Adrenergic modulation of post myocardial infarction immune responses

Daphne Steder (Würzburg)1, M. Delgobo (Würzburg)1, G. Ramos (Würzburg)1, S. Frantz (Würzburg)2

1Universitätsklinikum Würzburg Deutsches Zentrum für Herzinsuffizienz Würzburg, Deutschland; 2Universitätsklinikum Würzburg Medizinische Klinik und Poliklinik I Würzburg, Deutschland


Introduction: Following myocardial infarction (MI), distinct immune cell populations infiltrate the inflamed heart tissue and play a crucial role in cardiac repair whereas sustained immune activity can lead to cardiac maladaptive responses. MI is associated with pronounced activation of the neuroendocrine system, resulting in increased sympathetic tonus. However, it remains unclear how adrenergic signalling modulates immune cell responses post-MI. Herein, we hypothesised that chronic adrenergic activity polarises T-cells towards a pro-inflammatory phenotype, which may affect myocardial repair.

The expression of β-adrenergic receptors on distinct T-cell populations in vitro was analysed using the β-antagonist drug propranolol conjugated to bodipy-red fluorescent dye (pRED) and flow cytometry analysis. Mouse C57BL6/J T-cells were differentiated towards TH1, TH2, TH17 and Treg phenotypes in the presence of β-agonist isoprenaline (ISO- 100nM), to evaluate the effect of adrenergic stimulation on T-cell polarisation in vitro. The expression of β-adrenergic receptors was also estimated in cardiac leukocytes using a mouse model of MI with permanent ligation of the left anterior descending coronary artery. Cardiac leukocyte populations were assessed at an acute (5 days) and chronic (56 days) stage post MI.

In vitro differentiation of TH1 cells under the influence of ISO revealed an increased efficiency towards expression of transcription factor TBET and resulted in elevated interferon-γ production. Higher efficiency of TH differentiation was also seen on pro-inflammatory TH17 cells, while no differences were observed in Treg induction. Our in vivo MI model revealed an upregulation of the β-adrenergic receptor on CD4+ T-cells in the infarcted region of the heart 56 days post MI, while differences during the acute stage were mainly seen in monocytes/macrophages. To characterise the phenotype of pRED+ T-cells, we gated on CD29 (TH1), CCR6 (TH17) or CD25 (Tregs). Our findings suggest that CD29+ TH1 cells are the main population expressing high levels of β-adrenergic receptor in the infarcted heart. Re-analysis of single cell sequencing data from myocardial T-cells showed that Adrb2 is highly expressed on TH1 but not Treg cells. Our data reveals that β-adrenergic receptors are upregulated on CD4+ T-cells at the chronic stages following MI and are preferentially expressed in T-cells with a pro-inflammatory signature.

Together with our in vitro findings, we suggest that chronic adrenergic stimulation may push cardiac T-cells towards a pro-inflammatory phenotype. Further experiments will be conducted to mechanistically assess the impact of β-adrenergic signalling on T-cell responses.

Figure 1 – Modulation of adrenergic receptor responses on T-cells post-MI. (A) In vitro differentiated TH1 cells show higher expression of pRED and produce more interferon-γ following ISO stimulation. (B) Feature plot illustrates the Adrb2 expression on cardiac T-cells derived from Xia et al and Delgobo et al. studies. Higher Adrb2 expression is noted on T-cells annotated as TH1 cells, while lower expression is found on Tregs. (C) In vivo experiment design: Heart and LNs were collected 5 and 56 days post-MI. β-adrenergic receptor expression is increased at day 56 post-MI. (D) Expression of CD29 (TH1 marker) on T cells expressing high levels of β adrenergic-receptors (pRED+) and negative cells (open bars).
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