Department of Geriatric Respiratory and Critical Care, Anhui Geriatric Institute, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
Anhui Key Laboratory of Geriatric Molecular Medicine, Anhui Medical University, Hefei, China.
Front Immunol. 2020 Feb 7;11:172. doi: 10.3389/fimmu.2020.00172. eCollection 2020.
Toll-like receptor 2 (TLR2) is suggested to initiate the activation of NLRP3 inflammasome, and considered to be involved in asthma. The findings that melatonin modulates TLRs-mediated immune responses, together with the suppressing effect of TLRs on endogenous melatonin synthesis, support the possibility that a feedback loop exists between TLRs system and endogenous melatonin synthesis. To determine whether TLR2-melatonin feedback loop exists in allergic airway disease and regulates NLRP3 inflammasome activity, wild-type (WT) and TLR2 mice were challenged with OVA to establish allergic airway disease model. Following OVA challenge, WT mice exhibited increased-expression of TLR2, activation of NLRP3 inflammasome and marked airway inflammation, which were all effectively inhibited in the TLR2 mice, indicating that TLR2-NLRP3 mediated airway inflammation. Meanwhile, melatonin biosynthesis was reduced in OVA-challenged WT mice, while such reduction was notably rescued by TLR2 deficiency, suggesting that TLR2-NLRP3-mediated allergic airway inflammation was associated with decreased endogenous melatonin biosynthesis. Furthermore, addition of melatonin to OVA-challenged WT mice pronouncedly ameliorated airway inflammation, decreased TLR2 expression and NLRP3 inflammasome activation, further implying that melatonin in turn inhibited airway inflammation via suppressing TLR2-NLRP3 signal. Most interestingly, although melatonin receptor antagonist luzindole significantly reduced the protein expressions of ASMT, AANAT and subsequent level of melatonin in OVA-challenged TLR2 mice, it exhibited null effect on leukocytes infiltration, Th2-cytokines production and NLRP3 activity. These results indicate that a TLR2-melatonin feedback loop regulates NLRP3 inflammasome activity in allergic airway inflammation, and melatonin may be a promising therapeutic medicine for airway inflammatory diseases such as asthma.
Toll 样受体 2（TLR2）被认为能够启动 NLRP3 炎性小体的激活，并与哮喘有关。褪黑素调节 TLR 介导的免疫反应的发现，以及 TLR 对内源性褪黑素合成的抑制作用，支持 TLR 系统和内源性褪黑素合成之间存在反馈环的可能性。为了确定 TLR2-褪黑素反馈环是否存在于过敏性气道疾病中并调节 NLRP3 炎性小体的活性，使用野生型（WT）和 TLR2 小鼠进行卵清蛋白（OVA）激发以建立过敏性气道疾病模型。OVA 激发后，WT 小鼠表现出 TLR2 的高表达、NLRP3 炎性小体的激活和明显的气道炎症，而这些在 TLR2 小鼠中均被有效抑制，表明 TLR2-NLRP3 介导的气道炎症。同时，在 OVA 激发的 WT 小鼠中，褪黑素的生物合成减少，而 TLR2 缺乏则明显挽救了这种减少，表明 TLR2-NLRP3 介导的过敏性气道炎症与内源性褪黑素生物合成减少有关。此外，向 OVA 激发的 WT 小鼠中添加褪黑素可显著改善气道炎症，降低 TLR2 的表达和 NLRP3 炎性小体的激活，进一步表明褪黑素通过抑制 TLR2-NLRP3 信号来抑制气道炎症。最有趣的是，尽管褪黑素受体拮抗剂 luzindole 显著降低了 OVA 激发的 TLR2 小鼠中的 ASMT、AANAT 蛋白表达及其随后的褪黑素水平，但它对白细胞浸润、Th2 细胞因子产生和 NLRP3 活性没有影响。这些结果表明，TLR2-褪黑素反馈环调节过敏性气道炎症中的 NLRP3 炎性小体活性，并且褪黑素可能是治疗哮喘等气道炎症性疾病的有前途的治疗药物。
