Fibrinogen cleavage products and Toll-like receptor 4 promote the generation of programmed cell death 1 ligand 2-positive dendritic cells in allergic asthma

Abstract

Background: Inhaled protease allergens preferentially trigger T_H2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on induction of T_H2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce T_H2-favorable DCs in the airway remains unclear.

Objective: We sought to determine a subset of DCs responsible for T_H2 cell responses in allergic asthma and the mechanism by which protease allergens induce the DC subset in the airway.

Methods: Mice were challenged intranasally with protease allergens or fibrinogen cleavage products (FCPs) to induce allergic airway inflammation. DCs isolated from mediastinal lymph nodes were analyzed for surface phenotype and T-cell stimulatory function. Anti-Thy1.2 and Mas-TRECK mice were used to deplete innate lymphoid cells and mast cells, respectively. Adoptive cell transfer, bone marrow DC culture, anti-IL-13, and Toll-like receptor (TLR) 4-deficient mice were used for further mechanistic studies.

Results: Protease allergens induced a remarkable accumulation of T_H2-favorable programmed cell death 1 ligand 2 (PD-L2)⁺ DCs in mediastinal lymph nodes, which was significantly abolished in mice depleted of mast cells and, to a lesser extent, innate lymphoid cells. Mechanistically, FCPs generated by protease allergens triggered IL-13 production from wild-type mast cells but not from TLR4-deficient mast cells, which resulted in an increase in the number of PD-L2⁺ DCs. Intranasal administration of FCPs induced an increase in numbers of PD-L2⁺ DCs in the airway, which was significantly abolished in TLR4- and mast cell-deficient mice. Injection of IL-13 restored the PD-L2⁺ DC population in mice lacking mast cells.

Conclusion: Our findings unveil the "protease-FCP-TLR4-mast cell-IL-13" axis as a molecular mechanism for generation of T_H2-favorable PD-L2⁺ DCs in allergic asthma and suggest that targeting the PD-L2⁺ DC pathway might be effective in suppressing allergic T-cell responses in the airway.

Keywords: PD-L2(+) dendritic cells; Protease allergen; Toll-like receptor 4; fibrinogen cleavage product; mast cell.