Il-33 Inhibits Abdominal Aortic Aneurysm Formation Through the Pparγ-Ra Signaling Pathway

Objective: To explore the mechanism of IL-33 inhibiting aneurysms by detecting the key mechanism of phenotypic transformation of cells. To confirm the potential therapeutic function of IL-33 in a rat aortic pericardial patch angioplasty induced aneurysm model.Materials and methods: Based on the fact that IL-33 can promote M2 polarization, this study explored the related mechanisms of IL-33 based on the polarization of macrophages. First, we obtained transcriptome, proteome, and phosphorylated proteome data related to the polarization of macrophages induced by IL4 and LPS. WGCNA was used to obtain key proteins in macrophage M2 polarization induced by IL4. Time-course phosphoproteomics data were processed using gene-centric analysis to identify key proteins. Further, pathways were identified by enrichment analysis. Combined with the GSEA and KEGG pathway diagrams, we constructed the IL-33/ERK/PPARγ/RA signaling pathway. Vascular smooth muscle cells (VSMCs) were also regulated by this mechanism based on AAA scRNA-seq, and cell trajectory analysis was used to explore the regulatory effect of this pathway on VSMCs. Human AAA samples were stained by EVG and immunohistochemistry. S-D rat pericardial patch angioplasty induced aneurysm model was used, control and IL-33 coated patches were implanted in the rat aorta and harvested at day 30; samples were stained by histology, immunohistochemistry, and immunofluorescence.Results: Retinoic acid pathway plays a key role in the M2 polarization of macrophages, which also maintaining VSMC homeostasis. IL-33 can activate ERK/PPAR pathway, activate the retinoic acid pathway, and block endoplasmic reticulum (ER) stress. In human and rat, IL-33-RA pathway markers were significantly increased in AAA; the ER stress markers were aslo significantly increased in the AAA compared to the aorta. IL-33 coated patch can decrease AAA formation, promote M2 macrophages polarization and inhibit M1 polarization; IL-33 can also maintain VSMCs homeostasis, and inhibit secretory transformation by activating PPARγ -RA pathway.Conclusion: IL-33 activates the ERK/PPAR/ retinoic acid pathway, promotes macrophage M2 polarization, inhibits macrophage M1 polarization by inhibiting ER stress; IL-33 can also maintains VSMCs homeostasis, and inhibits secretory VSMCs transformation. IL-33 can effectively inhibit AAA formation in rat, it may be a potential therapeutic target in clinic.Funding Information: This study was funded by the National Natural Science Foundation of China (Grant No: 81870369), Health Science and Technology Innovation Fund for Distinguished Young Scholars of Henan Province (YXKC2021040), Introducing Foreign Intelligence Project of Henan Province (HNGD2022029). Declaration of Interests: Authors declare that they have no conflict of interest.Ethics Approval Statement: All protocols involving human biospecimens complied with all relevant ethical regulations, and informed consent was not needed. The study was approved by the Ethics Committee of First Affiliated Hospital of Zhengzhou University. Since the samples used were discarded samples, so there is no need for the informed consent.