Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230022, China.
State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, 200031, China.
Cell Mol Immunol. 2023 Jul;20(7):794-807. doi: 10.1038/s41423-023-01029-6. Epub 2023 May 23.
Interleukin-33 (IL-33) is a crucial nuclear cytokine that induces the type 2 immune response and maintains immune homeostasis. The fine-tuned regulation of IL-33 in tissue cells is critical to control of the type 2 immune response in airway inflammation, but the mechanism is still unclear. Here, we found that healthy individuals had higher phosphate-pyridoxal (PLP, an active form of vitamin B6) concentrations in the serum than asthma patients. Lower serum PLP concentrations in asthma patients were strongly associated with worse lung function and inflammation. In a mouse model of lung inflammation, we revealed that PLP alleviated the type 2 immune response and that this inhibitory effect relied on the activity of IL-33. A mechanistic study showed that in vivo, pyridoxal (PL) needed to be converted into PLP, which inhibited the type 2 response by regulating IL-33 stability. In mice heterozygous for pyridoxal kinase (PDXK), the conversion of PL to PLP was limited, and IL-33 levels were increased in the lungs, aggravating type 2 inflammation. Furthermore, we found that the mouse double minute 2 homolog (MDM2) protein, an E3 ubiquitin-protein ligase, could ubiquitinate the N-terminus of IL-33 and sustain IL-33 stability in epithelial cells. PLP reduced MDM2-mediated IL-33 polyubiquitination and decreased the level of IL-33 through the proteasome pathway. In addition, inhalation of PLP alleviated asthma-related effects in mouse models. In summary, our data indicate that vitamin B6 regulates MDM2-mediated IL-33 stability to constrain the type 2 response, which might help develop a potential preventive and therapeutic agent for allergy-related diseases.
白细胞介素-33（IL-33）是一种重要的核细胞因子，可诱导 2 型免疫反应并维持免疫稳态。组织细胞中 IL-33 的精细调节对于控制气道炎症中的 2 型免疫反应至关重要，但机制尚不清楚。在这里，我们发现健康个体的血清中磷酸吡哆醛（PLP，维生素 B6 的活性形式）浓度高于哮喘患者。哮喘患者血清中 PLP 浓度较低与肺功能和炎症恶化密切相关。在肺炎症的小鼠模型中，我们揭示了 PLP 可缓解 2 型免疫反应，而这种抑制作用依赖于 IL-33 的活性。机制研究表明，体内，吡哆醛（PL）需要转化为 PLP，通过调节 IL-33 的稳定性来抑制 2 型反应。在吡哆醛激酶（PDXK）杂合子的小鼠中，PL 转化为 PLP 的速度受到限制，并且肺部的 IL-33 水平增加，加重了 2 型炎症。此外，我们发现双微体 2 同源物（MDM2）蛋白，一种 E3 泛素蛋白连接酶，可以泛素化 IL-33 的 N 端并维持上皮细胞中 IL-33 的稳定性。PLP 减少了 MDM2 介导的 IL-33 多泛素化，并通过蛋白酶体途径降低了 IL-33 的水平。此外，吸入 PLP 可减轻哮喘相关小鼠模型中的相关作用。总之，我们的数据表明维生素 B6 通过调节 MDM2 介导的 IL-33 稳定性来限制 2 型反应，这可能有助于开发治疗过敏相关疾病的潜在预防和治疗药物。
