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De-Quan Li, Zhitao Su, Lili Zhang, Jing Lin, Cintia De Paiva, Stephen Pflugfelder; Dendritic Cell-produced TSLP Links Microbial Pathogens to Allergic Inflammation. Invest. Ophthalmol. Vis. Sci. 2013;54(15):3175.
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© ARVO (1962-2015); The Authors (2016-present)
Thymic stromal lymphopoietin (TSLP) has been identified to activate dendritic cells (DCs) to trigger Th2-dominant allergic inflammation. However, the role of DC-produced TSLP remains to be elucidated. The present study was to explore an autocrine mechanism of DCs in amplifying local allergic inflammation by producing TSLP that links microbial pathogens to allergy.
Bone marrow-derived DCs from BALB/c and MyD88 knockout mice were treated with or without microbial pathogens, ligands to Toll-like receptors (TLRs) 1-9, or TSLP. Murine models of the ocular topical challenge and experimental allergic conjunctivitis were used for in vivo study. The mRNA expression was determined by reverse transcription and quantitative real-time PCR (RT-qPCR). The protein production was evaluated by ELISA, Western blotting, flow cytometry, and immunofluorescent staining.
TSLP mRNA and protein were largely induced in DCs from BALB/c mice by lipopolysaccharide (LPS) and flagellin, ligands to TLR4 and TLR5 respectively. LPS and flagellin promoted DC maturation with enhanced expression of CD40, CD80, CD86 and MHC class II, as evaluated by flow cytometry. The expression of MyD88, NFκB1, NFκB2 and RelA, the nuclear translocation of NFκB p65, and the induction of TSLP mRNA and protein were significantly stimulated in DCs by flagellin, but blocked by TLR5 antibody or NFκB inhibitor, as analyzed by RT-qPCR, immunofluorescent staining, ELISA and Western blotting. These stimulatory effects of flagellin were also observed in DCs from MyD88+/+ but not in MyD88-/- mice. TSLP was found to promote expression of CD40, CD80, OX40 ligand, IL-13 and CCL17 by DCs. TSLP-producing DCs were further identified in vivo in mouse ocular surface and draining cervical lymph nodes by topically challenged LPS or flagellin. TSLP/OX40L signaling by DCs was also observed in ocular surface and cervical lymph nodes of BALB/c mice with experimental allergic conjunctivitis induced by short ragweed pollen.
Our findings demonstrated that DCs not only respond to TSLP, but also produce TSLP via TLR/MyD88/NFκB pathways in response to microbial pathogens, suggesting local allergic inflammation may be amplified by DC-produced TSLP through a potential autocrine mechanism.
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