biostudies-literatureChen WIntramural NIH HHS1021-1030https://www.ebi.ac.uk/biostudies/studies/S-EPMC11345751biostudies-literatureUnknown23(7)Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.Nature immunologyAllergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion.PMC11345751ZIA AI001169Zhang DLong GMa LLu XZhang JSun BJiang HFu YWu BWu DZhang RIv HChen WChen SFan WChen MLv DLi XHuang YZhu JZhong SZhang YZhu LYan CLing ZZhu SfalseAllergen protease-activated stress granule assembly and gasdermin D fragmentation control interleukin-33 secretion.Interleukin-33 (IL-33), an epithelial cell-derived cytokine that responds rapidly to environmental insult, has a critical role in initiating airway inflammatory diseases. However, the molecular mechanism underlying IL-33 secretion following allergen exposure is not clear. Here, we found that two cell events were fundamental for IL-33 secretion after exposure to allergens. First, stress granule assembly activated by allergens licensed the nuclear-cytoplasmic transport of IL-33, but not the secretion of IL-33. Second, a neo-form murine amino-terminal p40 fragment gasdermin D (Gsdmd), whose generation was independent of inflammatory caspase-1 and caspase-11, dominated cytosolic secretion of IL-33 by forming pores in the cell membrane. Either the blockade of stress granule assembly or the abolishment of p40 production through amino acid mutation of residues 309-313 (ELRQQ) could efficiently prevent the release of IL-33 in murine epithelial cells. Our findings indicated that targeting stress granule disassembly and Gsdmd fragmentation could reduce IL-33-dependent allergic airway inflammation.2022-01-01T00:00:00Z2022 Jul2025-04-21T15:26:28.337Z2025-04-21T15:26:28.337ZS-EPMC113457513579436910.1038/s41590-022-01255-6