| First Author | Cho M | Year | 2018 |
| Journal | J Allergy Clin Immunol | Volume | 142 |
| Issue | 2 | Pages | 530-541.e6 |
| PubMed ID | 29038008 | Mgi Jnum | J:286851 |
| Mgi Id | MGI:6405930 | Doi | 10.1016/j.jaci.2017.09.019 |
| Citation | Cho M, et al. (2018) Fibrinogen cleavage products and Toll-like receptor 4 promote the generation of programmed cell death 1 ligand 2-positive dendritic cells in allergic asthma. J Allergy Clin Immunol 142(2):530-541.e6 |
| abstractText | BACKGROUND: Inhaled protease allergens preferentially trigger TH2-mediated inflammation in allergic asthma. The role of dendritic cells (DCs) on induction of TH2 cell responses in allergic asthma has been well documented; however, the mechanism by which protease allergens induce TH2-favorable DCs in the airway remains unclear. OBJECTIVE: We sought to determine a subset of DCs responsible for TH2 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 TH2-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 TH2-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. |
