Minkyoung Cho1, Jeong-Eun Lee1, Hoyong Lim1, Hyun-Woo Shin2, Roza Khalmuratova3, Garam Choi1, Hyuk Soon Kim4, Wahn Soo Choi4, Young-Jun Park1, Inbo Shim1, Byung-Seok Kim1, Chang-Yuil Kang1, Jae-Ouk Kim5, Shinya Tanaka6, Masato Kubo6, Hui-Ying Tung7, Cameron T Landers8, David B Corry9, Farrah Kheradmand9, Yeonseok Chung10. 1. Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea. 2. Department of Pharmacology, College of Medicine, Seoul National University, Seoul, Korea; Department of Biomedical Sciences and Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, Korea. 3. Department of Pharmacology, College of Medicine, Seoul National University, Seoul, Korea. 4. School of Medicine, Konkuk University, Seoul, Korea. 5. Laboratory Science Division, International Vaccine Institute, Seoul, Korea. 6. Research Institute for Biomedical Science, Tokyo University of Science, Tokyo, and the RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan. 7. Department of Pathology & Immunology, Baylor College of Medicine, Houston, Tex. 8. Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Tex. 9. Department of Pathology & Immunology, Baylor College of Medicine, Houston, Tex; Department of Medicine, Baylor College of Medicine, Houston, Tex; Biology of Inflammation Center, Baylor College of Medicine, Houston, Tex. 10. Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, Korea. Electronic address: yeonseok@snu.ac.kr.
Abstract
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.
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.
Authors: Cameron T Landers; Hui-Ying Tung; J Morgan Knight; Matthew C Madison; Yifan Wu; Zhimin Zeng; Paul C Porter; Antony Rodriguez; Matthew J Flick; Farrah Kheradmand; David B Corry Journal: J Biol Chem Date: 2019-04-16 Impact factor: 5.157
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