Asthma attacks that are triggered by allergens cause CD4+ T helper type 2 (TH2) cells to release various cytokines, including interleukin-4 (IL-4), IL-5, and IL-13, and TH17 cells to release IL-17. Cytokines from TH2 cells trigger immunoglobulin E (IgE) synthesis, accumulation of eosinophils in airways, inflammation in the pulmonary system, and temporary airway obstruction (or airway hyperresponsiveness), and IL-17 from TH17 cells triggers accumulation of neutrophils in airways and airway hyperresponsiveness. Wilson et al. investigated the ability of bacterial products such as flagellin, which activates Toll-like receptor 5 (TLR5), and lipopolysaccharide (LPS), which activates TLR4, to act as priming agents in house dust extracts to cause allergic sensitization. Inflammatory responses were more pronounced in the airways of mice instilled with ovalbumin and partially purified flagellin from Salmonella typhimurium (which contains LPS), highly purified recombinant flagellin, and highly purified LPS than in those of mice instilled with ovalbumin alone. Furthermore, mice that were sensitized with S. typhimurium or recombinant flagellin and ovalbumin and then challenged with ovalbumin showed enhanced airway hyperresponsiveness and increased concentrations of IL-4, IL-5, and IL-13 in bronchial lavage fluid and of IgE in serum. When sensitized with S. typhimurium flagellin before ovalbumin challenge, Tlr4 –/– and wild-type mice accumulated greater numbers of eosinophils and produced more IL-5 than did Tlr5 –/– mice. In contrast, Tlr4 –/– mice accumulated fewer neutrophils in airways than did Tlr5 –/– or wild-type mice. These results suggested that flagellin contributed to the response of TH2 cells and that LPS contributed to the response of TH17 cells. Various house dust extracts enhanced allergic responses to ovalbumin to varying extents and contained flagellin as detected by immunoblotting. When sensitized and challenged with house dust extracts, Tlr5 –/– mice accumulated fewer eosinophils in their airways and did not develop airway hyperresponsiveness to the same extent as did Tlr4 –/– or wild-type mice. Individuals with mild to moderate asthma had higher titers of antibodies directed against flagellin than did control subjects. Thus, flagellin can prime allergic responses to indoor allergens and promote allergic asthma.
R. H. Wilson, S. Maruoka, G. S. Whitehead, J. F. Foley, G. P. Flake, M. L. Sever, D. C. Zeldin, M. Kraft, S. Garantziotis, H. Nakano, D. N. Cook, The Toll-like receptor 5 ligand flagellin promotes asthma by priming allergic responses to indoor allergens. Nat. Med. 18, 1705–1710 (2012). [PubMed]