首页|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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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.
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
Department of Respiratory and Critical Care Medicine,Shanghai Pulmonary Hospital,Institute of Respiratory Medicine,School of Medicine,Tongji University,507 Zhengmin Road,Shanghai 200433,China
Ministry of Science and Technology of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaShanghai Science and Technology Innovation ActionShanghai Science and Technology Innovation ActionShanghai Science and Technology Innovation ActionKey Scientific Innovation project of the Shanghai Municipal Education CommissionYouth Innovation Promotion Association of the Chinese Academy of Sciences
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