Plasmacytoid dendritic cells alleviate allergic asthma via airway epithelial cell-dependent thymosin β4 expression.
This study investigated the role of plasmacytoid dendritic cells (pDCs) during the active effector phase of allergic asthma, moving beyond their previously known role in immune tolerance. Using BDCA2-DTR transgenic mice in which pDCs can be selectively depleted with diphtheria toxin, researchers sensitized and challenged animals with house dust mite allergen. They found that pDC depletion worsened asthmatic inflammation by increasing CCR2-dependent recruitment of inflammatory monocyte-derived cells. RNA sequencing of lung pDCs revealed that the small anti-inflammatory peptide thymosin β4 (Tβ4) was among the most upregulated genes in asthmatic conditions. IL-33 released by airway epithelial cells was found to drive Tβ4 expression in pDCs, which represented the dominant pulmonary source of Tβ4. Mechanistically, Tβ4 suppressed IL-4/IL-13-induced JAK1/STAT6/EGR2 signaling in alveolar macrophages, reducing CCL2 production and monocyte recruitment. Tβ4 supplementation reversed disease exacerbation in pDC-depleted mice. Notably, reduced serum Tβ4 levels were observed in both asthmatic mice and a human cohort with active allergic asthma. Limitations include the predominantly murine mechanistic data and a small, cross-sectional human serum dataset that limits causal interpretation in humans.
Why this grade: The study is primarily mechanistic mouse work with only a small, cross-sectional human serum observation, providing insufficient evidence on its own to establish efficacy or causality in humans.
Background Plasmacytoid dendritic cells (pDCs) have been previously reported to induce immune tolerance to allergen by inhibiting allergic T H 2-cell priming. However, there is limited knowledge on pDC function during the T H 2 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 T H 2-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.
Educational summary of published research — not medical advice. Full text is shown only where licensing permits.