| 1 | Vitamin B-reath easier:vitamin B6 derivatives reduce IL-33 to limit lung inflammation显示文摘It has been known for some time that low PLP blood levels are common in asthmatic patients,and supplementation with vitamin B6 may reduce the severity of asthma symptoms[12].In the current study,a comparison of PLP levels in the plasma of asthmatic patients(n=52)and healthy controls(n=58)confirmed lower PLP concentrations in asthmatic patients,which correlated with reduced lung function and increased circulating eosinophils,suggestive of increased type 2 inflammation.Using several mouse models of acute lung inflammation,they confirmed that systemic or local administration of PLP reduced lung inflammation and eosinophil density,suggesting that PLP concentration may be directly controlling immune responses that lead to the development of allergic airway disease.ILC2s constitutively express ST2,and IL-33 profoundly promotes ILC2 expansion and secretion of IL-5 and IL-13 to mediate allergic reactions and support host defenses against parasitic worms.PLP reduces the number of type 2 innate lymphoid cells(ILC2s)and their expression of IL-5 and IL-13.Conversely,diet-induced vitamin B6 deficiency in mice increased papain-induced lung inflammation,including increasing the proportion of IL5+and IL-13+ILC2s.The authors revealed that PLP treatment decreased IL-33 levels in the bronchoalveolar lavage fluid(BALF)and lung and targeting IL-33 with an antibody during papain-induced lung inflammation did not reduce inflammation beyond that of PLP treatment alone.An important clue to the regulation of IL-33 was that PLP treatment did not modify IL-33 mRNA levels.Instead,pyridoxal(PL)treatment of a human alveolar basal epithelial cell line(A549)stably expressing full-length IL-33 with a hemagglutinin(HA)tag established that PL exposure potently decreased intracellular IL-33 protein levels.The researchers used this cell line to explore the underlying mechanisms and verified that PL conversion to PLP by pyridoxal kinase(PDXK)controlled the stability of IL-33.Consistent with these data,the IL-33 concentration and papain-induced lung inflammation were augmented significantly in PDXK-deficient mice.The author’s use of degradative pathway inhibitors and truncated IL-33 constructs pinpointed a mechanism involving protective ubiquitylation of the IL-33 N-terminal domain that is inhibited by vitamin B6.A comprehensive database search for proteome-wide known and predicted ubiquitin ligase/deubiquitinase-substrate interactions showed that mouse double minute 2 homolog(MDM2)was a likely E3 ubiquitin ligase interacting with IL-33.Recent studies have shown that MDM2,while best known for its regulation of p53,mediates the ubiquitination and stability of numerous nuclear proteins,including Foxp3,HDACs,and STATs[13,14,15].In the current work,MDM2 interacted with IL-33 via a RING domain to facilitate IL-33 stability via ubiquitination of lysines to control IL-33 homeostasis,and this ubiquitination could be inhibited by vitamin B6(Fig.2).It will be important for future studies to establish how precisely PLP suppresses the functional interactions between IL-33 and MDM2. | Hēth R.Turnquist | 2023 | Cellular & Molecular Immunology2023，20，12： | 0 |
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