RIPK3 collaborates with GSDMD to drive tissue injury in lethal polymicrobial sepsis
- 9 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 27 (9), 2568-2585
- https://doi.org/10.1038/s41418-020-0524-1
Abstract
Sepsis is a systemic inflammatory disease causing life-threatening multi-organ dysfunction. Accumulating evidences suggest that two forms of programmed necrosis, necroptosis and pyroptosis triggered by the pathogen component lipopolysaccharide (LPS) and inflammatory cytokines, play important roles in the development of bacterial sepsis-induced shock and tissue injury. Sepsis-induced shock and tissue injury required receptor-interacting protein kinase-3 (RIPK3) and mixed lineage kinase domain-like protein (MLKL) phosphorylation, caspase11 activation and gasdermin D (GSDMD) cleavage. However, the synergistic effect of necroptosis and pyroptosis in the pathological progress of sepsis remains elusive. In this study, we found that blockage of both necroptosis and pyroptosis (double deletion of Ripk3/Gsdmd or Mlkl/Gsdmd) resulted in accumulative protection against septic shock, systemic blood clotting and multi-organ injury in mice. Bone marrow transplantation confirmed that necroptosis and pyroptosis in both myeloid and nonmyeloid cells are indispensable in the progression of sepsis-induced multi-organ injury. Both RIPK3 and GSDMD signaling collaborated to amplify necroinflammation and tissue factor release in macrophages and endothelial cells, which led to tissue injury. Furthermore, cell death induced by inflammatory cytokines and high-mobility group box 1 could be prevented by double ablation of Ripk3/Gsdmd or Mlkl/Gsdmd, suggesting that a positive feedback loop interconnecting RIPK3/MLKL and GSDMD machinery and inflammation facilitated sepsis progression. Collectively, our findings demonstrated that RIPK3-mediated necroptosis and GSDMD-mediated pyroptosis collaborated to amply inflammatory signaling and enhance tissue injury in the process of sepsis, which may shed new light on two potential targets of combined therapeutic interventions for this highly lethal disorder.Keywords
This publication has 47 references indexed in Scilit:
- Distinct roles of RIP1–RIP3 hetero- and RIP3–RIP3 homo-interaction in mediating necroptosisCell Death & Differentiation, 2014
- Systemic inflammatory response syndrome (SIRS)Virulence, 2013
- Inhibitor of Apoptosis Proteins Limit RIP3 Kinase-Dependent Interleukin-1 ActivationImmunity, 2012
- RIP Kinase-Dependent Necrosis Drives Lethal Systemic Inflammatory Response SyndromeImmunity, 2011
- Programmed necrosis: backup to and competitor with apoptosis in the immune systemNature Immunology, 2011
- The NLRP3 inflammasome in health and disease: the good, the bad and the uglyClinical and Experimental Immunology, 2011
- RIP3, an Energy Metabolism Regulator That Switches TNF-Induced Cell Death from Apoptosis to NecrosisScience, 2009
- Immunodesign of experimental sepsis by cecal ligation and punctureNature Protocols, 2008
- Increased ICAM-1 Expression Causes Endothelial Cell Leakiness, Cytoskeletal Reorganization and Junctional AlterationsJournal of Investigative Dermatology, 2007
- Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shockNature Immunology, 2003