title: Short ragweed pollen triggers allergic inflammation through Toll-like receptor 4-dependent thymic stromal lymphopoietin/OX40 ligand/OX40 signaling pathways.
abstract: BACKGROUND
  Allergic diseases affect a large population. Pollen, an ubiquitous allergen, is the trigger of seasonal rhinitis, conjunctivitis, and asthma, as well as an exacerbating factor of atopic dermatitis. However, the underlying mechanism by which pollen induces thymic stromal lymphopoietin (TSLP)-triggered allergic inflammation through epithelial innate immunity is largely unknown.
  
  
  OBJECTIVE
  We sought to explore whether short ragweed (SRW) pollen induces TSLP/OX40 ligand (OX40L)/OX40 signaling through Toll-like receptor (TLR) 4-dependent pathways in patients with allergic disease.
  
  
  METHODS
  Three models were used for this study, a well-characterized murine model of allergic conjunctivitis induced by SRW pollen, a topical challenge model on the murine ocular surface, and a culture model of primary human corneal epithelium exposed to aqueous extract of defatted SRW pollen (SRWe).
  
  
  RESULTS
  The topical challenges with SRW pollen generated typical allergic conjunctivitis in BALB/c mice. Clinical signs, stimulated TSLP/OX40L/OX40 signaling, and T(H)2 cytokine levels in the ocular mucosa and draining cervical lymph nodes were significantly reduced or eliminated in TLR4-deficient (Tlr4-d) or myeloid differentiation primary response gene 88 (MyD88) knockout (MyD88(-/-)) mice compared with those seen in their wild-type littermates. SRWe stimulated TSLP production by ocular epithelia in wild-type but not Tlr4-d or MyD88(-/-) mice. SRWe-stimulated TSLP was blocked by TLR4 antibody and nuclear factor κB inhibitor in murine and human corneal epithelia.
  
  
  CONCLUSIONS
  For the first time, we have shown that SRW pollen, acting as a functional TLR4 agonist, initiates TLR4-dependent TSLP/OX40L/OX40 signaling, which triggers T(H)2-dominant allergic inflammation. These findings shed light on the understanding of mucosal epithelial innate immunity and create new therapeutic targets to cure allergic diseases.
authors.affiliation: Ocular Surface Center, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, TX 77030, USA. dequanl@bcm.tmc.edu
authors.forename: De-Quan
authors.initials: DQ
authors.lastname: Li
authors.forename: Lili
authors.initials: L
authors.lastname: Zhang
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pflugfelder
authors.forename: Cintia S
authors.initials: CS
authors.lastname: De Paiva
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Zhang
authors.forename: Guiqiu
authors.initials: G
authors.lastname: Zhao
authors.forename: Xiaofen
authors.initials: X
authors.lastname: Zheng
authors.forename: Zhitao
authors.initials: Z
authors.lastname: Su
authors.forename: Yangluowa
authors.initials: Y
authors.lastname: Qu
mesh_terms: D031164:Ambrosia / Q000276:immunology; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D053278:OX40 Ligand / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D006255:Rhinitis, Allergic, Seasonal / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology*; D000094632:Thymic Stromal Lymphopoietin
chemical_list: D000943:Antigens, Differentiation; D016207:Cytokines; D053278:OX40 Ligand; C406562:OX40Ig; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000094632:Thymic Stromal Lymphopoietin