Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7⁺ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target.

Toll 样受体 7 (TLR7) 因引发针对单链 RNA 病毒的免疫力而闻名，并且在人类和香烟烟雾 (CS) 诱发的实验性慢性阻塞性肺疾病 (COPD) 中都会增加。在这里，我们发现，在 TLR7 缺陷小鼠中，CS 诱导的肺气肿和 COPD 的严重程度降低，而吸入 TLR7 激动剂咪喹莫特，无需接触 CS 即可诱发肺气肿。在缺乏肥大细胞蛋白酶 6 的小鼠中，或者当用肥大细胞稳定剂色甘酸处理野生型小鼠时，这种咪喹莫特诱导的肺气肿会减轻。此外，抗 TLR7 单克隆抗体的治疗可抑制 CS 诱导的肺气肿、实验性 COPD 和小鼠肺肥大细胞的积累。最后， TLR7 mRNA 在 COPD 患者的现有数据集中增加，而 TLR7 ⁺肥大细胞在 COPD 肺部中增加，并且与 COPD 的严重程度相关。因此，我们的结果支持 TLR7 通过肥大细胞活性介导肺气肿和 COPD 的作用，并可能暗示 TLR7 作为潜在的治疗靶点。