| First Author | Rolski F | Year | 2024 |
| Journal | Cardiovasc Res | Volume | 120 |
| Issue | 1 | Pages | 82-94 |
| PubMed ID | 37879102 | Mgi Jnum | J:360535 |
| Mgi Id | MGI:7609912 | Doi | 10.1093/cvr/cvad158 |
| Citation | Rolski F, et al. (2024) TNF-alpha protects from exacerbated myocarditis and cardiac death by suppressing expansion of activated heart-reactive CD4+ T cells. Cardiovasc Res 120(1):82-94 |
| abstractText | AIMS: Tumour necrosis factor alpha (TNF-alpha) represents a classical pro-inflammatory cytokine, and its increased levels positively correlate with the severity of many cardiovascular diseases. Surprisingly, some heart failure patients receiving high doses of anti-TNF-alpha antibodies showed serious health worsening. This work aimed to examine the role of TNF-alpha signalling on the development and progression of myocarditis and heart-specific autoimmunity. METHODS AND RESULTS: Mice with genetic deletion of TNF-alpha (Tnf+/- and Tnf-/-) and littermate controls (Tnf+/+) were used to study myocarditis in the inducible and the transgenic T cell receptor (TCRM) models. Tnf+/- and Tnf-/- mice immunized with alpha-myosin heavy chain peptide (alphaMyHC) showed reduced myocarditis incidence, but the susceptible animals developed extensive inflammation in the heart. In the TCRM model, defective TNF-alpha production was associated with increased mortality at a young age due to cardiomyopathy and cardiac fibrosis. We could confirm that TNF-alpha as well as the secretome of antigen-activated heart-reactive effector CD4+ T (Teff) cells effectively activated the adhesive properties of cardiac microvascular endothelial cells (cMVECs). Our data suggested that TNF-alpha produced by endothelial in addition to Teff cells promoted leucocyte adhesion to activated cMVECs. Analysis of CD4+ T lymphocytes from both models of myocarditis showed a strongly increased fraction of Teff cells in hearts, spleens, and in the blood of Tnf+/- and Tnf-/- mice. Indeed, antigen-activated Tnf-/- Teff cells showed prolonged long-term survival and TNF-alpha cytokine-induced cell death of heart-reactive Teff. CONCLUSION: TNF-alpha signalling promotes myocarditis development by activating cardiac endothelial cells. However, in the case of established disease, TNF-alpha protects from exacerbating cardiac inflammation by inducing activation-induced cell death of heart-reactive Teff. These data might explain the lack of success of standard anti-TNF-alpha therapy in heart failure patients and open perspectives for T cell-targeted approaches. |
