Jae-Uoong Shim1, Shee Eun Lee2, Won Hwang3, Changhon Lee4, Jung-Won Park5, Jung-Ho Sohn5, Jong Hee Nam6, Young Kim6, Joon Haeng Rhee7, Sin-Hyeog Im8, Young-Il Koh9. 1. Division of Allergy, Asthma and Clinical Immunology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea. 2. Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju, Korea. 3. School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea; Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, Korea. 4. Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, Korea; Division of Integrative Biosciences and Biotechnology (IBB), Pohang University of Science and Technology, Pohang, Korea. 5. Division of Allergy and Immunology, Department of Internal Medicine and Institute of Allergy, Yonsei University College of Medicine, Seoul, Korea. 6. Department of Pathology, Chonnam National University Medical School, Gwangju, Korea. 7. Clinical Vaccine R&D Center, National Research Laboratory of Molecular Microbial Pathogenesis, Research Institute for Vibrio Infections, Department of Microbiology, Chonnam National University Medical School, Gwangju, Korea. Electronic address: jhrhee@chonnam.ac.kr. 8. Academy of Immunology and Microbiology (AIM), Institute for Basic Science (IBS), Pohang, Korea; Division of Integrative Biosciences and Biotechnology (IBB), Pohang University of Science and Technology, Pohang, Korea. Electronic address: iimsh@postech.ac.kr. 9. Division of Allergy, Asthma and Clinical Immunology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea. Electronic address: yikoh@jnu.ac.kr.
Abstract
BACKGROUND: Although the hygiene hypothesis suggests that microbial infections could subvert asthma and thus a microbial product might serve as a therapeutic adjuvant for asthma, the relationship between bacterial components and asthma is complex. Recently, low levels of flagellin, the Toll-like receptor (TLR) 5 ligand, have been reported to promote asthma. OBJECTIVE: We show that a therapeutic dose of flagellin suppresses asthma and that the effect occurs through generating regulatory dendritic cells (rDCs) and regulatory T (Treg) cells. METHODS: Ovalbumin (OVA)-induced wild-type and TLR5 knockout asthmatic mice were treated intranasally with a mixture of OVA and 10 μg of a flagellin B (FlaB; of Vibrio vulnificus). OVA/FlaB-treated rDCs were adoptively transferred to mice with OVA-induced asthma. Anti-CD25 mAb was used to deplete Treg cells. A mixture of house dust mite (HDM) and FlaB was used to treat mice with HDM-induced asthma. Blood CD14(+) monocyte-derived dendritic cells from HDM-sensitive asthmatic patients were treated with FlaB and incubated with autologous CD4(+) T cells. RESULTS: An OVA/FlaB mixture ameliorated OVA-induced asthma by inhibiting TH1/TH2/TH17 responses in a TLR5-dependent manner through generating rDCs and Treg cells. The adoptive transfer of OVA/FlaB-treated dendritic cells inhibited OVA-induced asthma, whereas the depletion of CD25(+) cells eliminated the inhibitory effect. A similar effect of FlaB was observed in mice with HDM-induced asthma. In patients with HDM-sensitive asthma, FlaB-treated rDCs inhibited HDM-stimulated TH1/TH2 responses while enhancing Treg cells in an IL-10-dependent manner. CONCLUSION: These findings collectively suggest that flagellin could be used as a tolerogenic adjuvant to treat allergic asthma.
BACKGROUND: Although the hygiene hypothesis suggests that microbial infections could subvert asthma and thus a microbial product might serve as a therapeutic adjuvant for asthma, the relationship between bacterial components and asthma is complex. Recently, low levels of flagellin, the Toll-like receptor (TLR) 5 ligand, have been reported to promote asthma. OBJECTIVE: We show that a therapeutic dose of flagellin suppresses asthma and that the effect occurs through generating regulatory dendritic cells (rDCs) and regulatory T (Treg) cells. METHODS:Ovalbumin (OVA)-induced wild-type and TLR5 knockout asthmatic mice were treated intranasally with a mixture of OVA and 10 μg of a flagellin B (FlaB; of Vibrio vulnificus). OVA/FlaB-treated rDCs were adoptively transferred to mice with OVA-induced asthma. Anti-CD25 mAb was used to deplete Treg cells. A mixture of house dust mite (HDM) and FlaB was used to treat mice with HDM-induced asthma. Blood CD14(+) monocyte-derived dendritic cells from HDM-sensitive asthmatic patients were treated with FlaB and incubated with autologous CD4(+) T cells. RESULTS: An OVA/FlaB mixture ameliorated OVA-induced asthma by inhibiting TH1/TH2/TH17 responses in a TLR5-dependent manner through generating rDCs and Treg cells. The adoptive transfer of OVA/FlaB-treated dendritic cells inhibited OVA-induced asthma, whereas the depletion of CD25(+) cells eliminated the inhibitory effect. A similar effect of FlaB was observed in mice with HDM-induced asthma. In patients with HDM-sensitive asthma, FlaB-treated rDCs inhibited HDM-stimulated TH1/TH2 responses while enhancing Treg cells in an IL-10-dependent manner. CONCLUSION: These findings collectively suggest that flagellin could be used as a tolerogenic adjuvant to treat allergic asthma.
Authors: G S Whitehead; S Hussain; R Fannin; C S Trempus; C L Innes; S H Schurman; D N Cook; S Garantziotis Journal: Lung Date: 2020-02-14 Impact factor: 2.584
Authors: Linda M Lee; Ming Ji; Meenal Sinha; Matthew B Dong; Xin Ren; Yanli Wang; Clifford A Lowell; Sankar Ghosh; Richard M Locksley; Anthony L DeFranco Journal: PLoS One Date: 2016-12-15 Impact factor: 3.240