Macrophage-derived GSDMD promotes abdominal aortic aneurysm and aortic smooth muscle cells pyroptosis

Macrophage is a vital factor in determining the fate of abdominal aortic aneurysm (AAA). The crosstalk between macrophage and other cells plays a crucial role in the development of aneurysm. Gasdermin D (GSDMD) is a vital executive protein of pyroptosis, which is a novel programmed cell death associated with inflammation. In this study, we identified aortic macrophage as the main expressing cell of GSDMD in AAA. Using Gsdmd-/-ApoE-/- mouse and AAV-F4/80-shGSDMD, we demonstrated the potential role of macrophage-derived GSDMD in AAA and aortic pyroptosis induced by Ang II in vivo. In vitro experiments showed that GSDMD promotes the pyroptosis of mouse primary peritoneal macrophages (MPMs), murine aortic vascular smooth muscle cells (MOVAS) and primary smooth muscle cells. Mechanistically, a mouse cytokine antibody array showed that Gsdmd-/- inhibited LPS + nigericin (LN)- induced secretion of multiple cytokines from MPMs. Furthermore, GSDMD is involved in the crosstalk between MPMs and MOVAS via cytokine secretion. This study provides a novel fundamental insight into macrophage-derived GSDMD in AAA and showed that GSDMD could be a promising therapeutic target for AAA.