Tumour necrosis factor-α in cardiac inflammation: friend or foe?

This editorial refers to ‘TNF-α protects from exacerbated myocarditis and cardiac death by suppressing expansion of activated heart-reactive CD4+ T cells’, by F. Rolski et al., https://doi.org/10.1093/cvr/cvad158. The pathological role of tumour necrosis factor-α (TNF-α) in acute and chronic human cardiovascular disease remains ambiguous. While population-based studies in heart failure (HF) with reduced and preserved ejection fraction have consistently demonstrated elevated serum levels of this ‘pro-inflammatory’ cytokine, randomized controlled trials of TNF-α blockade have not shown any positive impact on clinical outcomes, and there is some evidence of harm in certain patient subgroups (e.g. non-ischaemic cardiomyopathy).1,2 In the setting of acute myocarditis (AM), levels of peripheral TNF-α are raised and endomyocardial detection of TNF-α mRNA has been shown to correlate with left ventricular (LV) dysfunction.3 However, in contrast to HF, very little human data exist on the effect of TNF-α blockade in AM. Translating the negative findings from the use of infliximab (usually combined with high-dose glucocorticoids) in immune checkpoint inhibitor-related myocarditis to viral disease seems unwise given the small number of patients treated to date (n = 18 in published studies since 2018) and the lack of significant clinical overlap between the two conditions.4 Looking at the effect of TNF-α blockade on cardiac function in patients with autoimmune joint disease is no more revealing. In patients with rheumatoid arthritis (RA), the use of anti-TNF therapies has been associated with both improved indices of LV function and an increased risk of HF admission (hazard ratio 1.7; 95% confidence interval 1.07–2.69).5 Controlling autoimmune-associated systemic inflammation via TNF-α inhibition does however seem to reduce the risk from atherosclerotic disease: the incidence of myocardial infarction is lower in patients with psoriasis and RA treated with TNF-α inhibitors.6,7 Unfortunately, this beneficial effect cannot be extended to patients with an acute coronary syndrome, where TNF blockade has been shown to increase platelet activation.8 In summary, our current understanding of TNF-α biology has not facilitated the identification of a specific cardiovascular cohort who is likely to derive a clinically meaningful benefit from targeted anti-cytokine therapy. Given the above, Rolski et al.9 have investigated the role of TNF-α through genetic deletion in two animal surrogates of autoimmune myocarditis: experimental autoimmune myocarditis and the transgenic T-cell receptor (TCR-M) model, which they combined with an in vitro study of the effects of TNF-α on endothelial activation (Figure 1). The authors conclude that TNF-α signalling initially promotes the development of AM by activating cardiac endothelial cells. However, in the chronic disease phase, they also show that TNF-α exerts a protective role by promoting activation-induced cell death (AICD) of autoimmune effector T cells. Although these observations provide a basis to understand the conflicting data on anti-TNF-α therapy in inflammatory cardiovascular diseases, some caveats must be highlighted to help readers better understand the limitations of these models. For example, in the TCR-M model, a supra-physiological repertoire of autoreactive T cells is involved in the development of disease. It is conceivable that AICD might be enhanced in such a large T-cell cohort. In addition, both models rely upon a relatively acute autoimmune response, which in clinical settings, with the exception of some forms of AM, has already reached a chronic phase at presentation. The role of TNF-α in autoimmune myocarditis. Rolski et al. propose a dual and opposite role for TNF-α in the development of autoimmune myocarditis. In the early phase of inflammation (1), TNF-α promotes inflammation by activating the vascular endothelium and the recruitment of autoreactive effector T lymphocytes (Teff). Subsequently, TNF-α triggers AICD of infiltrating effector T cells, thus undertaking a homoeostatic role. This work gives rise to several questions including (3) the relative contribution of TNFR1 and TNFR2, the effect on the recruitment of other immune cells such as monocytes (4) and on immune (macrophages) and parenchymal (cardiomyocytes and fibroblasts) cells of the myocardium (5). Finally, the influence of systemic inflammation, microenvironmental factors, and additional cytokines (6) on the differential effects of exposure to TNF-α remains unclear. AICD, activation-induced cell death; TNF-α, tumour necrosis factor-α; TNFR1 and TNFR2, TNF receptor-1 and -2. This study also raises several questions regarding the different mechanistic roles played by TNF-α during the dynamic evolution of an immune response. Firstly, the relative contribution of TNF receptor-1 and -2 (TNFR1 and TNFR2) in mediating the phase-dependent effect of TNF-α in cardiac inflammation remains unclear, especially as TNFR2 is more frequently associated with homoeostatic cellular responses.10 Along these lines, while this study focuses on endothelial cells and T cells, other cells expressing TNFR are likely to respond to exposure to TNF-α and contribute either directly or indirectly to the evolving inflammatory response. For example, circulating monocytes are likely to be recruited as a result of TNF-α-induced activation of the vascular endothelium and respond and differentiate in response to TNF-α while infiltrating the myocardium. Cardiac macrophages have been implicated in the development of local inflammatory responses, but the functional consequence of their exposure to TNF-α in this model is unclear. A more general question revolves around the pathophysiology of TNF-α and its contribution to cardiac injury in systemic and local cardiovascular inflammation. Specifically, while there is broad consensus that anti-TNF therapy is beneficial in preventing the atherosclerotic (cardiovascular) complications of systemic autoimmunity, its effect on cardiac inflammatory conditions remains controversial, with a pejorative effect reported in clinical trials and in the present study.1,2,4,9 There are various possibilities that remain to be investigated that could explain these differential outcomes. These include the influence of TNF-α in chronic vs. acute inflammation, the features of the inflammatory process (different cytokines and immune cell involvement), and the potential differential effect on distinct tissue microenvironments characterized by quantitatively and qualitatively different resident immune cells and metabolic status. While more studies are needed to address these pending questions, an important take-home message of this study is that successful therapeutic targeting of molecular mediators of inflammation requires an in-depth knowledge of the dynamic nature of the inflammatory process and the role of these mediators in different phases of this process. Albeit rapidly expanding, our understanding of cardiac immunity is still at its infancy and remains a substantial unmet need for the—as yet elusive—safe and efficacious treatment of heart inflammation.