DJ-1 governs airway progenitor cell/eosinophil interactions to promote allergic inflammation

Background DJ-1 is an antioxidant protein known to regulate mast cell mediated allergic response, but its role in airway eosinophilic interactions and allergic inflammation is not known. Objective The aim of this study was to investigate the role of DJ-1 in airway eosinophilic inflammation in vitro and in vivo. Methods Ovalbumin-induced airway allergic inflammation was established in mice. ELISA was adopted to analyze DJ-1 and cytokine levels in mouse bronchoalveolar lavage fluid. Transcriptional profiling of mouse lung tissues was conducted by single-cell RNA sequencing technology. The role of DJ-1 in the differentiation of airway progenitor cells into goblet cells was examined by organoid cultures, immunofluorescence staining, quantitative PCR, and cell transplantation in normal, DJ-1 knockout (KO), or conditional DJ-1 KO mice. Results We observed that DJ-1 was increased in the lung tissues of ovalbumin-sensitized and challenged mice. DJ-1 KO mice exhibited reduced airway eosinophil infiltration and goblet cell differentiation. Mechanistically, we discovered that eosinophil-club cell interactions are reduced in the absence of DJ-1. Organoid cultures indicated that eosinophils impair the proliferative potential of club cells. Intratracheal transplantation of DJ-1-deficient eosinophils suppresses airway goblet cell differentiation. Loss of DJ-1 inhibits the metabolism of arachidonic acid into cysteinyl leukotrienes in eosinophils while these secreted metabolites promote airway goblet cell fate in organoid cultures and in vivo. Conclusion DJ-1-mediated interactions between airway epithelial progenitor cells and immune cells are essential in controlling airway goblet cell metaplasia and eosinophilia. Blockade of the DJ-1 pathway is protective against airway allergic inflammation. After PBS of OVA challenge, total lung cells from three randomly selected WT mice or DJ-1 KO mice were pooled for scRNA-seq analysis (1 sample of WT-PBS, 1 sample of WT-OVA, 1 sample of DJ-1 KO-OVA).