JNK–TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis

Feb 26, 2016Journal of pineal research

The JNK-TLR9 pathway may cause allergic airway inflammation by lowering melatonin production

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Abstract

TLR9 deficiency effectively inhibited airway inflammation in a mouse model of allergic airway disease.

TLR9 expression increased alongside airway inflammation following OVA challenge.
Deficiency of TLR9 reduced serum OVA-specific immunoglobulin E (IgE) levels, pulmonary inflammatory cell recruitment, mucus secretion, and inflammatory cytokine production in bronchoalveolar lavage fluid (BALF).
Hydroxyindole-o-methyltransferase (HIOMT) protein levels and melatonin levels in serum and BALF decreased in OVA-challenged wild-type mice, while deficiency of TLR9 restored these levels.
Inhibition of JNK reduced TLR9 expression after OVA exposure and promoted resolution of allergic airway inflammation in wild-type mice, but not in TLR9-deficient mice.
The findings suggest that the JNK-TLR9 signaling pathway may mediate allergic airway inflammation by suppressing melatonin production.

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Toll-like receptors (TLRs) play pivotal role in the pathogenesis of allergic airway diseases such as asthma. TLR9 is one of the most extensively studied TLRs as an approach to treat asthma. In this study, we investigated the role of TLR9 in the allergic airway inflammation and the underlying mechanism. Wild-type (WT) mice and TLR9(-/-) mice were sensitized and challenged with OVA to establish allergic airway disease model. We found that the expression of TLR9 was elevated concomitantly with airway inflammation post-OVA challenge, and TLR9 deficiency effectively inhibited airway inflammation, including serum OVA-specific immunoglobulin E (IgE), pulmonary inflammatory cell recruitment, mucus secretion, and bronchoalveolar lavage fluid (BALF) inflammatory cytokine production. Meanwhile, the protein expression of hydroxyindole-o-methyltransferase (HIOMT) in lung tissues, the level of melatonin in serum, and BALF were reduced in OVA-challenged WT mice, while these reductions were significantly restored by TLR9 deficiency. Additionally, we showed that although TLR9 deficiency had no effect on OVA-induced phosphorylation of JNK, inhibition of JNK by specific inhibitor SP600125 significantly decreased OVA-induced expression of TLR9, suggesting that JNK is the upstream signal molecular of TLR9. Furthermore, SP600125 treatment promoted resolution of allergic airway inflammation in OVA-challenged WT mice, but not further ameliorated allergic airway inflammation in OVA-challenged TLR9(-/-) mice. Similarly, SP600125 significantly restored the protein expression of HIOMT and the level of melatonin in OVA-challenged WT mice, while such effect was not further enhanced by TLR9 deficiency. Collectively, our results indicated that JNK-TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis.

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JNK–TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis

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