National Center for Respiratory Medicine, State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China; Department of Pulmonary and Critical Care Medicine, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
Intensive Care Unit, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, PR China.
Toxicol Lett. 2021 Sep 15;348:28-39. doi: 10.1016/j.toxlet.2021.05.010. Epub 2021 May 28.
Almost three billion people in developing countries are exposed to biomass smoke (BS), which predisposes them to developing chronic obstructive pulmonary disease (COPD). COPD is associated with abnormal innate and adaptive immune responses in the lungs and systemic circulation, but the mechanisms underlying BS-COPD development are uncertain. We investigated the role of dendritic cells (DCs) and interleukin (IL)-17A in BS-COPD. We investigated T helper cell responses in the BS-exposed COPD rat model by flow cytometry, quantitative PCR, and enzyme-linked immunosorbent assays. We conducted ex vivo experiments to determine which antigen-presenting cells induce Th17 cell responses. We evaluated the in vitro effects of BS-related particulate matter (BRPM) (2.5 μm) on the function of bone marrow-derived dendritic cells (BMDCs). We found that BS exposure enhanced Th17 responses in the lungs of the COPD-modelled rats, and the stimulated DCs (but not the macrophages) were sufficient to induce naïve CD4 + T cells to produce IL-17A in ex vivo experiments. BRPM significantly enhanced the maturation and activation of DCs through Toll-like receptor 2 (TLR2), but not TLR4, and induced Th17 responses. Therefore, BS activated lung DCs through TLR2, which led to Th17 responses and emphysema in the rats. This process is possibly therapeutically targetable.
发展中国家几乎有 30 亿人接触生物质烟雾(BS),这使他们易患慢性阻塞性肺疾病(COPD)。COPD 与肺部和全身循环中的异常固有和适应性免疫反应有关,但 BS-COPD 发展的机制尚不确定。我们研究了树突状细胞(DC)和白细胞介素(IL)-17A 在 BS-COPD 中的作用。我们通过流式细胞术、定量 PCR 和酶联免疫吸附试验研究了 BS 暴露的 COPD 大鼠模型中的辅助性 T 细胞反应。我们进行了离体实验以确定哪种抗原呈递细胞诱导 Th17 细胞反应。我们评估了 BS 相关颗粒物(BRPM)(2.5μm)对骨髓来源的树突状细胞(BMDC)功能的体外影响。我们发现,BS 暴露增强了 COPD 模型大鼠肺部的 Th17 反应,而刺激的 DC(而不是巨噬细胞)足以在离体实验中诱导幼稚 CD4+T 细胞产生 IL-17A。BRPM 通过 Toll 样受体 2(TLR2)而非 TLR4 显著增强了 DC 的成熟和激活,并诱导了 Th17 反应。因此,BS 通过 TLR2 激活肺部 DC,导致大鼠发生 Th17 反应和肺气肿。该过程可能具有治疗靶向性。