https://doi.org/10.1007/s00392-024-02526-y
1LMU Klinikum der Universität München Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten München, Deutschland
Introduction:
Immune cells in the murine pericardial adipose tissue (PAT) contribute to post-myocardial infarction (MI) immune responses and cardiac healing (PMID: 29167227). However, it remains unknown how the inflammatory response in the PAT is initiated and regulated. Given the extensive sympathetic activation after MI as well as growing appreciation for a role of neuroimmune interactions in cardiovascular disease, we hypothesize that adrenergic signals are key regulators of pericardial immune cell responses. Our preliminary findings in an invasive permanent MI model (LAD ligation) support this hypothesis and were now further explored in a minimal invasive MI induction model in order to avoid surgery-induced immune activation.
Immune cells in the murine pericardial adipose tissue (PAT) contribute to post-myocardial infarction (MI) immune responses and cardiac healing (PMID: 29167227). However, it remains unknown how the inflammatory response in the PAT is initiated and regulated. Given the extensive sympathetic activation after MI as well as growing appreciation for a role of neuroimmune interactions in cardiovascular disease, we hypothesize that adrenergic signals are key regulators of pericardial immune cell responses. Our preliminary findings in an invasive permanent MI model (LAD ligation) support this hypothesis and were now further explored in a minimal invasive MI induction model in order to avoid surgery-induced immune activation.
Methods:
10-12 weeks old female C57Bl/6J mice were subjected to ultrasound-guided minimally-invasive induction of acute MI (MiMI; PMID 32854590). Leukocyte counts and the expression of adrenergic receptor beta-2 (ADRB2) in the PAT were assessed by flow cytometry 1, 3 and 5 days post-MI. Norepinephrine (NE) and other markers of adrenergic signaling were measured by ELISA, Western Blot and qPCR in PAT lysates. Systemic ADRB2 blocking was performed by intraperitoneal injection of ICI-118,551 (1 mg/kg/day).
Results:
MiMI resulted in a significant expansion of immune cells in the PAT, with neutrophil and Ly6C+ monocyte counts peaking 1 day post-MI followed by ΜΦs (CCR2+TIMD4-) and B220+ B cells 3 days post-MI. In most subsets, the percentage of proliferating Ki67+ cells was greatly increased, while leukocyte counts returned to baseline levels 5 days post-MI. Highest ADRB2 expression was found in the myeloid population, followed by lymphocytes and non-immune cells. ADRB2 on myeloid cells was downregulated after MI in accordance with severely depleted NE stores of the PAT. Tyrosine hydroxylase (TH) – the rate-limiting enzyme of NE synthesis – was significantly upregulated in whole tissue as well as by pericardial ΜΦs, whereas mRNA levels of catecholamine degradation enzymes were downregulated. Mice that received ADRB2 antagonist treatment showed significantly increased immune cell counts in the PAT after MI compared to the vehicle control.
MiMI resulted in a significant expansion of immune cells in the PAT, with neutrophil and Ly6C+ monocyte counts peaking 1 day post-MI followed by ΜΦs (CCR2+TIMD4-) and B220+ B cells 3 days post-MI. In most subsets, the percentage of proliferating Ki67+ cells was greatly increased, while leukocyte counts returned to baseline levels 5 days post-MI. Highest ADRB2 expression was found in the myeloid population, followed by lymphocytes and non-immune cells. ADRB2 on myeloid cells was downregulated after MI in accordance with severely depleted NE stores of the PAT. Tyrosine hydroxylase (TH) – the rate-limiting enzyme of NE synthesis – was significantly upregulated in whole tissue as well as by pericardial ΜΦs, whereas mRNA levels of catecholamine degradation enzymes were downregulated. Mice that received ADRB2 antagonist treatment showed significantly increased immune cell counts in the PAT after MI compared to the vehicle control.
Conclusion:
Stress-induced NE release after MI was associated with ADRB2 desensitization of local immune cells, proliferation and recruitment as well as upregulation of the NE synthesis machinery in murine PAT. Interference with acute ADRB2 activation augmented the inflammatory response, which emphasizes a role of ADRB2 for controlling the pericardial immune reaction post-MI. The underlying mechanisms as well as the potential effect on cardiac outcome need to be further investigated.