| Autor: |
Pei-Ju Tsai, Wei-Chan Hsu, Ming-Yu Chen, Po-Chiang Chan, Cheng-Yuan Kao, Wen-Jye Lin, Tsung-Hsien Chuang, Su-Fang Lin, Guann-Yi Yu, Yu-Wen Su |
| Rok vydání: |
2023 |
| DOI: |
10.21203/rs.3.rs-2616509/v1 |
| Popis: |
Phosphatase and tensin homolog (PTEN) is a negative regulator for PI3K signaling essential for B cell development. To explore the physiological effects of PTEN mutation on peripheral B cells, we generated CD23/cre-PTENFlox/Flox (CD23-cKO) mice in this study to avoid the developmental arrest. The mutant mice develop systemic inflammation associated with B cell expansion in the early phase followed with a severe immune cell-infiltration in multiple vital organs. PTEN deficiency leads to an accumulation of PI(3)P, an increase of lysosomal recruitment of TLR9/p38 complex, and an aberrant activation of TLR9/IL-6 axis in B cells. Interestingly, cholesterol biosynthesis pathway is upregulated in mutant cells upon TLR9 engagement. A blockade of cholesterol biosynthesis by targeting SQLE greatly reduces the level of PI(3)P and the interaction between TLR9 and p38, which lowers the level of TLR9-induced IL-6. Thus, PTEN represents a critical metabolic checkpoint that fine-tunes lipid and cholesterol homeostasis to control TLR9-driven inflammation. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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