Flagellin suppresses experimental asthma by generating regulatory dendritic cells and T cells

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• 作者：Jae-Uoong Shim ; PhD^a ; ^&lowast ; ; Shee Eun Lee ; PhD^b ; ^&lowast ; ; Won Hwang ; MS^c ; ^g ; ^&lowast ; ; Changhon Lee ; MS^g ; ^h ; Jung-Won Park ; MD^d ; Jung-Ho Sohn ; MS^d ; Jong Hee Nam ; MD^e ; Young Kim ; MD ; PhD^e ; Joon Haeng Rhee ; MD ; PhD^f ; ^{jhrhee@chonnam.ac.kr" class="auth_mail" title="E-mail the corresponding author} ; Sin-Hyeog Im ; PhD^g ; ^h ; ^{iimsh@postech.ac.kr" class="auth_mail" title="E-mail the corresponding author} ; Young-Il Koh ; MD ; PhD^a ; ^{yikoh@jnu.ac.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Asthma ; Toll-like receptor 5 ; flagellin ; dendritic cells ; regulatory T cells
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：137
• 期：2
• 页码：426-435
• 全文大小：2284 K

文摘

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 T_H1/T_H2/T_H17 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 T_H1/T_H2 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.