A critical role for MALAT1 in gram-negative bacteria-induced coagulation via regulation of caspase-11 signaling

Our previous animal studies suggested the critical role of the type I interferon (IFNβ) and high-mobility group box 1 (HMGB1) axis in coagulation; however, the predictive value of IFNβ/HMGB1 for the clinical onset of septic disseminated intravascular coagulation (DIC) remains unknown.

This study aimed to further elaborate on the pathogenesis of sepsis-associated DIC and identify potential biomarkers suitable for the early prediction of DIC.

IFNβ/HMGB1 plasma levels were measured in septic patients without DIC at admission. The onset of septic DIC was assessed 48 hours thereafter. We subsequently compared the leukocyte transcriptomes of patients with and without DIC. A series of genetically modified mice, including IFNα/βR1^-/-, Tlr4^-/-, Malat1^-/-, Casp1^-/-, and Casp11^-/- mice, as well as Malat1^flox/flox or Gpx4^flox/flox in combination with Cdh5-, Alb-, Vav- and Lyz2-Cre mice, were used to investigate the mechanisms.

The plasma level of IFNβ but not HMGB1 in septic patients showed a consistent correlation with the onset of DIC. We identified an HMGB1-bypassing signaling pathway in which IFNβ stimulates macrophages to express high levels of the long noncoding RNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in response to gram-negative bacteria. Deletion of Malat1 specifically in macrophages restored glutathione exhaustion and enhanced glutathione peroxidase 4 activity by maintaining Yin-Yang 1-mediated Hba-a1 expression, which dampens lipopolysaccharide internalization and caspase-11 activation, and suppressed caspase-11/GSDMD-dependent phosphatidylserine exposure, thereby protecting against bacteria-induced coagulation.

Our study unveils a novel immunocoagulation pathway in which MALAT1 fuels caspase-11-dependent coagulation by inhibiting glutathione peroxidase 4 activity, which provides new insights into the coagulation mechanisms in bacterial sepsis.