Specific inhibition of SHP2 suppressed abdominal aortic aneurysm formation in mice by augmenting the immunosuppressive function of MDSCs
Yonggang Lu, Qian Ma, He Tan, Xinxin Li, Xue Zhang, Yanqing TieLife Sciences2021
Aims: To address the roles of SHP2 in regulating angiotensin II (Ang II) induced abdominal aortic aneurysm (AAA) and the potential molecular mechanisms. Main methods: AAA model was established in apolipoprotein E-deficient (apoE−/−) mice infused with Ang II. Suprarenal aortic luminal diameters were ultrasonically measured to determine the presentation of AAA in mice. The inflammatory and immunosuppressive factors in serum were detected by ELISA. AAA lesion size, positive macrophages and elastic laminae degradation were examined by histological analysis. Myeloid-derived suppressor cells (MDSCs) were measured by flow cytometry after magnetic bead sorting. Bioinformatics analysis was applied to screen the crucial genes related the progression of AAA. Key findings: Treatment with PHPS1 (SHP2 inhibitor) significantly decreased the vascular diameter of AAA. Histological analysis showed that PHPS1 obviously reduced the Masson positive area, macrophages positive area, as well as the damage rate of elastic laminae. Moreover, PHPS1 suppressed the expression of INF-γ, TNF-α and MMPs, as well as elevated IL-10 and arginase-1 expression. Additionally, PHPS1 enhanced the expression of granulocytic MDSCs (G-MDSCs). By consulting with bioinformatics, STAT3 was selected. In G-MDSCs, PHPS1 stimulation obviously increased the phosphorylation level of STAT3, as well as elevated the protein expression of C/EBPβ and arginase-1. However, the above phenomena can be blocked after Stattic (STAT3 inhibitor) treatment. Significance: SHP2 may affect the AAA progression by interfering with expansion and function of MDSCs to regulate the body immunity, which might afford a novel direction for the treatment of patients with AAA.