Welcome to Wei Lab!
Laboratory Introduction
Wei lab belongs to Department of Immunology, School of Basic Medical Sciences, Fudan University. We study vascular immunology by focusing on non-coding RNAs and organelle interactions and attempt to get better understanding of macrophage phenotypic plasticity and pathophysiology of atherosclerosis. We cooperate with Prof. Le Kang's group in Guangzhou National Lab, and focus on the metabolic reprogramming of antigen presenting cells in HDM-induced allergic asthma.
魏园园课题组隶属于复旦大学基础医学院免疫学系。我们从事血管免疫学研究，从非编码RNA及细胞器互作的角度出发，着力于阐明巨噬细胞极化的分子调控机制、巨噬细胞能量代谢转换在动脉粥样硬化形成过程中的作用以及巨噬细胞在肥胖与动脉粥样硬化关系中的作用。我们与广州实验室康乐院士课题组合作，聚焦于抗原呈递细胞的代谢重编程在尘螨引起的过敏性哮喘中的作用。
New publications
Long non-coding RNAs (lncRNAs) represent crucial transcriptional and post-transcriptional gene regulators during antimicrobial responses in the host innate immune system. Studies have shown that lncRNAs are expressed in a highly tissue- and cell-specific- manner and are involved in the differentiation and function of innate immune cells, as well as inflammatory and antiviral processes, through versatile molecular mechanisms. These lncRNAs function via the interactions with DNA, RNA, or protein in either cis or trans pattern, relying on their specific sequences or their transcriptions and processing. The dysregulation of lncRNA function is associated with various human non-infectious diseases, such as inflammatory bowel disease, cardiovascular diseases, and diabetes mellitus. Here, we provide an overview of the regulation and mechanisms of lncRNA function in the development and differentiation of innate immune cells, and during the activation or repression of innate immune responses. These elucidations might be beneficial for the development of therapeutic strategies targeting inflammatory and innate immune-mediated diseases.
MicroRNAs (miRNAs) play a key role in fine-tuning host immune homeostasis and responses through the negative regulation of mRNA stability and translation. The pathways regulated by miRNAs are well characterized, but the precise mechanisms that control the miRNA-mediated regulation of gene expression during immune cell-development and immune responses to invading pathogens are incompletely understood. Context-specific interactions of miRNAs with
other RNA species or proteins may modulate the function of a given miRNA. Dysregulation of miRNA function is associated with various human diseases, such as cardiovascular diseases and cancers. Here, we review the potential modulators of miRNA function in the immune system,
including the transcription regulators of miRNA genes, miRNA-processing enzymes, factors affecting miRNA targeting, and intercellular communication.
Yunhui Jia & Yuanyuan Wei. Modulators of MicroRNA Function in the Immune System.
Int. J. Mol. Sci. 2020; 21(7): 2357.
Jia Y, Cheng L, Yang J, Mao J, Xie Y, Yang X,Zhang X, Wang D, Zhao Z, Schober A, Wei Y*. miR-223-3p Prevents
Necroptotic Macrophage Death by Targeting Ripk3 in a Negative Feedback Loop and Consequently Ameliorates Advanced Atherosclerosis. Arterioscler Thromb Vasc Biol. 2024 Jan;44(1):218-237.
Yang X, Zhang X, Tian Y, Yang J, Jia Y, Xie Y, Cheng L, Chen S, Wu L, Qin Y, Zhao Z, Zhao D, Wei Y*. Srsf3-Dependent APA Drives Macrophage Maturation and Limits Atherosclerosis. Circulation Research. 2025 Apr 25;136(9):985-1009.
BACKGROUND: The formation of large necrotic cores results in vulnerable atherosclerotic plaques, which can lead to severe cardiovascular diseases. However, the specific regulatory mechanisms underlying the development of necrotic cores remain unclear.
METHODS: To evaluate how the modes of lesional cell death are reprogrammed during the development of atherosclerosis, the expression levels of key proteins that are involved in the necroptotic, apoptotic, and pyroptotic pathways were compared between different stages of plaques in humans and mice. Luciferase assays and loss-of-function studies were performed to identify the microRNA-mediated regulatory mechanism that protects foamy macrophages from necroptotic cell death. The role of this mechanism in atherosclerosis was determined by using a knockout mouse model with perivascular drug administration and tail vein injection of microRNA inhibitors in Apoe −/− mice.
RESULTS: Here, we demonstrate that the necroptotic, rather than the apoptotic or pyroptotic, pathway is more activated in advanced unstable plaques compared with stable plaques in both humans and mice, which closely correlates with necrotic core formation. The upregulated expression of Ripk3 (receptor-interacting protein kinase 3) promotes the C/EBPβ (CCAAT/enhancer binding protein beta)-dependent transcription of the microRNA miR-223-3p, which conversely inhibits Ripk3 expression and forms a negative feedback loop to regulate the necroptosis of foamy macrophages. The knockout of the Mir223 gene in bone marrow cells accelerates atherosclerosis in Apoe −/− mice, but this effect can be rescued by Ripk3 deficiency or treatment with the necroptosis inhibitors necrostatin-1 and GSK-872. Like the Mir223 knockout, treating Apoe −/− mice with miR-223-3p inhibitors increases atherosclerosis.
CONCLUSIONS: Our study suggests that miR-223-3p expression in macrophages protects against atherosclerotic plaque rupture by limiting the formation of necrotic cores, thus providing a potential microRNA therapeutic candidate for atherosclerosis.
BACKGROUND:
Circulating monocytes largely contribute to macrophage buildup in atheromata, which is crucial for clearing subendothelial LDLs (low-density lipoproteins) and dead cells; however, the transitional trajectory from monocytes to macrophages in atherosclerotic plaques and the underlying
regulatory mechanism remain unclear. Moreover, the role of alternative polyadenylation, a posttranscriptional regulator of cell fate, in monocyte/macrophage fate decisions during atherogenesis is not entirely understood.
METHODS: To identify monocyte/macrophage subtypes in atherosclerotic lesions and the effect of alternative polyadenylation on these subtypes and atherogenesis, single-cell RNA sequencing, 3′-end sequencing, flow cytometric, and histopathologic analyses were performed on plaques obtained from Apoe−/− mouse arteries with or without myeloid deletion of Srsf3(serine/ arginine-rich splicing factor 3). L-azidohomoalanine metabolic labeling assay, and metabolomic profiling were conducted to disclose the underlying mechanisms. Reprogramming of widespread alternative
polyadenylation patterns was estimated in human plaques via bulk RNA sequencing.
RESULTS:
We identified a subset of lesional cells in a monocyte-to-macrophage transitional state, which exhibited high expression of chemokines in mice. Srsf3 deletion caused a maturation delay of these transitional cells and phagocytic impairment of lesional macrophages, aggravating atherosclerosis. Mechanistically, Srsf3 deficiency shortened 3′ untranslated regions of mitochondria-associated Aars2 (alanyl-tRNA synthetase2), disrupting its translation. The resultant impairment of protein synthesis in mitochondria led to mitochondrial dysfunction with declined NAD+ levels,activation of the integrated stress response, and metabolic reprogramming in macrophages. Administering an NAD+ precursor nicotinamide mononucleotide or the integrated stress response inhibitor partially restored Srsf3-deficient macrophage maturation, and nicotinamide mononucleotide treatment mitigated the proatherosclerotic effects of Srsf3 deficiency.Consistently, Srsf3 downregulation, global 3′ untranslated region shortening, and
accumulation of these transitional macrophages were associated with atherosclerosis progression in humans.
CONCLUSIONS:
Our study reveals that Srsf3-dependent generation of long 3′ untranslated region is required for efficient mitochondrial translation, which promotes mature phagocytic macrophage formation, thereby playing a protective role in atherosclerosis.
Current reaesrch interest
Atherosclerosis is a leading -but potentially preventable- cause of death and disability worldwide resulting in devastating diseases, such as myocardial infarction due to coronary artery disease or stroke. The current concept of atherogenesis includes a central role of apolipoprotein B-containing lipoproteins, such as LDL or remnant lipoproteins, which trigger a chronic inflammatory response of the vessel wall dominated by the infiltration of monocyte-derived macrophages. Multiple stimuli, including cytokines, chemokines and modified lipoproteins, may dynamically modulate the macrophage phenotype in atherosclerotic lesions. Our lab aims to understand how macrophage phenotype is regulated during atherosclerosis progression, and figure out the potential therapeutic application of targeting macrophages in atherosclerosis.
Regulatory RNAs in macrophages and atherosclerosis
Our research has found that regulatory RNAs, such as miRNAs, play crucial roles in atherosclerosis by regulating macrophage polarization and metabolism. However, how regulatory RNA functions are modulated in macrophages during atherosclerosis progression is still unknown.
Metabolic reprogramming of antigen presenting cells in HDM induced allergic asthma
When encountered with allergen, antigen presenting cells are not only activated to priming type 2 immune response, but also accompanied with metabolic reprogramming. How the immune reaction type is influenced by the metabolic changes of antigen presenting cells is not well-understood.
Contribution of organelle interactions to macrophage functions
and atherosclerosis progression
It is known that organelles communicate with each other to maintain cellular homeostasis. However, how signals are transduced among organelles to determine the immune functions of macrophages has not been clear yet.
Lab news
2023-8 热烈祝贺课题组博士后解玉怀博士获得国自然青年项目(2024-2026)资助！
2023-10 祝贺课题组第一个博士研究生贾云慧顺利完成学位答辩！
2025-5 祝贺课题组博士研究生程连平、张鑫顺利完成学位答辩！
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