TLR7 Agonist Suppresses Group 2 Innate Lymphoid Cell?mediated Inflammation via IL-27?Producing Interstitial Macrophages
TLR7 Agonist Suppresses Group 2 Innate Lymphoid Cell?mediated Inflammation via IL-27?Producing Interstitial Macrophages
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TLR7 激动剂通过产生间质巨噬细胞抑制 2 组先天淋巴细胞介导的炎症
DOI：
10.1165/rcmb.2021-0042oc
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发表时间：
2021
影响因子：
6.4
通讯作者：
Fukunaga Koichi
中科院分区：
文献类型：
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作者：
Okuzumi Shinichi;Miyata Jun;Kabata Hiroki;Mochimaru Takao;Kagawa Shizuko;Masaki Katsunori;Irie Misato;Morita Hideaki;Fukunaga Koichi
第2组先天性淋巴样细胞（ILC 2）通过大量产生2型细胞因子在哮喘的病理生理学中发挥重要作用。最近的研究表明，TLR 7（Toll样受体7）信号传导偏向于哮喘的1型炎症反应，这可能导致新的治疗策略的发展。然而，TLR 7信号转导对ILC 2依赖性非过敏性嗜酸性粒细胞炎症的影响仍不清楚。在这项研究中，我们研究了TLR 7激动剂R848在IL-33诱导的嗜酸性气道炎症小鼠模型中的作用。鼻内施用R848减少气道嗜酸性粒细胞和ILC 2的浸润、上皮细胞中的粘液产生和2型细胞因子产生。流式细胞术分析鉴定了IL-33刺激后肺中表达高水平TLR 7的间质巨噬细胞（IM）数量增加。IL-33诱导的IM也表达高水平的交替激活（M2）型基因和趋化因子（CCL 17和CCL 24）。然而，R848刺激改变了这些基因的表达，并引发了IL-27的产生。共培养实验表明，IL-33诱导的IM直接抑制响应于R848的ILC 2活化。此外，R848对ILC 2诱导的2型炎症的抑制作用在缺乏IL-27受体的WSX-1缺陷小鼠中是有缺陷的。总之，这些发现表明R848刺激IL-33诱导的IM以通过IL-27抑制ILC 2介导的2型气道炎症。这些发现强调了TLR 7激动剂和/或IL-27级联在非过敏性哮喘中的治疗潜力。
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.