Vitamin B6 regulates IL-33 homeostasis to alleviate type 2 inflammation
Vitamin B6 regulates IL-33 homeostasis to alleviate type 2 inflammation
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DOI：
10.1038/s41423-023-01029-6
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发表时间：
2023-05
影响因子：
24.1
通讯作者：
Songling Zhu;Shufen Zhong;K. Cheng;Li-sha Zhang;J. Bai;Zu Cao;Su Wang;Wen Chen;Shipeng Cheng;Liyan Ma;Z. Ling;Yuying Huang;Wangpeng Gu;Xiaoyu Sun;C. Yi;Meng Zhao;S. Liang;Jin-fu Xu;Bing Sun;Yaguang Zhang
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文献类型：
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作者：
Songling Zhu;Shufen Zhong;K. Cheng;Li-sha Zhang;J. Bai;Zu Cao;Su Wang;Wen Chen;Shipeng Cheng;Liyan Ma;Z. Ling;Yuying Huang;Wangpeng Gu;Xiaoyu Sun;C. Yi;Meng Zhao;S. Liang;Jin-fu Xu;Bing Sun;Yaguang Zhang
白介素33(IL-33)是一种重要的核因子，可诱导2型免疫应答，维持免疫稳态。IL-33在组织细胞中的微调调节对于控制呼吸道炎症中的2型免疫反应至关重要，但其机制尚不清楚。在这里，我们发现健康人血清中的磷酸盐-吡哆醛(PLP，维生素B6的一种活性形式)浓度高于哮喘患者。哮喘患者血清PLP浓度降低与肺功能恶化和炎症反应密切相关。在小鼠肺部炎症模型中，我们发现PLP可以减轻2型免疫反应，这种抑制作用依赖于IL-33的活性。一项机制研究表明，在体内，吡哆醛(PL)需要转化为PLP，PLP通过调节IL-33的稳定性来抑制2型反应。在PDXK杂合子小鼠中，PL向PLP的转化受到限制，肺组织中IL-33水平升高，从而加重了2型炎症。此外，我们还发现，小鼠双分钟2同源蛋白(MDM2)是一种E3泛素蛋白连接酶，可以泛素化IL-33的N末端，并维持IL-33在上皮细胞中的稳定性。PLP通过蛋白酶体途径减少MDM2介导的IL-33多泛素化，降低IL-33水平。此外，吸入PLP可减轻小鼠模型中与哮喘相关的影响。综上所述，我们的数据表明维生素B6调节MDM2介导的IL-33的稳定性以抑制2型反应，这可能有助于开发一种潜在的变态反应相关疾病的预防和治疗药物。
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.