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Hypoxia-inducible factor 2α promotes pathogenic polarization of stem-like Th2 cells via modulation of phospholipid metabolism
Zou X. et al.
Immunity. 2024
Allergic asthma is a common chronic respiratory immune disease characterized by chronic inflammation and hyperresponsiveness of the airways, usually due to abnormal activation of helper type 2 T cells (Th2 cells) triggered by allergens. Currently, asthma afflicts more than 300 million people worldwide, and its prevalence continues to rise in many developed regions. Although existing medications, such as bronchodilators and glucocorticoids, are effective in relieving symptoms, they do not cure asthma and are often resistant to them, especially in some severely ill patients, which limits their therapeutic efficacy. Therefore, the development of novel therapeutic strategies has become a hot issue in asthma treatment research. This study not only reveals the critical role of HIF2α in the differentiation and function of pathogenic Th2 cells, but also provides experimental evidence and ideas on how to treat allergic asthma by precisely targeting HIF2α, which has significant clinical value. In addition, the results reveal that small molecule inhibitors of HIF2α have good potential for drug development and deserve further evaluation of their safety and efficacy in preclinical studies. It is reasonable to believe that targeting HIF2α will not only be limited to the treatment of asthma, but may also play an important role in the treatment of other type II immune-related diseases (e.g., allergic rhinitis, eczema, inflammatory bowel disease, etc.).
DOI: 10.1016/j.immuni.2024.11.001
02
Theobald H. et al.
Nat Immunol. 2024
In this study the authors developed an environmental exposure simulation model of intranasal β-glucan exposure and utilized single-cell transcriptomics, high-latitude imaging, and other techniques in conjunction with in vivo and in vitro cellular developmental and functional experiments in mice. Functionally, the authors found that a single intranasal β-glucan exposure induced pulmonary immune stress leading to a massive production of apolipoprotein E (ApoE)-dependent monocyte-derived alveolar macrophages (ApoE+CD11b+ AMs), a significant enhancement of the glycolytic capacity of ApoE+CD11b+ MoAM, which were highly phagocytic, and a reduction of the load after infection with Legionella pneumophila or alleviate the bleomycin-induced fibrosis phenotype. In terms of molecular mechanisms, ApoE+CD11b+ MoAM is regulated by the Dectin-1-CARD9 pathway, and the maintenance of ApoE+CD11b+ MoAM is dependent on paracrine ApoE and M-CSF. Therefore, in the present study, ApoE was identified as a low-grade inflammation-associated M-CSF triggered by the Dectin-1-CARD9 pathway in the lung immune-adaptive microenvironment. CSF-controlled monocyte-macrophage differentiation triggered by the Dectin-1-CARD9 pathway in the pulmonary immune-adaptive microenvironment.
DOI: 10.1038/s41590-024-01830-z
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