington University in St. Louis Division of Cardiology and the Johns Hopkins University Division of Cardiology. The authors acknowledge Dr. Doug Mann for critical discussions of this work. The authors acknowledge Dr. Erica Lantelme, Dr. Hao Zhang, the Washington University Flow Cytometry & Fluorescence Activated Cell Sorting Core and the Bloomberg School of Public Health Cell Sorting Facility for
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