Melatonin (N-acetyl-5-methoxytrytamine), which is synthesized by the pineal gland or extra-pineal tissues (17), has been identified as a powerful immune-modulatory and anti-inflammatory molecule (18). Exogenous administration of melatonin has been reported to pronouncedly ameliorate airway inflammation (19, 20). Similarly, endogenous melatonin, which is produced from tryptophan (Trp) by converting 5-hydroxytryptamine (5-HT) successively by two key enzymes AANAT and ASMT, is also tightly associated with the pathogenesis of asthma (21, 22). It has been reported that endogenous melatonin synthesis is suppressed by activation of TLR9 (22), while other study shows that melatonin is able to inhibit TLRs-mediated inflammation (23), suggesting there may be a feedback loop between TLRs system and endogenous melatonin synthesis. More notably, it has been recently identified that a novel molecular target for melatonin is NLRP3 in murine model of septic response, liver injury and acute lung injury (24–26). However, it is uncertain whether TLR2-melatonin feedback loop exists in allergic airway disease, and regulates NLRP3 inflammasome activity.