On the other hand, melatonin has been evidenced to significantly inhibit airway inflammation (49, 56), and suppress TLR3/4-mediated inflammation in liver injury (23). Most notably, NLRP3 is a novel molecular target for melatonin in murine model of septic response, liver injury and acute lung injury (24–26). Consistent with these findings in animals, melatonin also has been shown to exert inhibitory effect on TLRs including TLR3/4/9 signaling in macrophage (57–59) and NLRP3 inflammasome in epithelial cells (60). Therefore, we asked whether endogenous melatonin, which was regulated by TLR2 signal, alleviated allergic airway inflammation through directly suppressing NLRP3 inflammasome activity or feedback controlling TLR2-NLRP3 signal. Our current study showed that treatment of melatonin notably alleviated OVA-induced airway inflammation in WT mice, which was consistent with previous findings (19, 56). However, we extended previous observations by showing that melatonin treatment strongly inhibited OVA-induced protein expressions of TLR2, NLRP3, mature IL-1β and caspase1(p20), as well as lowered the levels of NLRP3-associated IL-1β and IL-18 in BALF in WT mice, suggesting that melatonin mitigates allergic airway inflammation by inhibiting TLR2 and NLRP3 inflammasome activity. Considering the data shown above that TLR2 signaling regulated melatonin synthesis, we speculated that a TLR2-melatonin feedback loop may exist in allergic airway disease, and melatonin elicits its effect on activation of NLRP3 inflammasome through TLR2 signal. Additionally, we found that exogenous addition of melatonin further increased protein expression of ASMT, as well as elevated the level of 5-HT in BALF and melatonin in lung homogenate in OVA-challenged WT mice. These interesting data suggested that the proven effect of exogenous melatonin in the resolution of inflammation was paralleled by the effect of endogenous synthesized melatonin.