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Nature Immunology:molecular cell Excellence Center, etc. reveal the new mechanism of allergen regulating the release of IL-33 from lung epithelial cells

On July 6, Nature Immunology published online the research results completed by the sun Bing research group of the molecular and cell science excellence and innovation center of the Chinese Academy of Sciences in cooperation with the Affiliated Hospital of Guangdong Medical University (allergens protections activated stress granules assembly and gsdmd fragmentation control IL-33 secret). This study revealed the molecular mechanism of IL-33 release from epithelial cells during allergen protease induced type II immune response. Studies have shown that protease exposure activates epithelial cells independent of eIF2 α (eukaryotic initiation factor 2 α) Phosphorylated stress particles (SGS) are assembled to promote the nucleocytoplasmic transport of IL-33; Protease stimulation induces cells to produce a new gasdermin D (gsdmd) N-terminal shear P40 functional fragment, which can form pores on the cell membrane and directly promote the release of cytoplasmic IL-33 outside the cell. These two mechanisms jointly and effectively regulate the secretion of IL-33 in the nucleus, and propose a new treatment strategy for the intervention of IL-33 dependent airway allergic diseases.

Mechanism of gsdmd regulating the release of IL-1 family proteins

Respiratory allergic diseases such as asthma and hay fever (allergic rhinitis) are common diseases that perplex human beings. These diseases are usually aggravated and worsened when patients are exposed to allergens such as dust mites, molds, bacteria, plant pollen and animal dander. The protease active components in allergens are important pathogenic factors. A variety of serine proteases and cysteine proteases from dust mites (HDM), Aspergillus fumigatus and Bacillus licheniformis have been reported to efficiently induce the release of interleukin 33 (IL-33) in vivo and in vitro. IL-33 is a type II inflammatory factor that is constitutively expressed and located in the nucleus. It can quickly respond to environmental damage stimulation and release it outside the cell, thus triggering allergic inflammatory response. It plays a key role in triggering respiratory inflammatory diseases such as asthma. Although the extracellular function of IL-33 has been widely reported, little is known about how it responds to the stimulation of external damage signals (including protease) and then releases from the nucleus to the outside of the cell.

This study established a mouse lung allergy model induced by allergen protease and a cell model of IL-33 release from human lung epithelial cells. In vitro studies have found that IL-33 can be rapidly released into the cells in response to the stimulation of a variety of allergen proteases within 30 minutes. This process is accompanied by the activation of gsdmd protein with cell death function, that is, the production of a new form of N-terminal shear P40, but not with obvious cell death. This phenomenon also exists in immune cells such as macrophages (bone marrow-derived macrophages). Knockout of gsdmd in macrophages can significantly inhibit the release of IL-33 stimulated by allergen protease, and the cleavage of gsdmd P40 and the release of IL-33 do not depend on the classical inflammatory caspase family protease, so this is a newly discovered pathway of gsdmd cleavage activation. Further mechanism research shows that allergen protease can quickly induce the assembly and activation of cell stress granules, and then promote the nucleocytoplasmic transfer of IL-33. IL-33 entering the cytoplasm cannot be directly released, but needs the help of gsdmd P40 induced by allergen protease to be released outside the cell. Various allergen proteases can induce the assembly of emergency particles, but they are different from the classical eIF2 α- P-dependent emergency particle assembly, allergen protease promotes eIF2 α Degradation, thereby promoting emergency particle assembly. Use eIF2 α Actinomycin D, an inhibitor of cytokines, can effectively inhibit the release of IL-33 induced by allergen protease. It was found that in mice, the expression of gsdmd protein increased in the lungs of mice with HDM induced type II immune response. Knockout of gsdmd in mice can effectively inhibit the airway immune response induced by HDM and papain. In asthmatic patients, the study also observed that the lung expression of gsdmd was positively correlated with IL-33 in lung lavage fluid and IgE in blood, suggesting that inhibiting gsdmd protein cleavage may be a new strategy for the treatment of type II immune response.

The research work was supported by the National Natural Science Foundation of China, the Ministry of science and technology, the Shanghai Science and technology innovation action plan, and the animal experiment technology platform/chemical biology platform/cell biology platform/molecular biology platform of the public technology service center of the molecular cell Excellence Center.

Original link:https://www.nature.com/articles/s41590-022-01255-6