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Toll-Like Receptor 2 Directly Activates Pulmonary Type2 Innate Lymphoid Cells and Modify the Asthmatic Phenotype
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A1307 - Toll-Like Receptor 2 Directly Activates Pulmonary Type2 Innate Lymphoid Cells and Modify the Asthmatic Phenotype
Author Block: T. Ishii1, Y. Nikura2, Y. Murakami2, T. Nagase1, N. Yamashita2; 1Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 2Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan.
(Rationale) Type2 innate lymphoid cells (ILC2s) are the main source of IL-5 and IL-13 in allergic airway inflammation. Innate immune receptors such as Toll-like receptors (TLRs) expressed on epithelial cells could contribute to ILC2 activation through IL-33 production, but the direct contribution of TLRs on ILC2s remains to be elucidated. We previously demonstrated TLR2 agonist PAM could directly activate pulmonary ILC2s through TLR2. In this study, we further investigated the role of TLR2 on ILC2s in the pathogenesis of asthma.
(Methods) After intranasal administration of IL-33 to wild type, TLR2KO and TLR4KO female mice, ILC2s were isolated from harvested lungs using a cell sorter. Then, ILC2s were incubated with IL-2 and other stimulus (PAM, house dust mite extract (HDM) or IL-33). In some experiments, signaling inhibitors that involve TLR2 or Dectin-1 were used. As in vivo model, the mice were treated with IL-33 and rested until lung recruitment of eosinophils regressed. Then mice were subject to intranasal PAM+HDM or vehicles treatment and analyzed for airway hyperresponsiveness, ILC2 proliferation, and cell infiltration in the airway.
(Results) In vitro stimulation on isolated ILC2s showed that PAM could induce IL-13 and IL-5 production and exhibit a synergistic effect on HDM stimulation. Both effects were dependent on TLR2 and NF-κB signaling. By PAM+HDM stimulation in vivo, wild type mice showed ILC2 proliferation in the lung, airway hyperresponsiveness, and increase in both neutrophils and eosinophils in BALF. TLR2KO failed to show ILC2 proliferation and airway hyperresponsiveness, and showed suppressed number of neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF).
(Conclusion) TLR2-NF-κB signaling is involved in the direct activation of pulmonary ILC2 and the synergistic effect on HDM activation. In vivo model showed asthmatic characteristics through TLR2 pathway. These data revealed the new pathway of ILC2s activation on the pathogenesis of asthma.
Author Block: T. Ishii1, Y. Nikura2, Y. Murakami2, T. Nagase1, N. Yamashita2; 1Department of Respiratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 2Department of Pharmacotherapy, Research Institute of Pharmaceutical Sciences, Musashino University, Tokyo, Japan.
(Rationale) Type2 innate lymphoid cells (ILC2s) are the main source of IL-5 and IL-13 in allergic airway inflammation. Innate immune receptors such as Toll-like receptors (TLRs) expressed on epithelial cells could contribute to ILC2 activation through IL-33 production, but the direct contribution of TLRs on ILC2s remains to be elucidated. We previously demonstrated TLR2 agonist PAM could directly activate pulmonary ILC2s through TLR2. In this study, we further investigated the role of TLR2 on ILC2s in the pathogenesis of asthma.
(Methods) After intranasal administration of IL-33 to wild type, TLR2KO and TLR4KO female mice, ILC2s were isolated from harvested lungs using a cell sorter. Then, ILC2s were incubated with IL-2 and other stimulus (PAM, house dust mite extract (HDM) or IL-33). In some experiments, signaling inhibitors that involve TLR2 or Dectin-1 were used. As in vivo model, the mice were treated with IL-33 and rested until lung recruitment of eosinophils regressed. Then mice were subject to intranasal PAM+HDM or vehicles treatment and analyzed for airway hyperresponsiveness, ILC2 proliferation, and cell infiltration in the airway.
(Results) In vitro stimulation on isolated ILC2s showed that PAM could induce IL-13 and IL-5 production and exhibit a synergistic effect on HDM stimulation. Both effects were dependent on TLR2 and NF-κB signaling. By PAM+HDM stimulation in vivo, wild type mice showed ILC2 proliferation in the lung, airway hyperresponsiveness, and increase in both neutrophils and eosinophils in BALF. TLR2KO failed to show ILC2 proliferation and airway hyperresponsiveness, and showed suppressed number of neutrophils and eosinophils in bronchoalveolar lavage fluid (BALF).
(Conclusion) TLR2-NF-κB signaling is involved in the direct activation of pulmonary ILC2 and the synergistic effect on HDM activation. In vivo model showed asthmatic characteristics through TLR2 pathway. These data revealed the new pathway of ILC2s activation on the pathogenesis of asthma.
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