Tumor necrosis factor-α confers cardioprotection through ectopic expression of keratins K8 and K18

Abstract

The adult myocardium demonstrates a unique system of adaptation upon stress stimuli, in an effort to maintain its overall homeostasis. This compensatory mechanism remains a mystery1. Tumor Necrosis Factor-α (TNF-α) is one of the major stress-induced pro-inflammatory cytokines that is up-regulated in heart failure1,2 and its sustained expression is considered detrimental for the heart1,3–9. Although previous studies have shown that lower levels of TNF-α confer cytoprotection in the myocardium following ischemic reperfusion injury10, such action in heart failure remains elusive. Here we propose a novel cardioprotective function for TNF-α overexpression in a genetic heart failure model, the desmin deficient mice, through NF-κB-mediated cardiomyocyte ectopic expression of keratin 8 (K8) and keratin 18 (K18)11, two simple epithelia-specific Intermediate Filament (IF) proteins. The ectopically expressed K8 and K18 (K8/K18) form a cytoskeletal network that localizes mainly at the Intercalated Discs (IDs). This alternative K8/K18 cytoskeleton confers cardioprotection by a mechanism that maintains ID and mitochondrial integrity and function. Importantly, we demonstrated that K8/K18 ectopic induction takes place in other genetic and experimental models of heart failure and showed a cardioprotective function in mice subjected to transverse aortic constriction. Finally, we discovered that in cardiomyocytes of human failing myocardium, where TNF-α is induced2, K8/K18 are also ectopically expressed and localize primarily at IDs, where desmin cannot be detected. This is the first report to propose a TNFα-mediated cardiac ectopic expression of K8/K18 IF proteins, which may act as stress-induced cardioprotective factors in the failing heart, a phenomenon of major clinical significance as it also extends to human heart failure.

Mesenchymal stem cells promote macrophage polarization toward M2b-like cells

“…During skeletal muscle repair, satellite cells are major targets of TNFα signaling that promotes the early proliferative stage of myogenesis [43]. In the case of heart, TNFα has a cardioprotective function in mice [44]. On the other hand, mononuclear phagocytes engage in a bidirectional interaction with MSCs [20].…”

TNF biology, pathogenic mechanisms and emerging therapeutic strategies

“…One study showed that TNF desensitizes macrophages to the deleterious effects of secondary inflammatory challenges (tolerization) 76 . Others have described homeostatic effects of TNF in tissue regeneration, such as neuronal remyelination 83 , cardiac remodelling 84 and cartilage regeneration 85 . In addition, TNF has suppressive effects on adaptive immune processes in models of autoimmunity such as autoimmune encephalitis 12 .…”

Chronic Heart Failure and Inflammation

“…This is supported by recent animal data that argue that TNF-α may be cardioprotective through its ability to form stress-induced cytoskeleton filaments that prevent deterioration of cardiac function and potentially removal of damaged mitochondria, through the process of autophagy. 47,48 Thus, the wrong therapeutic threshold may have been applied to TNF-α blockade. Although unlikely to occur, should future trials of TNF-α blockade proceed, they should be focused on modestly lowering TNF-α levels using low-dose pharmacological inhibition.…”

“…113 For example, cardiac-specific deletion of the NF-κB subunit, p65, showed reduced cardiac hypertrophy after TAC, reduced pathological remodeling, and preserved contractile function, 114 whereas other reports argue for a protective role for the NF-κB pathway. 47,115 These differential effects, some of which are downstream of TLR signaling, but also many other cell surface receptors, reflect that the role of traditional proinflammatory signaling cascades, such NF-κB, are dependent on the cell type and microenvironment in which they are engaged. This emphasizes the importance of cause and the temporal aspect of disease progression after different initial insults.…”