Caspase-12 exhibits non-redundant functions in response to endoplasmic reticulum stress to promote GSDMD-mediated NETosis, leading to thoracic aortic dissection.

BACKGROUND

Thoracic aortic dissection (TAD) is a highly lethal condition that is characterized by inflammatory cell infiltration. Recent evidence has indicated that Gasdermin D (GSDMD) plays an important role in vascular inflammation and degeneration. However, its effects on neutrophil extracellular trap formation and release (NETosis) during TAD remain unknown.

METHODS

A TAD mouse model was generated using four-week-old male neutrophil-specific GSDMD-knockout mice (GSDMDF/F; ElaneCre) and dimethyl fumarate (DMF)-treated C57BL/6J mice by administering β-aminopropionitrile monofumarate (BAPN; 1 g/kg/day) in their drinking water for 4 weeks. Immunoprecipitation and immunofluorescence assays were performed to examine the role of the endoplasmic reticulum (ER) and its associated protein, caspase-12, in GSDMD-induced NETosis.

RESULTS

GSDMD was elevated and co-localized primarily in neutrophils in the aortic tissues of patients with TAD and mice with BAPN-induced TAD. This was accompanied by increased NETosis. Neutrophil-specific GSDMD knockout and the NETosis inhibitor, GSK484, mitigated TAD development in mice. However, GSK484 did not provide additional therapeutic effects against TAD in the neutrophil-specific, GSDMD knockout mice. Mechanistically, ER stress promoted GSDMD cleavage by caspase-4/11, thereby inducing NETosis. Furthermore, caspase-12 exhibited non-redundant functions in the cleavage of GSDMD by caspase-4/11. The GSDMD inhibitor, DMF, partially prevented TAD development.

CONCLUSIONS

The ER stress/GSDMD/NETosis signaling pathway provides a potential therapeutic target for the prevention and treatment of TAD.