title: Toll-like receptor ligands LPS and poly (I:C) exacerbate airway hyperresponsiveness in a model of airway allergy in mice, independently of inflammation.
abstract: It is well-established that bacterial and viral infections have an exacerbating effect on allergic asthma, particularly aggravating respiratory symptoms, such as airway hyperresponsiveness (AHR). The mechanism by which these infections alter AHR is unclear, but some studies suggest that Toll-like receptors (TLRs) play a role. In this study, we investigated the impact of TLR3 and TLR4 ligands on AHR and airway inflammation in a model of pre-established allergic inflammation. Female BALB/c mice were sensitised and challenged intranasally (i.n.) with either PBS or ovalbumin (OVA) and subsequently i.n. challenged with poly (I:C) (TLR3) or LPS (TLR4) for four consecutive days. The response to methacholine was measured in vivo; cellular and inflammatory mediators were measured in blood, lung tissue and broncheoalveolar lavage fluid (BALF). OVA challenge resulted in an increase in AHR to methacholine, as well as increased airway eosinophilia and TH2 cytokine production. Subsequent challenge with TLR agonists resulted in a significant increase in AHR, but decreased TLR-specific cellular inflammation and production of immune mediators. Particularly evident was a decline in LPS-induced neutrophilia and neutrophil-associated cytokines following LPS and poly (I:C) treatment. The present data indicates that TLRs may play a pivotal role in AHR in response to microbial infection in allergic lung inflammation. These data also demonstrate that aggravated AHR occurs in the absence of an exacerbation in airway inflammation and that allergic inflammation impedes a subsequent inflammatory response to TLRs. These results may parallel clinical signs of microbial asthma exacerbation, including an extended duration of illness and increased respiratory symptoms.
authors.affiliation: Divison of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Starkhammar
authors.affiliation: Divison of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olivia
authors.initials: O
authors.lastname: Larsson
authors.affiliation: Divison of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Susanna
authors.initials: S
authors.lastname: Kumlien Georén
authors.affiliation: Divison of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Marina
authors.initials: M
authors.lastname: Leino
authors.affiliation: Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Sven-Erik
authors.initials: SE
authors.lastname: Dahlén
authors.affiliation: Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden; Institute for Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Adner
authors.affiliation: Divison of ENT Diseases, CLINTEC, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Lars-Olaf
authors.initials: LO
authors.lastname: Cardell
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D005260:Female; D007249:Inflammation / Q000276:immunology* / Q000378:metabolism; D008024:Ligands; D051379:Mice; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D011070:Poly I-C / Q000276:immunology / Q000378:metabolism*; D012137:Respiratory System / Q000187:drug effects / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism
chemical_list: D008024:Ligands; C519703:TLR3 protein, mouse; C493487:Tlr4 protein, mouse; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4; D010047:Ovalbumin; D011070:Poly I-C
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