Abstract
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.
Highlights
Asthma is one of the common respiratory diseases characterized by persistent or non-resolving allergen-driven inflammation
Immunohistochemistry and western blot results showed that Toll-like receptor 2 (TLR2) protein expression was significantly increased in OVA-challenged WT mice in comparison with that of control mice (Figures 1B,C), and TLR2 was expressed on various types of cells, such as epithelial cells and leukocytes
We demonstrated that OVA-induced allergic airway inflammation occurred in parallel with increasedexpression of TLR2, activation of nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome and decreased biosynthesis of melatonin
Summary
Asthma is one of the common respiratory diseases characterized by persistent or non-resolving allergen-driven inflammation. The other important type of intracellular PRRs, nucleotide-binding oligomerization domain-like receptors (NLRs) has been reported to be strongly associated with inflammatory diseases [5, 6]. The activation of NLRP3 inflammasome proteolytically cleaves pro-caspase-1 into active caspase-1, which in turn promotes maturation of IL-1β and IL-18 [9]. These two NLRP3-associated cytokines are critical in the initiation and amplification of inflammatory process [5]. TLRs and NLRs are two important kinds of PRRs, the formation and activation of NLRP3 inflammasome has been suggested to be initiated by TLRs [8, 15, 16]. The crosstalk between TLR2 and NLRP3 inflammasome activity in the allergic airway diseases, as well as the underlying mechanism is not clear
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