Abstract 335 Neuronal control of immune cell responses in the pericardial adipose tissue after acute myocardial infarction

Background:
Murine pericardial adipose tissue (PAT) contains a high density of fat-associated lymphoid cluster (FALCs) in which leukocytes rapidly expand after acute myocardial infarction (MI). The MI-induced inflammation translates into enhanced granulopoiesis in the bone marrow and regulates cardiac healing and outcome. However, it remains unknown how PAT-resident immune cells sense cardiac injury. We hypothesize immunomodulatory effects of the sympathetic nervous system (SNS) which we studied in an experimental mouse model of acute MI.

Methods:
10-12 weeks old female C57Bl/6J mice were subjected to permanent LAD ligation and changes in expression levels of neuronal markers in whole-tissue lysates from the PAT were assessed by qPCR on day 3, 5, 7 and 10 post-MI. Immunostaining and whole mounted organ multiphoton microscopy was used to visualize pericardial FALC innervation. Leukocytes from mice without MI were sorted from the PAT and neuronal receptor expression was examined by qPCR. Immune cell counts of infarcted mice treated with the specific β2-adrenergic receptor (ADRB2) antagonist ICI-118,551 (1mg/kg/day; i.p) were measured via flow cytometry and compared to vehicle-treated controls on day 3, 5 and 7 post-MI.

Results:
Expression levels of the noradrenergic marker tyrosine hydroxylase (TH) in the PAT were significantly increased and peaked at day 5 post-MI (p=0.0095). ADRB2 was found to be expressed on PAT-resident immune cells with T and B cells displaying higher levels than myeloid cells (ΔCt value of 9.81 and 9.56 vs. 8.91, respectively). Three-dimensional PAT imaging confirmed the presence of SNS fibers innervating the FALC microcirculation. Mice systemically treated with ICI-118-551 showed a diminished general leukocyte increase 5 days post-MI in the PAT (p=0.0082) and heart (p=0.0958) but promoted blood leukocytosis (p=0.0723) compared to controls.

Conclusion:
Inhibition of catecholamine sensing altered immune cell dynamics, resulting in a dampened inflammatory response in the PAT and heart after infarction. The distinct innervation pattern of TH in the PAT supports the relevance of sympathetic stimuli for immune cell activation after MI. Overall, we speculate that sympathetic hyperactivity after MI contributes to the local activation of FALC-resident immune cells in the PAT, which deserves further mechanistic investigation.

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02087-y
Neuronal control of immune cell responses in the pericardial adipose tissue after acute myocardial infarction
A. Kaltenbach¹, S. Steffens¹, S. Mohanta¹, M. Horckmans², M. Bianchini¹, S.-L. Puhl³, für die Studiengruppe: DZHK
¹Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, LMU Klinikum der Universität München, München; ²Institute of Interdisciplinary Research (IRIBHM), Université Libre de Bruxelles, Brüssel, BE; ³Deutsches Zentrum für Herzinsuffizienz, Universitätsklinikum Würzburg, Würzburg;
Background: Murine pericardial adipose tissue (PAT) contains a high density of fat-associated lymphoid cluster (FALCs) in which leukocytes rapidly expand after acute myocardial infarction (MI). The MI-induced inflammation translates into enhanced granulopoiesis in the bone marrow and regulates cardiac healing and outcome. However, it remains unknown how PAT-resident immune cells sense cardiac injury. We hypothesize immunomodulatory effects of the sympathetic nervous system (SNS) which we studied in an experimental mouse model of acute MI. Methods: 10-12 weeks old female C57Bl/6J mice were subjected to permanent LAD ligation and changes in expression levels of neuronal markers in whole-tissue lysates from the PAT were assessed by qPCR on day 3, 5, 7 and 10 post-MI. Immunostaining and whole mounted organ multiphoton microscopy was used to visualize pericardial FALC innervation. Leukocytes from mice without MI were sorted from the PAT and neuronal receptor expression was examined by qPCR. Immune cell counts of infarcted mice treated with the specific β2-adrenergic receptor (ADRB2) antagonist ICI-118,551 (1mg/kg/day; i.p) were measured via flow cytometry and compared to vehicle-treated controls on day 3, 5 and 7 post-MI. Results: Expression levels of the noradrenergic marker tyrosine hydroxylase (TH) in the PAT were significantly increased and peaked at day 5 post-MI (p=0.0095). ADRB2 was found to be expressed on PAT-resident immune cells with T and B cells displaying higher levels than myeloid cells (ΔCt value of 9.81 and 9.56 vs. 8.91, respectively). Three-dimensional PAT imaging confirmed the presence of SNS fibers innervating the FALC microcirculation. Mice systemically treated with ICI-118-551 showed a diminished general leukocyte increase 5 days post-MI in the PAT (p=0.0082) and heart (p=0.0958) but promoted blood leukocytosis (p=0.0723) compared to controls. Conclusion: Inhibition of catecholamine sensing altered immune cell dynamics, resulting in a dampened inflammatory response in the PAT and heart after infarction. The distinct innervation pattern of TH in the PAT supports the relevance of sympathetic stimuli for immune cell activation after MI. Overall, we speculate that sympathetic hyperactivity after MI contributes to the local activation of FALC-resident immune cells in the PAT, which deserves further mechanistic investigation.
https://dgk.org/kongress_programme/ht2022/aBS679.html