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Endothelial caspase‐11 induces endothelial pyroptosis and lung vascular injury
Author(s) -
Xiong Shiqin,
Cheng Kwong Tai,
Rehman Jalees,
Malik Asrar B
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.825.9
Subject(s) - pyroptosis , inflammation , endothelial stem cell , caspase 1 , lipopolysaccharide , vascular permeability , immunology , medicine , inflammasome , chemistry , microbiology and biotechnology , biology , pathology , biochemistry , in vitro
Sepsis‐induced acute lung injury (ALI) results in increased lung vascular permeability, endothelial cell death, enhanced polymorphonuclear neutrophil (PMN) sequestration, and lung inflammation. Pyroptosis is a form of rapid cell death mediated by caspase‐11 and activated by bacterial endotoxin (lipopolysaccharide or LPS) breaching the plasmalemma which has been primarily studied in phagocytic cells such as macrophages or neutrophils. The potential role of pyroptosis as a mediator of endothelial cell death and enhanced vascular permeability during ALI is not clear. Here we show that lung microvascular endothelial cells (EC) internalized LPS and induced pyroptosis of ECs as characterized by EC lysis, interleukin‐1β generation, and gasdermin D cleavage. Caspase‐11 but not toll‐like receptor 4 (TLR4) was required for the induction of EC pyroptosis. Pyroptosis was evident by gasdermin D cleavage in lungs from WT mice but not in EC‐specific caspase‐11 EC − / − mice. EC injury, pulmonary edema and PMN sequestration induced by LPS were prevented in caspase‐11 EC − / − mice when compared to control group, indicating that the EC‐expressed caspase‐11 was responsible for the ALI. Thus, activation of caspase‐11 in ECs, and consequent induction of EC pyroptosis, is a primary mechanism of ALI pathophysiology. Support or Funding Information T32‐HL007829, HL090152, HL118068.