title: Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP.
abstract: Ozone exposure is associated with exacerbation of reactive airways disease. We have previously reported that the damage-associated molecular pattern, hyaluronan, is required for the complete biological response to ambient ozone and that hyaluronan fragments signal through toll-like receptor 4 (TLR4). In this study, we further investigated the role of TLR4 adaptors in ozone-induced airway hyperresponsiveness (AHR) and the direct response to hyaluronan fragments (HA). Using a murine model of AHR, C57BL/6J, TLR4-/-, MyD88-/-, and TIRAP-/- mice were characterized for AHR after exposure to either ozone (1 ppm × 3 h) or HA fragments. Animals were characterized for AHR with methacholine challenge, cellular inflammation, lung injury, and production of pro-inflammatory cytokines. Ozone-exposed C57BL/6J mice developed cellular inflammation, lung injury, pro-inflammatory cytokines, and AHR, while mice deficient in TLR4, MyD88 or TIRAP demonstrated both reduced AHR and reduced levels of pro-inflammatory cytokines including TNFα, IL-1β, MCP-1, IL-6 and KC. The level of hyaluronan was increased after inhalation of ozone in each strain of mice. Direct challenge of mice to hyaluronan resulted in AHR in C57BL/6J mice, but not in TLR4-/-, MyD88-/-, or TIRAP-/- mice. HA-induced cytokine production in wild-type mice was significantly reduced in TLR4-/-, MyD88-/-, or TIRAP-/- mice. In conclusion, our findings support that ozone-induced airway hyperresponsiveness is dependent on the HA-TLR4-MyD88-TIRAP signaling pathway.
authors.affiliation: Department of Medicine, Duke University, Durham, North Carolina, United States of America.
authors.forename: Zhuowei
authors.initials: Z
authors.lastname: Li
authors.forename: Erin N
authors.initials: EN
authors.lastname: Potts-Kant
authors.forename: Stavros
authors.initials: S
authors.lastname: Garantziotis
authors.forename: W Michael
authors.initials: WM
authors.lastname: Foster
authors.forename: John W
authors.initials: JW
authors.lastname: Hollingsworth
mesh_terms: D000818:Animals; D006820:Hyaluronic Acid / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D010126:Ozone / Q000633:toxicity*; D017472:Receptors, Interleukin-1 / Q000502:physiology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000502:physiology*
chemical_list: D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C499045:TIRAP protein, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D010126:Ozone; D006820:Hyaluronic Acid
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