Tumor necrosis factor-α is toxic via receptor 1 and protective via receptor 2 in a murine model of myocardial infarction

Abstract

Tumor necrosis factor (TNF)-α induced in damaged myocardium has been considered to be cardiotoxic. TNF-α initiates its biological effects by binding two distinct receptors: R1 (p55) and R2 (p75). Although TNF-α has been shown to be cardiotoxic via R1-mediated pathways, little is known about the roles of R2-mediated pathways in myocardial infarction (MI). We created MI in R1 knockout (R1KO), R2KO, and wild-type (WT) mice by ligating the left coronary artery. Functional, histological, and biochemical analyses were performed 4 wk after ligation. Although infarct size was not different among WT, R1KO, and R2KO mice, post-MI survival was significantly improved in R1KO but not R2KO mice. R1KO significantly ameliorated contractile dysfunction after MI, whereas R2KO significantly exaggerated ventricular dilatation and dysfunction. Myocyte hypertrophy and interstitial fibrosis in noninfarct myocardium was exacerbated in R2KO but not in R1KO mice. Expression of R1, which was not affected by MI and was nullified in R1KO mice, was significantly upregulated in R2KO mice. In contrast, expression of R2, which was significantly upregulated by MI and was nullified in R2KO mice, was unaffected in R1KO mice. Meanwhile, TNF-α expression, which was significantly upregulated in noninfarct myocardium after MI, was not affected by R1KO or R2KO. However, transcript levels of IL-6, IL-1β, transforming growth factor-β, and monocyte chemotactic protein-1, which were significantly upregulated after MI, were significantly downregulated in R1KO mice. In contrast, transcript levels of IL-6 and IL-1β were significantly further upregulated in R2KO mice. TNF-α is toxic via R1 and protective via R2 in a murine model of MI. Selective blockade of R1 may be a candidate therapeutic intervention for MI.

Signaling Pathways in Cardiac Myocyte Apoptosis

“…Consistently, global deficiency of TNF- α reduced inflammatory cell infiltration and cardiac rupture after permanent ischemia or I/R injury [113, 114]. The fact that deletion of TNF- α receptor 1 (TNFR1), but not TNFR2, protected the heart against I/R injury suggested that the detrimental effect of TNF- α was likely mediated by TNFR1 [115, 116]. Indeed, studies from an independent group revealed that knockout of TNFR1 attenuated apoptosis and suppressed activation of NF- κ B, p38, and JNK2 in a permanent ligation model, while deletion of TNFR2 augmented apoptosis and enhanced activation of NF- κ B and p38, suggesting that activation of TNFR1 and TNFR2 mediates detrimental and beneficial signals, respectively [117].…”

Apoptosis in ischemic heart disease

“…In an in vivo murine model of myocardial infarction, TNF-α showed its cardiotoxic effect through receptor TNFR1 and cardioprotective effect through TNFR2. Mice lacking TNFR2 demonstrated worse post-IM survival, more severe ventricular dysfunction, and exacerbated myocyte hypertrophy and interstitial fibrosis in non-infarct myocardium—compared to TNFR1-knockout mice [29]. …”

TNF Receptor 2 and Disease: Autoimmunity and Regenerative Medicine

“…According to in vitro and in vivo studies, TNF or TNFR2 agonism is associated with pancreatic regeneration (57–59), cardioprotection (60, 61), remyelination (5, 6), survival of some neuron subtypes (5, 62, 63), and stem cell proliferation (11, 64–66). …”

“…Knockout of the tnfr2 gene in a mouse model produces a higher rate of heart failure and reduced survival after myocardial infarction (60). TNFR1 signaling is deleterious and TNFR2 signaling is protective in regeneration and repair processes following infarcted myocardium in female mice (61).…”

“…In the field of neuroregeneration, the Ting laboratory showed TNF similarly promoted proliferation of oligodendrocytes progenitors and remyelination (6). Gradually the broader literature reported the regenerative effect of TNF and TNFR2 agonism on heart regeneration, bone marrow stem cells, and even neuron regeneration in the setting of Parkinson’s disease model in mice (11, 60, 66, 107). …”