RIPK3 collaborates with GSDMD to drive tissue injury in lethal polymicrobial sepsis.

Cell Death and Differentiation
Hui ChenYanfang Xu

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 endoth...Continue Reading

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Citations

Sep 26, 2020·Frontiers in Cell and Developmental Biology·Benedikt KolbrinkStefan Krautwald
Mar 6, 2021·Cell Death and Differentiation·Yinshuang LiYanfang Xu
Mar 12, 2021·Nature Reviews. Drug Discovery·Xing LiuJudy Lieberman
May 25, 2021·International Journal of Cancer. Journal International Du Cancer·Mingxia JiangYanjing Li
Jun 3, 2021·Biomolecules·Emma C Tovey CrutchfieldJoanne M Hildebrand
Jul 13, 2021·Immunological Investigations·Cong WangMing Xu
Aug 3, 2021·Chinese Journal of Traumatology = Zhonghua Chuang Shang Za Zhi·Ruo-Xi ZhangDao-Lin Tang

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Methods Mentioned

BETA
PCR
X-ray
ELISA
Assay
protein assay
electrophoresis
transfection
FACS
flow cytometry

Software Mentioned

FlowJo
Image J
Prism
GraphPad

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