COVID-19 is associated with liver injury and elevated IL-6. We hypothesized that IL-6 trans-signaling in liver sinusoidal endothelial cells (LSECs) leads to endotheliopathy (a proinflammatory and procoagulant state) and liver injury in COVID-19.Coagulopathy, endotheliopathy, and ALT were retrospectively analyzed in a subset (n=68), followed by a larger cohort(n=3,780) of COVID-19 patients. Liver histology from 43 COVID-19 patients was analyzed for endotheliopathy and its relationship to liver injury. Primary human LSECs were used to establish the IL-6 trans-signaling mechanism.Factor VIII, fibrinogen, D-dimer, vWF activity/antigen (biomarkers of coagulopathy/endotheliopathy) were significantly elevated in COVID-19 patients with liver injury (elevated ALT). IL-6 positively correlated with vWF antigen(P=0.02), factor VIII activity(P=0.02), and D-dimer(P<0.0001). On liver histology, COVID-19 patients with elevated ALT had significantly increased vWF and platelet staining, supporting a link between liver injury, coagulopathy, and endotheliopathy. Intralobular neutrophils positively correlated with platelet(P<0.0001) and vWF(P<0.01) staining, and IL-6 levels positively correlated with vWF staining(P<0.01). IL-6 trans-signaling leads to increased expression of procoagulant (Factor VIII, vWF) and proinflammatory factors, increased cell surface vWF(P<0.01), and increased platelet attachment in LSECs. These effects were blocked by soluble gp130 (IL-6 trans-signaling inhibitor), JAK inhibitor Ruxolitinib, and STAT1/3 siRNA knockdown. Hepatocyte fibrinogen expression was increased by the supernatant of LSECs subjected to IL-6 trans-signaling.COVID-19 is associated with coagulopathy and endotheliopathy in the liver endothelium driven by IL-6 trans-signaling, a possible mechanism of liver injury.Patients with SARS-CoV-2 infection often have liver injury, but why this occurs remains unknown. High levels of interleukin-6 (IL-6) and its circulating receptor, which form a complex to induce inflammatory signals, have been observed in COVID-19 patients. This paper demonstrates that the IL-6 signaling complex causes harmful changes to liver sinusoidal endothelial cells and may promote blood clotting and contribute to liver injury.
Matthew J McConnell, Nao Kawaguchi, Reiichiro Kondo, Aurelio Sonzogni, Lisa Licini, Clarissa Valle, Pietro A Bonaffini, Sandro Sironi, Maria Grazia Alessio, Giulia Previtali, Michela Seghezzi, Xuchen Zhang, Alfred Lee, Alexander B Pine, Hyung J Chun, Xinbo Zhang, Carlos Fernandez-Hernando, Hua Qing, Andrew Wang, Christina Price, Zhaoli Sun, Teruo Utsumi, John Hwa, Mario Strazzabosco, Yasuko Iwakiri