27‐Hydroxycholesterol Exacerbates the Pathogenesis of Asthma

ABSTRACT 27‐Hydroxycholesterol (27‐HC) is an oxidative metabolite of cholesterol and an oxysterol catalysed by the mitochondrial cytochrome P450 enzyme, sterol 27‐hydroxylase (CYP27A1). In addition to inducing the release of eosinophil chemotactic factors such as RANTES and Eotaxin, 27‐HC enhances the differentiation of lung fibroblasts into myofibroblasts and promotes the production of extracellular matrix proteins. Therefore, it is possible that 27‐HC may play a significant role in the pathogenesis of asthma. In this study, we observed elevated expression of CYP27A1 and increased production of 27‐HC in the lung tissues of asthmatic mice, with alveolar macrophages (AMs) identified as the primary source of 27‐HC. 27‐HC induced an increase in total cell count and eosinophil number in the bronchoalveolar lavage fluid of asthmatic mice, exacerbated inflammatory cell infiltration into lung tissues, and heightened airway hyper‐responsiveness, thereby aggravating asthma. The alarmin, IL‐33, within airways induced 27‐HC production by AMs via the NF‐κB signalling pathway. Furthermore, 27‐HC was shown to inhibit the phagocytosis of apoptotic cells (efferocytosis) by airway epithelial cells (AECs) through AMPK activation. Thus, in asthmatic mice, 27‐HC, predominantly derived from AMs, influences the efferocytotic function of AECs, demonstrating that cross‐talk between macrophages and epithelial cells regulates asthma pathogenesis. This study provides valuable insight into the molecular mechanisms underlying asthma and offers theoretical and experimental data for identifying novel therapeutic targets for clinical asthma management.