Plasmacytoid dendritic cells alleviate allergic asthma via airway epithelial cell-dependent thymosin β4 expression.

BACKGROUND: Plasmacytoid dendritic cells (pDCs) have been previously reported to induce immune tolerance to allergen by inhibiting allergic T2-cell priming. However, there is limited knowledge on pDC function during the T2 effector phase of allergic asthma. OBJECTIVE: We sought to investigate the role of pDCs in ongoing allergic asthma following airway sensitization and challenge with house mite dust. METHODS: Blood dendritic cell antigen 2-diphtheria toxin receptor (BDCA2-DTR) mice were used for pDC depletion. RNA sequencing of sorted mouse lung pDCs, in vitro cell experiments, and in vivo CCR2 blockade or thymosin β4 (Tβ4) supplementation were performed to elucidate the underlying mechanism. RESULTS: pDC depletion during house mite dust challenge enhanced CCR2-dependent inflammatory monocyte-derived cell accumulation, leading to exacerbated T2-mediated allergic asthma phenotypes. RNA-sequencing analysis revealed that the anti-inflammatory peptide thymosin β4 (Tβ4) was among the most upregulated genes in asthmatic lung pDCs. Airway epithelial cell-derived IL-33 was required for upregulating Tβ4 expression in pDCs, which represented the main source of Tβ4 in asthmatic lungs. Importantly, Tβ4 supplementation reversed the exacerbation of asthmatic phenotypes in BDCA2-DTR mice. Alveolar macrophages were identified as the major source of CCL2 and the target of Tβ4 in asthmatic lungs. Mechanistically, Tβ4 inhibited IL-4/IL-13-induced phosphorylation of Janus kinase 1 and signal transducer and activator of transcription 6 and downstream early growth response 2 expression in macrophages, thereby reducing CCL2 expression and subsequent inflammatory monocyte-derived cell recruitment. Unexpectedly, decreased serum Tβ4 levels were detected in mice and humans with ongoing allergic asthma. This could be due to increased uptake of Tβ4 by alveolar macrophages, which was required for its inhibitory effect on CCL2 expression. CONCLUSIONS: Lung pDCs exert anti-inflammatory effects in allergic asthma via expressing Tβ4, which could have therapeutic potential.