How COVID-19 induces cytokine storm with high mortality

Abstract

The newly emerging coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, but has rapidly spread all over the world. Some COVID-19 patients encounter a severe symptom of acute respiratory distress syndrome (ARDS) with high mortality. This high severity is dependent on a cytokine storm, most likely induced by the interleukin-6 (IL-6) amplifier, which is hyper-activation machinery that regulates the nuclear factor kappa B (NF-κB) pathway and stimulated by the simultaneous activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells including alveolar epithelial cells and endothelial cells. We hypothesize that IL-6-STAT3 signaling is a promising therapeutic target for the cytokine storm in COVID-19, because IL-6 is a major STAT3 stimulator, particularly during inflammation. We herein review the pathogenic mechanism and potential therapeutic targets of ARDS in COVID-19 patients.

Fig. 1

IL-6-STAT3 signaling is a potential therapeutic target for COVID-19 mediated by cytokine storm. SARS-CoV-2 enters cells via cell membrane-localized ACE2 depending on TMPRSS2 and CatB/L activities for viral S protein priming. The viral pathogen-associated molecular patterns trigger IL-6 production followed by activation of the NF-κB pathway via PRRs in both immune and non-immune cells, leading to an inflammatory response. On the other hand, upon the occupancy of ACE2 by SARS-CoV-2, the increased serum level of free Ang II due to a reduction of ACE2-mediated degradation also promotes activation of the NF-κB pathway via AT1R, followed by IL-6 production. Simultaneously, Ang II-AT1R signaling activates ADAM17 and ADAM10 protease activity, and the resulting production of TNF-α, sIL-6Rα, and EGF initiates the TNFR-NF-κB, IL-6R-STAT3, and EGF-NF-κB signaling pathways. Consequently, the concomitant inflammatory cascades of NF-κB- and STAT3-mediated signaling further augment NF-κB activity and establish an inflammatory circuit, the IL-6 amplifier (IL-6 AMP), which describes an IL-6-based positive feedback loop for inflammation in non-immune cells. Thus, the cytokine storm caused by the hyper-activation of NF-κB in IL-6 AMP may cause fatal symptoms such as ARDS, severe pneumonia, multiorgan failure, and coagulation in a subgroup of hospitalized COVID-19 patients. In line with this, the blockade of IL-6-STAT3 signaling should shed light on the treatment of severe COVID-19