Mus musculus Raw sequence reads

Alveolar epithelial type II (AT2) cells participate in epithelial repair following injury and contribute to lung immune defense by producing surfactant proteins. These cells also secrete various proinflammatory cytokines and chemokines, which may exacerbate disease severity. However, the detailed molecular mechanisms through which AT2 cells regulate inflammatory immune responses in asthma remain unclear. Here, we identify that chemokine (C-C motif) ligand 8 (CCL8) is increased in AT2 cells of asthma, which drives inflammation through amplifying type 2 helper (Th2) responses and recruiting eosinophils. Notably, ubiquitin-specific peptidase 18 (USP18) deficiency causes eosinophil and Th2 cell accumulation, exacerbating pulmonary inflammation, consistent with the results in mice with AT2 cell-specific USP18 knockdown after ovalbumin (OVA) or house dust mite (HDM) stimulation. In contrast, CCL8-specific knockdown in AT2 cells reverses the increased Th2-associated inflammation observed in USP18-deficient mice following OVA challenge. Mechanistically, USP18 interacts with and stabilizes suppressor of cytokine signaling 1 (SOCS1) by inhibiting its ubiquitination and degradation, ultimately reducing CCL8 production via STAT3-ERK signaling in a negative feedback manner. Overall, this study elucidates the molecular mechanism of the USP18-SOCS1 complex in regulating CCL8 production, and identifies CCL8 and USP18 as key molecules in AT2-coordinated asthmatic inflammation, suggesting that they are promising therapeutic targets for asthma.