Adenosine Formed by CD73 on T Cells Inhibits Cardiac Inflammation and Fibrosis and Preserves Contractile Function in Transverse Aortic Constriction–Induced Heart Failure

Abstract

Our data provide first evidence that CD73 on T cells plays an important anti-inflammatory role in TAC-induced heart failure, which is associated with antifibrotic activity and reduced production of proinflammatory cytokines most likely by activation of the adenosine A2a receptor.

Leukocyte-Dependent Regulation of Cardiac Fibrosis

“…Mechanistically, a few targets have been investigated in their role for inducing pro-fibrotic T cell actions. Namely, studies have determined an involvement of CD73 and adenosine generation, as T cell-specific CD73 knockout mice show enhanced fibrosis (Borg et al, 2017;Quast et al, 2017). These studies suggest that adenosine functions in an autocrine manner to reduce the production of pro-inflammatory andfibrotic cytokines (Borg et al, 2017).…”

“…B and T Cells Ischemia Depletion of TNFα T regulatory cells improves fibrosis post MI (Bansal et al, 2019) Pressure Overload B cell depletion results in decreased fibrosis following TAC (Ma et al, 2019) IFNγ T cells promote myofibroblast trans differentiation and cardiac fibrosis (Nevers et al, 2017) CD73 expressing T cells attenuate fibrosis following TAC (Quast et al, 2017) Myocarditis/DCM TNFα secreting B cells correlate with greater fibrosis in DCM patients (Yu et al, 2013) MI, myocardial infarction; CD, cluster of differentiation; Arg-1, arginase 1; GAL3, galectin-3; MPO, myeloperoxidase; NGAL, neutrophil gelatinase-associated lipocalin; NETosis, neutrophil extracellular trap formation; IL-10, interleukin 10; TGFβ, transforming growth factor beta; MCP-1, monocyte chemoattractant protein 1; Gata6, GATA binding protein 6; PDGF, platelet derived growth factor; FGF, fibroblast growth factor; MMP, matrix metallopeptidase; TIMP, tissue inhibitor of metalloproteinases; IL-1β, interleukin 1 beta; TGFβ, transforming growth factor beta; BATF3, basic leucine zipper transcription factor ATF-like 3; IFNγ, interferon gamma; TNFα, tumor necrosis factor alpha.…”

“…T cells come in many subsets, some of which have divergent functions in cardiac fibrosis. For one, CD4 + T cells accumulate in the heart post-MI and -TAC, and are associated with enhanced cardiac fibrosis (Laroumanie et al, 2014;Nevers et al, 2015Nevers et al, , 2017Bansal et al, 2017Bansal et al, , 2019Borg et al, 2017;Quast et al, 2017). Studies have shown increased Th1 polarization following injury, leading to the production of pro-inflammatory and -fibrotic cytokines like interferon γ (IFNγ) (Laroumanie et al, 2014;Nevers et al, 2017).…”

Adenosine, Via A 2B Receptors, Inhibits Human (P-SMC) Progenitor Smooth Muscle Cell Growth

“…For example, A 2B -receptor expression is increased following vascular injury, 14 and knockdown of A 2B receptors as well as CD73 (an ecto-nucleotidase that converts 5'-AMP to adenosine on cell surfaces) results in vessel wall thickening. [16][17][18] Also, treatment with A 2B -receptor agonists prevents injury-induced neointima formation, 14 and CD73-derived adenosine prevents cardiac fibrosis and heart failure. 18 As reviewed before, 13 via A 2B receptors, adenosine inhibits abnormal growth of multiple cell types involved in cardiovascular and renal diseases.…”

“…[16][17][18] Also, treatment with A 2B -receptor agonists prevents injury-induced neointima formation, 14 and CD73-derived adenosine prevents cardiac fibrosis and heart failure. 18 As reviewed before, 13 via A 2B receptors, adenosine inhibits abnormal growth of multiple cell types involved in cardiovascular and renal diseases. Specifically, activation of A 2B receptors inhibits the growth of human glomerular mesangial cells (phenotypically similar to vascular SMCs), rat preglomerular SMCs, and rat cardiac fibroblasts.…”