In:
American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 317, No. 1 ( 2019-07-01), p. H190-H200
Abstract:
Although the cardioprotective effect of adenosine is undisputed, the role of the adenosine A 2b receptor (A 2b R) in ischemic cardiac remodeling is not defined. In this study we aimed to unravel the role A 2b R plays in modulating the immune response and the healing mechanisms after myocardial infarction. Genetic and pharmacological (PSB603) inactivation of A 2b R as well as activation of A 2b R with BAY60-6583 does not alter cardiac remodeling of the infarcted (50-min left anterior descending artery occlusion/reperfusion) murine heart. Flow cytometry of immune cell subsets identified a significant increase in B cells, NK cells, CD8 and CD4 T cells, as well as FoxP3-expressing regulatory T cells in the injured heart in A 2b R-deficient mice. Analysis of T-cell function revealed that expression and secretion of interleukin (IL)-2, interferon (IFN)γ, and tumor necrosis factor (TNF)α by T cells is under A 2b R control. In addition, we found substantial cellular heterogeneity in the response of immune cells and cardiomyocytes to A 2b R deficiency: while in the absence of A 2b R, expression of IL-6 was greatly reduced in cardiomyocytes and immune cells except T cells, and expression of IL-1β was strongly reduced in cardiomyocytes, granulocytes, and B cells as determined by quantitative PCR. Our findings indicate that A 2b R signaling in the ischemic heart triggers substantial changes in cardiac immune cell composition of the lymphoid lineage and induces a profound cell type-specific downregulation of IL-6 and IL-1β. This suggests the presence of a targetable adenosine–A 2b R–IL-6-axis triggered by adenosine formed by the ischemic heart. NEW & NOTEWORTHY Genetic deletion and pharmacological inactivation/activation of A 2b R does not alter cardiac remodeling after MI but is associated by compensatory upregulation of various pro- and anti-inflammatory immune cell subsets (B cells, NK cells, CD8 and CD4 T cells, regulatory T cells). In the inflamed heart, A 2b R modulates the expression of IL-2, IFNγ, TNFα in T cells and of IL-6 in cardiomyocytes, monocytes, granulocytes and B cells. This suggests an important adenosine–IL-6 axis, which is controlled by A 2b R via local adenosine.
Type of Medium:
Online Resource
ISSN:
0363-6135
,
1522-1539
DOI:
10.1152/ajpheart.00029.2019
Language:
English
Publisher:
American Physiological Society
Publication Date:
2019
detail.hit.zdb_id:
603838-4
detail.hit.zdb_id:
1477308-9
SSG:
12
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