Anhui Geriatric Institute, Department of Geriatric Respiratory and Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Jixi Road 218, Hefei, Anhui, 230022, PR China; Key Laboratory of Geriatric Molecular Medicine of Anhui Province, Jixi Road No.218, Hefei, Anhui, 230022, PR China; Key Laboratory of Respiratory Disease Research and Medical Transformation of Anhui Province, Jixi Road 218, Hefei, Anhui, 230022, PR China.
Division of Life Sciences and Medicine, University of Science and Technology of China, Huang Shan Road 443, Hefei, Anhui, 230027, PR China.
Free Radic Biol Med. 2023 May 1;200:102-116. doi: 10.1016/j.freeradbiomed.2023.03.007. Epub 2023 Mar 11.
As a pattern recognition receptor which activates innate immune system, toll-like receptor 2 (TLR2) has been reportedly mediates allergic airway inflammation (AAI), yet the underlying mechanism remains elusive. Here, in a murine AAI model, TLR2 mice showed decreased airway inflammation, pyroptosis and oxidative stress. RNA-sequencing revealed that allergen-induced hif1 signaling pathway and glycolysis were significantly downregulated when TLR2 was deficient, which were confirmed by lung protein immunoblots. Glycolysis inhibitor 2-Deoxy-d-glucose (2-DG) inhibited allergen-induced airway inflammation, pyroptosis, oxidative stress and glycolysis in wild type (WT) mice, while hif1α stabilizer ethyl 3,4-dihydroxybenzoate (EDHB) restored theses allergen-induced changes in TLR2 mice, indicating TLR2-hif1α-mediated glycolysis contributes to pyroptosis and oxidative stress in AAI. Moreover, upon allergen challenge, lung macrophages were highly activated in WT mice but were less activated in TLR2 mice, 2-DG replicated while EDHB reversed such effect of TLR2 deficiency on lung macrophages. Likewise, both in vivo and ex vivo WT alveolar macrophages (AMs) exhibited higher TLR2/hif1α expression, glycolysis and polarization activation in response to ovalbumin (OVA), which were all inhibited in TLR2 AMs, suggesting AMs activation and metabolic switch are dependent on TLR2. Finally, depletion of resident AMs in TLR2 mice abolished while transfer of TLR2 resident AMs to WT mice replicated the protective effect of TLR2 deficiency on AAI when administered before allergen challenge. Collectively, we suggested that loss of TLR2-hif1α-mediated glycolysis in resident AMs ameliorates allergic airway inflammation that inhibits pyroptosis and oxidative stress, therefore the TLR2-hif1α-glycolysis axis in resident AMs may be a novel therapeutic target for AAI.
作为激活固有免疫系统的模式识别受体，Toll 样受体 2（TLR2）据报道介导过敏性气道炎症（AAI），但其潜在机制尚不清楚。在这里，在小鼠 AAI 模型中，TLR2 小鼠显示气道炎症、细胞焦亡和氧化应激减少。RNA 测序显示，TLR2 缺乏时，过敏原诱导的 hif1 信号通路和糖酵解明显下调，肺蛋白免疫印迹证实了这一点。糖酵解抑制剂 2-脱氧-D-葡萄糖（2-DG）抑制野生型（WT）小鼠过敏原诱导的气道炎症、细胞焦亡、氧化应激和糖酵解，而 hif1α 稳定剂 3,4-二羟基苯甲酸乙酯（EDHB）恢复 TLR2 小鼠过敏原诱导的这些变化，表明 TLR2-hif1α 介导的糖酵解有助于 AAI 中的细胞焦亡和氧化应激。此外，在过敏原攻击时，WT 小鼠的肺巨噬细胞高度激活，但 TLR2 小鼠的肺巨噬细胞激活较少，2-DG 复制而 EDHB 逆转 TLR2 缺乏对肺巨噬细胞的这种作用。同样，在体内和体外，WT 肺泡巨噬细胞（AMs）对卵清蛋白（OVA）表现出更高的 TLR2/hif1α 表达、糖酵解和极化激活，而 TLR2 AMs 则均受到抑制，表明 AMs 的激活和代谢转换依赖于 TLR2。最后，TLR2 小鼠驻留 AMs 的耗竭消除了，而 TLR2 驻留 AMs 转移到 WT 小鼠中，在过敏原攻击前给予时复制了 TLR2 缺乏对 AAI 的保护作用。总之，我们认为驻留 AMs 中 TLR2-hif1α 介导的糖酵解丧失可改善过敏性气道炎症，从而抑制细胞焦亡和氧化应激，因此驻留 AMs 中的 TLR2-hif1α-糖酵解轴可能成为 AAI 的新治疗靶点。
