USP18 confers protection against allergic asthma by suppressing CCL8 production in alveolar type II epithelial cells

Alveolar epithelial type II (AT2) cells participate in epithelial repair and lung immune defense, while the detailed molecular mechanisms through which AT2 cells regulate inflammatory immune responses in asthma remain unclear. Ubiquitin-specific peptidase 18 (USP18) has been implicated in immune regulation, but its role in asthma pathogenesis is not fully understood.

USP18 expression in AT2 cells was analyzed in both mouse models of allergic asthma and asthmatic patients. Functional studies were conducted using USP18 knockout mice, AT2 cell-specific chemokine (C-C motif) ligand 8 (CCL8) knockdown, and exogenous CCL8 treatment. Th2 responses, eosinophil recruitment, and chemokine production were assessed. Mechanistic investigations focused on USP18-mediated regulation of SOCS1 stability and downstream ERK-STAT3 signaling.

USP18 is increased in AT2 cells from both mouse models of asthma and asthmatic patients, and played a protective role in the progression of allergic asthma by suppressing Th2 responses and reducing CCL8 production. Notably, USP18 deficiency causes increased CCL8 in AT2 cells, which in turn recruits Th2 cells and eosinophils, thereby exacerbating allergic asthma. Consistently, CCL8 treatment induced asthmatic inflammation and knocking down CCL8 in AT2 cells of USP18 knockout mice alleviates asthma symptoms. Mechanistically, USP18 stabilizes SOCS1 by inhibiting its ubiquitination and degradation, leading to reduced CCL8 production through the ERK-STAT3 signaling pathway in a negative feedback loop.

Overall, these findings reveal a previously unrecognized role for USP18 in regulating CCL8 production during asthma progression, highlighting USP18 and CCL8 as potential therapeutic targets for asthma treatment.