How COVID-19 induces cytokine storm with high mortality

Shintaro Hojyo, Mona Uchida, Kumiko Tanaka, Rie Hasebe, Yuki Tanaka, Masaaki Murakami, Toshio Hirano, Shintaro Hojyo, Mona Uchida, Kumiko Tanaka, Rie Hasebe, Yuki Tanaka, Masaaki Murakami, Toshio Hirano

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.

Conflict of interest statement

Competing interestsThe authors declare that they have no commercial or financial relationships that could be construed as a potential conflict of interest.

© The Author(s) 2020.

Figures

Fig. 1
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

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