Caspase 6 promotes innate immune activation by functional crosstalk between RIPK1-IκBα axis in liver inflammation

Cell Commun Signal. 2023 Oct 12;21(1):282. doi: 10.1186/s12964-023-01287-x.

Abstract

Background: Caspase 6 is an essential regulator in innate immunity, inflammasome activation and host defense. We aimed to characterize the causal mechanism of Caspase 6 in liver sterile inflammatory injury.

Methods: Human liver tissues were harvested from patients undergoing ischemia-related hepatectomy to evaluate Caspase 6 expression. Subsequently, we created Caspase 6-knockout (Caspase 6KO) mice to analyze roles and molecular mechanisms of macrophage Caspase 6 in murine models of liver ischemia/reperfusion (IR) injury.

Results: In human liver biopsies, Caspase 6 expression was positively correlated with more severe histopathological injury and higher serum ALT/AST level at one day postoperatively. Moreover, Caspase 6 was mainly elevated in macrophages but not hepatocytes in ischemic livers. Unlike in controls, the Caspase 6-deficient livers were protected against IR injury, as evidenced by inhibition of inflammation, oxidative stress and iron overload. Disruption of macrophage NF-κB essential modulator (NEMO) in Caspase 6-deficient livers deteriorated liver inflammation and ferroptosis. Mechanistically, Caspase 6 deficiency spurred NEMO-mediated IκBα phosphorylation in macrophage. Then phosphorylated-inhibitor of NF-κBα (p-IκBα) co-localized with receptor-interacting serine/ threonine-protein kinase 1 (RIPK1) in the cytoplasm to degradate RIPK1 under inflammatory conditions. The disruption of RIPK1-IκBα interaction preserved RIPK1 degradation, triggering downstream apoptosis signal-regulating kinase 1 (ASK1) phosphorylation and inciting NIMA-related kinase 7/NOD-like receptor family pyrin domain containing 3 (NEK7/NLRP3) activation in macrophages. Moreover, ablation of macrophage RIPK1 or ASK1 diminished NEK7/NLRP3-driven inflammatory response and dampened hepatocyte ferroptosis by reducing HMGB1 release from macrophages.

Conclusions: Our findings underscore a novel mechanism of Caspase 6 mediated RIPK1-IκBα interaction in regulating macrophage NEK7/NLRP3 function and hepatocytes ferroptosis, which provides therapeutic targets for clinical liver IR injury. Video Abstract.

Keywords: Caspase 6; Ferroptosis; Innate immunity; Liver Ischemia reperfusion.

Publication types

  • Research Support, Non-U.S. Gov't
  • Video-Audio Media

MeSH terms

  • Animals
  • Caspase 6* / metabolism
  • Humans
  • Immunity, Innate*
  • Inflammation / metabolism
  • Ischemia / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • NF-KappaB Inhibitor alpha / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
  • Proteins / metabolism
  • Receptor-Interacting Protein Serine-Threonine Kinases / metabolism
  • Signal Transduction*

Substances

  • Caspase 6
  • NF-KappaB Inhibitor alpha
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Proteins
  • Receptor-Interacting Protein Serine-Threonine Kinases
  • RIPK1 protein, human