TLR7 Agonist Suppresses Group 2 Innate Lymphoid Cell-mediated Inflammation via IL-27-Producing Interstitial Macrophages.
Group 2 innate lymphoid cells (ILC2s) play an important role in the pathophysiology of asthma via the robust production of type 2 cytokines. Recent studies have demonstrated that TLR7 (Toll-like receptor 7) signaling skews toward a type 1 inflammatory response in asthma, which may lead to the development of novel treatment strategies. However, the effect of TLR7 signaling on ILC2-dependent nonallergic eosinophilic inflammation remains unclear. In this study, we investigated the effects of R848, a TLR7 agonist, in a mouse model of IL-33-induced eosinophilic airway inflammation. Intranasal administration of R848 decreased infiltration of airway eosinophils and ILC2s, mucus production in epithelial cells, and type 2 cytokine production. Flow cytometric analysis identified an increased number of interstitial macrophages (IMs) expressing a high level of TLR7 in the lung upon IL-33 stimulation. IL-33-induced IMs also expressed high levels of alternatively activated (M2)-type genes and chemokines (CCL17 and CCL24). However, R848 stimulation modified these gene expressions and elicited the production of IL-27. Coculture experiments revealed that IL-33-induced IMs directly suppressed ILC2 activation in response to R848. In addition, the inhibitory effects of R848 on ILC2-induced type 2 inflammation were defective in WSX-1-deficient mice lacking the IL-27 receptor. Taken together, these findings indicate that R848 stimulates IL-33-induced IMs to suppress ILC2-mediated type 2 airway inflammation via IL-27. These findings highlight the therapeutic potential of TLR7 agonists and/or IL-27 cascades in nonallergic asthma.
['Okuzumi|Shinichi|S|', 'Miyata|Jun|J|0000-0002-3189-1702', 'Kabata|Hiroki|H|0000-0001-8853-6149', 'Mochimaru|Takao|T|0000-0002-1505-6651', 'Kagawa|Shizuko|S|', 'Masaki|Katsunori|K|0000-0003-0909-9409', 'Irie|Misato|M|', 'Morita|Hideaki|H|', 'Fukunaga|Koichi|K|0000-0001-7460-1990']
D000818:Animals D001249:Asthma D054414:Chemokine CCL17 D054423:Chemokine CCL24 D004804:Eosinophils D007093:Imidazoles D007113:Immunity, Innate D007249:Inflammation D000067596:Interleukin-33 D007378:Interleukins D008168:Lung D008214:Lymphocytes D008264:Macrophages D008562:Membrane Glycoproteins D051379:Mice D008807:Mice, Inbred BALB C D018345:Mice, Knockout D018123:Receptors, Interleukin D015398:Signal Transduction D051199:Toll-Like Receptor 7
interstitial macrophage ILC2 asthma R848 IL-33