BACKGROUND/AIMS: Sepsis is a systemic inflammatory response during infection. There are limited therapeutic options for sepsis patients. Interleukin (IL)-33 has been reported recently with a beneficial effect in mouse sepsis. METHODS: In this study, we initiated a clinical study to measure serum levels of pro-inflammatory cytokines including IL-33 in sepsis patients. Next, we employed cecal ligation and puncture (CLP) to study the role of IL-33 during sepsis. To further dissect the molecular mechanism, we used in vivo knockout models and in vitro knockdown murine embryonic fibroblasts (MEFs) to investigate the cross-talk between IL-33 and IL-17 signaling, and to identify the potential downstream mediators. RESULTS: IL-33 and IL-17 were upregulated in both clinical and experimental sepsis. In CLP, IL-33 (-/-) mice showed higher mortality rate, and IL-33 treatment improved the survival rate. Elevated proinflammatory cytokines in sepsis were related to IL-17 from γδT cells. IL-33 treatment suppressed production of these cytokines by targeting IL-17 signaling both in vivo and in vitro. Finally, IL-33 was shown to inhibit the IL-17 pathway via activating suppressor of cytokine signaling (SOCS)-3. CONCLUSION: Collectively, the results suggest that IL-33 plays a negative regulatory role in sepsis progression by inhibiting IL-17 pathway through activating SOCS3. This finding would inspire a new therapeutic strategy for treating sepsis.
BACKGROUND/AIMS: Sepsis is a systemic inflammatory response during infection. There are limited therapeutic options for sepsispatients. Interleukin (IL)-33 has been reported recently with a beneficial effect in mousesepsis. METHODS: In this study, we initiated a clinical study to measure serum levels of pro-inflammatory cytokines including IL-33 in sepsispatients. Next, we employed cecal ligation and puncture (CLP) to study the role of IL-33 during sepsis. To further dissect the molecular mechanism, we used in vivo knockout models and in vitro knockdown murine embryonic fibroblasts (MEFs) to investigate the cross-talk between IL-33 and IL-17 signaling, and to identify the potential downstream mediators. RESULTS:IL-33 and IL-17 were upregulated in both clinical and experimental sepsis. In CLP, IL-33 (-/-) mice showed higher mortality rate, and IL-33 treatment improved the survival rate. Elevated proinflammatory cytokines in sepsis were related to IL-17 from γδT cells. IL-33 treatment suppressed production of these cytokines by targeting IL-17 signaling both in vivo and in vitro. Finally, IL-33 was shown to inhibit the IL-17 pathway via activating suppressor of cytokine signaling (SOCS)-3. CONCLUSION: Collectively, the results suggest that IL-33 plays a negative regulatory role in sepsis progression by inhibiting IL-17 pathway through activating SOCS3. This finding would inspire a new therapeutic strategy for treating sepsis.
Authors: Paulette A Krishack; Tyler J Louviere; Trevor S Decker; Timothy G Kuzel; Jared A Greenberg; Daniel F Camacho; Cara L Hrusch; Anne I Sperling; Philip A Verhoef Journal: JCI Insight Date: 2019-03-21
Authors: Ivan Ramirez-Moral; Dana C Blok; Jochem H Bernink; M Isabel Garcia-Laorden; Sandrine Florquin; Louis Boon; Cornelis Van't Veer; Matthias Mack; Simona Saluzzo; Sylvia Knapp; Hergen Spits; Alex F de Vos; Tom van der Poll Journal: J Pathol Date: 2021-01-19 Impact factor: 7.996