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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.

Dephosphorylated Polymerase I and Transcript Release Factor Prevents Allergic Asthma Exacerbations by Limiting IL-33 Release