Prospective Roles of Tumor Necrosis Factor-Alpha (TNF-α) in COVID-19: Prognosis, Therapeutic and Management

Abstract

The coronavirus disease 2019 (COVID-19) became a worldwide concern at the beginning of 2020 and has affected millions. Several previous studies revealed the impact of the imbalanced innate immune response on the progression of COVID-19 and its disease outcomes. High levels of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukins are produced readily by innate immune cells to fight Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infections. Nonetheless, cytokine-mediated inflammatory events are also linked to detrimental lung injury and respiratory failure, which can result in deaths among COVID-19 patients. TNF-α is amongst the early cytokines produced to mediate proinflammatory responses and enhance immune cell infiltration in response to SARS-CoV-2 infections. In COVID-19, TNF-α-mediated inflammation can cause detrimental tissue damage and gradually promotes lung fibrosis, which later results in pneumonia, pulmonary edema, and acute respiratory distress syndrome. This review, therefore, aims to deliberate the immunomodulatory roles of TNF-α in promoting inflammation and its relation with COVID-19 morbidity and mortality. In addition, this review also proposes the potential of TNF-α as a biomarker for the prognosis of severe COVID-19 and its related complications and as a molecular target for anti-TNF-α therapy.

Keywords: COVID-19; SARS-CoV-2; TNF-α; cytokines; inflammation.

Figure 1

Antiviral defense of IFN. (a) Viral RNA (vRNA) can be recognized by pathogen pattern receptors (PPR) on the cell surface and retinoic acid-like receptors (RLR) in the cytosol. The vRNA sensing by PPR can be initiated by toll-like receptors (TLR)-3, -7, and -8, which then activates gene transcription factors, i.e., interferon regulatory factors (IRF)-3 and -7. IRF-3 and -7 are then translocated into the cell nucleus to express interferon (IFN)-β and interferon-α, respectively. The cytosolic viral dsRNA, on the other hand, is recognized by retinoic-like receptors (RLR) such as retinoic acid-inducible gene-1 (RIG-I) and melanoma differentiation-associated protein 5 (MDA-5). The RLR/vRNA complex subsequently binds to the mitochondrial-antiviral signaling (MAVS) protein located on the mitochondrial outer membrane. Upon the activation of MAVS, IRF-3 is phosphorylated via TANK-binding kinase (TBK)-1 to enhance the expression of IFN-β. (b) The antiviral cascades of IFN α/β demand the activation of Janus kinase/tyrosine kinase/signal transducer and activator of transcription (JAK/TYK/STAT) signaling. Activating the JAK/TYK/STAT transcription signaling pathway results in the expression of antiviral proteins, oligoadenylate synthetase (OAS), and protein kinase R (PKR), which are responsible for viral RNA degradation and inhibition of viral protein synthesis, respectively.

Figure 2

TNFR-1- and TNFR-2-mediated inflammatory responses in the TNF-α signaling pathway. (a) Upon TNFR-1 activation, TRADD is attracted to TNFR1 together with TRAF2 to phosphorylate NF-κβ and activate MAPK as well to regulate the expression of proinflammatory molecules. In addition, TRADD also binds to FADD, which leads to cell apoptosis via caspase-8. (b) In the event of TNFR-2 activation, the recruitment of TRAF2-cIAP complex to TNFR-2 activates the NF-κB pathway, which results in the regulation of inflammation.