Nur77 Attenuates Inflammasome Activation by Inhibiting Caspase-1 Expression in Pulmonary Vascular Endothelial Cells

Am J Respir Cell Mol Biol. 2021 Sep;65(3):288-299. doi: 10.1165/rcmb.2020-0524OC.


Inflammasomes are intracellular multiprotein complexes that help trigger and maintain the inflammatory response as part of the innate immune system. Recently, it has been increasingly recognized that aberrant inflammasome activation is critically involved in endothelial dysfunction in a variety of human diseases, such as atherosclerosis, acute lung injury (ALI), and type 2 diabetes. The molecular mechanisms underlying endothelial inflammasome activation, however, have not been completely elucidated. In the present study, we identified orphan nuclear receptor Nur77 as a novel regulator in controlling inflammasome activation in vascular endothelial cells (ECs). We demonstrated that LPS-induced inflammasome activation was significantly inhibited by ectopic overexpression of Nur77, predominantly through transcriptional suppression of caspase-1 expression in vascular ECs. Consistent with this observation, we found that LPS-induced inflammasome activation was significantly augmented in lung ECs isolated from Nur77-knockout mice. Mechanistically, we showed that Nur77-induced inhibition of caspase-1 expression was due to an inhibition of IRF1 (IFN regulatory factor 1) expression and its subsequent binding to the caspase-1 promoter. Importantly, in a mouse model of LPS-induced ALI, Nur77 knockout led to a marked activation of caspase-1 in the lung, increased alveolar and circulating IL-1β levels, and exacerbated ALI, all of which were substantially inhibited by administration of caspase-1 inhibitor. Together, our results support the presence of an important role for Nur77 in controlling inflammasome activation in vascular ECs and suggest that Nur77 could be a novel therapeutic target for the treatment of human diseases associated with aberrant inflammasome activation, such as ALI and atherosclerosis.

Keywords: IFN regulatory factor 1; Nur77; acute lung injury; caspase-1; inflammasome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / genetics
  • Acute Lung Injury / metabolism
  • Animals
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism
  • Caspase 1 / biosynthesis*
  • Caspase 1 / genetics
  • Diabetes Mellitus, Type 2 / genetics
  • Diabetes Mellitus, Type 2 / metabolism
  • Gene Expression Regulation, Enzymologic*
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Inflammasomes / genetics
  • Inflammasomes / metabolism*
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / metabolism
  • Mice
  • Mice, Knockout
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / genetics
  • Nuclear Receptor Subfamily 4, Group A, Member 1 / metabolism*


  • IRF1 protein, human
  • Inflammasomes
  • Interferon Regulatory Factor-1
  • Irf1 protein, mouse
  • NR4A1 protein, human
  • Nr4a1 protein, mouse
  • Nuclear Receptor Subfamily 4, Group A, Member 1
  • Casp1 protein, mouse
  • Caspase 1