title: JNK-TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis.
abstract: 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.
authors.affiliation: Anhui Geriatric Institute, Department of Pulmonary, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Hui-Mei
authors.initials: HM
authors.lastname: Wu
authors.affiliation: Anhui Geriatric Institute, Department of Pulmonary, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Qi-Ying
authors.initials: QY
authors.lastname: Shen
authors.affiliation: Anhui Geriatric Institute, Department of Pulmonary, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: Anhui Geriatric Institute, Department of Pulmonary, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Shi-Hai
authors.initials: SH
authors.lastname: Zhang
authors.affiliation: Anhui Geriatric Institute, Department of Pulmonary, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Pei-Ting
authors.initials: PT
authors.lastname: Shen
authors.affiliation: Center for Reproductive Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Ya-Jing
authors.initials: YJ
authors.lastname: Liu
authors.affiliation: Anhui Geriatric Institute, Department of Pulmonary, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Rong-Yu
authors.initials: RY
authors.lastname: Liu
mesh_terms: D000818:Animals; D001249:Asthma / Q000378:metabolism*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006967:Hypersensitivity / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008550:Melatonin / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011014:Pneumonia / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000378:metabolism*
chemical_list: C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D008550:Melatonin
keywords: TLR9; allergic airway inflammation; c-Jun NH2 terminal kinase; melatonin synthesis; signal pathway