How COVID-19 induces cytokine storm with high mortality
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(2020) 40:37
REVIEW
Inflammation and Regeneration
Open Access
How COVID-19 induces cytokine storm with high mortality Shintaro Hojyo1†, Mona Uchida1†, Kumiko Tanaka1, Rie Hasebe1, Yuki Tanaka1, Masaaki Murakami1* and Toshio Hirano1,2*
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 hyperactivation 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.
Background Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has globally spread to an ongoing pandemic since the first case of infection was reported in 2019. Patients with poor prognostic features upon hospital admission frequently encounter complications with significant mortality, particularly by acute respiratory distress syndrome (ARDS) with a broad spectrum of diseases such as multiorgan failure, and blood clots [1]. No effective vaccine strategy or approved medication for the treatment of this contagious disease has been established, although clinical trials are intensively being performed (https://clinicaltrials.gov/ct2/who_table). Accumulating evidence suggests that the severity of COVID-19 is associated with an increased level of inflammatory mediators including cytokines and * Correspondence: [email protected]; [email protected] † Shintaro Hojyo and Mona Uchida contributed equally to this work. 1 Molecular Psychoimmunology, Institute for Genetic Medicine, Graduate School of Medicine, Hokkaido University, Hokkaido 060-0815, Japan Full list of author information is available at the end of the article
chemokines such as interleukin (IL)-2, IL-7, IL-10, tumor necrosis factor (TNF), granulocyte colonystimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP1; also known as CCL2), macrophage inflammatory protein 1 alpha (MIP1α; also known as CCL3), CXC-chemokine ligand 10 (CXCL10), C-reactive protein, ferritin, and D-dimers in blood upon SARSCoV-2 infection [2–10]. Of note, among the elevated inflammatory mediators, the blood IL-6 level is highly correlated with the disease mortality when COVID-19 survivors and non-survivors are compared [1, 11], suggesting th
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