Dephosphorylated polymerase I and transcript release factor prevents allergic asthma exacerbations by limiting IL-33 release
| Autor: | Yingmeng Ni, Jimin Hao, Xiaoxia Hou, Wei Du, Youchao Yu, Tiantian Chen, Zhuang Wei, Yangyang Li, Fuxiang Zhu, Shuaiwei Wang, Rui Liang, Dan Li, Yue Lu, Kan Liao, Bin Li, Guochao Shi |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
0301 basic medicine
lcsh:Immunologic diseases. Allergy Immunology Pathogenesis asthma exacerbation 03 medical and health sciences Immune system PTRF medicine Immunology and Allergy Secretion Sensitization Original Research Gene knockdown biology Chemistry respiratory system respiratory tract diseases Interleukin 33 Ovalbumin 030104 developmental biology medicine.anatomical_structure biology.protein IL33 airway epithelial cells lcsh:RC581-607 allergic asthma |
| Zdroj: | Frontiers in Immunology Frontiers in Immunology, Vol 9 (2018) |
| Popis: | Background: Asthma is a chronic inflammatory disease characterized by airway inflammation and airway hyperresponsiveness (AHR). IL-33 is considered as one of the most critical molecules in asthma pathogenesis. IL-33 is stored in nucleus and passively released during necrosis. But little is known about whether living cells can release IL-33 and how this process is regulated. Objective: We sought to investigate the role of polymerase I and transcript release factor (PTRF) in IL-33 release and asthma pathogenesis. Methods: Ovalbumin (OVA)-induced asthma model in PTRF+/− mice were employed to dissect the role of PTRF in vivo. Then, further in vitro experiments were carried out to unwind the potential mechanism involved. Results: In OVA asthma model with challenge phase, PTRF+/− mice showed a greater airway hyper-reaction, with an intense airway inflammation and more eosinophils in bronchoalveolar lavage fluid (BALF). Consistently, more acute type 2 immune response in lung and a higher IL-33 level in BALF were found in PTRF+/− mice. In OVA asthma model without challenge phase, airway inflammation and local type 2 immune responses were comparable between control mice and PTRF+/− mice. Knockdown of PTRF in 16HBE led to a significantly increased level of IL-33 in cell culture supernatants in response to LPS or HDM. Immunoprecipitation assay clarified Y158 as the major phosphorylation site of PTRF, which was also critical for the interaction of IL-33 and PTRF. Overexpression of dephosphorylated mutant Y158F of PTRF sequestered IL-33 in nucleus together with PTRF and limited IL-33 extracellular secretion. Conclusion: Partial loss of PTRF led to a greater AHR and potent type 2 immune responses during challenge phase of asthma model, without influencing the sensitization phase. PTRF phosphorylation status determined subcellular location of PTRF and, therefore, regulated IL-33 release. |
| Databáze: | OpenAIRE |
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