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Cardiac sarcoidosis (CS) is a poorly understood disease and is characterized by the focal accumulation of immune cells, thus leading to the formation of granulomata (GL). To identify the developmental principles of fatal GL, fluorescence microscopy and Western blot analysis of CS and control patients is presented here. CS is visualized macroscopically by positron emission tomography (PET)/ computed tomography (CT). A battery of antibodies is used to determine structural, cell cycle and inflammatory markers. GL consist of CD68+, CD163+ and CD206+ macrophages surrounded by T-cells within fibrotic areas. Cell cycle markers such as phospho-histone H3, phospho-Aurora and Ki67 were moderately present; however, the phosphorylated ERM (ezrin, radixin and moesin) and Erk1/2 proteins, strong expression of the myosin motor protein and the macrophage transcription factor PU.1 indicate highly active GL. Mild apoptosis is consistent with PI3 kinase and Akt activation. Massive amounts of the IL-1R antagonist reflect a mild activation of stress and inflammatory pathways in GL. High levels of oncostatin M and the Reg3A and Reg3γ chemokines are in accordance with macrophage accumulation in areas of remodeling cardiomyocytes. We conclude that the formation of GL occurs mainly through chemoattraction and less by proliferation of macrophages. Furthermore, activation of the oncostatin/Reg3 axis might help at first to wall-off substances but might initiate the chronic development of heart failure. [ABSTRACT FROM AUTHOR]

• 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. 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. [ABSTRACT FROM AUTHOR]