Plasmacytoid dendritic cell deficiency in neonates enhances allergic airway inflammation via reduced production of IFN-\u03b1

Min Wu,Feili Gong,Hebin Chen,Yafei Huang,Erwin W Gelfand,Ketai Shi,Bing Liu,Miao He,Hangyu Liu,Han Jiang,Runshi Shang,Liuchuang Gao,Junyan Han,Shan Gao

doi:10.1038/s41423-019-0333-y

Abstract

Allergic asthma, a chronic inflammatory airway disease associated with type 2 cytokines, often originates in early life. Immune responses at an early age exhibit a Th2 cell bias, but the precise mechanisms remain elusive. Plasmacytoid dendritic cells (pDCs), which play a regulatory role in allergic asthma, were shown to be deficient in neonatal mice. We report here that this pDC deficiency renders neonatal mice more susceptible to severe allergic airway inflammation than adult mice in an OVA-induced experimental asthma model. Adoptive transfer of pDCs or administration of IFN-α to neonatal mice prevented the development of allergic inflammation in wild type but not in IFNAR1−/− mice. Similarly, adult mice developed more severe allergic inflammation when pDCs were depleted. The protective effects of pDCs were mediated by the pDC-/IFN-α-mediated negative regulation of the secretion of epithelial cell-derived CCL20, GM-CSF, and IL-33, which in turn impaired the recruitment of cDC2 and ILC2 cells to the airway. In asthmatic patients, the percentage of pDCs and the level of IFN-α were lower in children than in adults. These results indicate that impairment of pDC-epithelial cell crosstalk in neonates is a susceptibility factor for the development of allergen-induced allergic airway inflammation.

Highlights

Asthma is an airway inflammatory syndrome resulting from a number of endotypes
In parallel, following IFN-α administration in the neonatal mice or using IFN-α receptor 1-deficient (IFNAR1−/−) mice, we determined that Plasmacytoid DCs (pDCs) mediated immunosuppressive activity through IFN-α release, which suppressed the secretion of CCL20, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-33 from epithelial cells, leading to impaired recruitment of cDC2 and ILC2 cells
Allergic airway inflammation and cellular responses are increased in neonatal mice To test whether neonatal mice develop a more polarized Th2 cell response and have enhanced airway responsiveness compared to the adult mice, the neonatal and adult mice were sensitized with i.p. injections of OVA-aluminum hydroxide (OVA-alum) on day 0 and day 7 and challenged with OVA via airway 1 week later (OVA/OVA; Fig. 1a)

Summary

Introduction

Asthma is an airway inflammatory syndrome resulting from a number of endotypes. A prevalent form is allergic asthma, which is defined as an unbalanced adaptive immune response to inhaled allergens. According to the results of adoptive pDC transfer into neonatal mice or depletion of pDCs in adult mice, pDCs were shown to be capable of suppressing allergic airway responses. In parallel, following IFN-α administration in the neonatal mice or using IFN-α receptor 1-deficient (IFNAR1−/−) mice, we determined that pDCs mediated immunosuppressive activity through IFN-α release, which suppressed the secretion of CCL20, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-33 from epithelial cells, leading to impaired recruitment of cDC2 and ILC2 cells.

Methods

Results

Conclusion