Macrophages represent the major pool of IL-7Rα expressing cells in patients with myocarditis

Highlights

• Myocardial inflammation is initially protective but often leads to heart failure.

• Main infiltrating cells are macrophages and T cells but B cells are rarely present.

• Surprisingly, macrophages but not T cells are the major IL-7Rα expressing population.

• The IL-7Rα cascade is activated and might regulate trafficking of macrophages.

• Consumption of IL-7 by macrophages might reduce the number of cardiac T and B cells.

Abstract

Myocarditis is characterized by infiltration and activation of cytokine as well as chemokine receptors frequently producing heart failure. Causes are often infections triggering inflammatory and immune responses but these initial lines of defense might be finally disastrous. To identify mediators we screened various receptors by confocal microscopy and identified cardiac interleukin-7 (IL-7) receptor-α (IL-7Rα) expressing cells in patients with myocarditis. IL-7Rα⁺ cells were analyzed by markers for leukocytes (CD45), B cells (CD19), T cells (CD3, CD4, CD8) and macrophages (CD68, CD163, CD206). Immune cells were hardly detected in controls. In patients with myocarditis main inflammatory populations consisted of macrophages and T cells. B cells were hardly present. 90% of CD68⁺ macrophages but less than 20% of CD3⁺ T cells were IL-7Rα⁺. This was surprising since T and B lymphocytes are generally regarded as the major IL-7Rα⁺ cells. Since IL-7 acts as a chemokine, the expression of its receptor might orchestrate cardiac macrophage infiltration. In contrast, consumption of IL-7 by IL-7Rα⁺ cardiac macrophages might potentially prevent a certain overshooting immune reaction and sepsis by reducing proliferation and survival of lymphocytes. Our data suggest a participation of IL-7Rα⁺ macrophages in the development of myocarditis and heart failure.

Introduction

Myocarditis (MyoC) is a heart disease which is accompanied by focal as well as diffuse infiltration of mononuclear cells such as macrophages (Mph) and T cells. While some patients completely recover from myocarditis its progression produces dilated cardiomyopathy, heart failure (HF) and sudden death. Causes of myocarditis are frequently infections triggering inflammatory as well as immune responses in order to preserve and heal the heart. Important regulators of infiltration are a number of distinct groups of chemokines [1].

Under various chemokine systems screened and analyzed the interleukin-7 (IL-7) receptor-α (IL-7Rα or CD127) attracted especially our attention since deficiency of this interleukin pathway in mice and humans results in severe lymphopenia and is associated with severe combined immunodeficiency (SCID). These patients are especially vulnerable to infections because interleukin-7 is needed for survival, proliferation and differentiation of T as well as B lymphocytes [2]. Furthermore, the IL-7Rα system is also important for the development of tissue-resident macrophages [3] and pre-clinical studies indicate that IL-7 exerts beneficial effects during sepsis [4]. Since the IL-7Rα recruits macrophages which are able to secrete interleukin-7 we wanted to know whether the activation of this receptor system might be involved in the development of myocarditis [2], [5]. An overall hypothetical scheme of the IL-7Rα as a participant in the development of myocarditis and potential pharmacological interventions are discussed (Fig. 2C).