TLR5 participates in the TLR4 receptor complex and promotes MyD88-dependent signaling in environmental lung injury
Salik Hussain,
Collin G Johnson,
Joseph Sciurba,
Xianglin Meng,
Vandy P Stober,
Caini Liu,
Jaime M Cyphert-Daly,
Katarzyna Bulek,
Wen Qian,
Alma Solis,
Yosuke Sakamachi,
Carol S Trempus,
Jim J Aloor,
Kym M Gowdy,
W Michael Foster,
John W Hollingsworth,
Robert M Tighe,
Xiaoxia Li,
Michael B Fessler,
Stavros Garantziotis
Affiliations
Salik Hussain
National Institute of Environmental Health Sciences, Research Triangle Park, United States; Department of Physiology and Pharmacology, School of Medicine, West Virginia University, Morgantown, United States
Collin G Johnson
National Institute of Environmental Health Sciences, Research Triangle Park, United States; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, United States
Joseph Sciurba
National Institute of Environmental Health Sciences, Research Triangle Park, United States; Department of Veterinary Medicine, North Carolina State University, Raleigh, United States
Xianglin Meng
National Institute of Environmental Health Sciences, Research Triangle Park, United States; Department of ICU, First Affiliated Hospital of Harbin Medical University, Harbin, China
Vandy P Stober
National Institute of Environmental Health Sciences, Research Triangle Park, United States
Caini Liu
Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, United States
Jaime M Cyphert-Daly
National Institute of Environmental Health Sciences, Research Triangle Park, United States; Duke University Medical Center, Durham, United States
Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, United States; Department of Immunology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
Wen Qian
Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, United States
Alma Solis
National Institute of Environmental Health Sciences, Research Triangle Park, United States
Yosuke Sakamachi
National Institute of Environmental Health Sciences, Research Triangle Park, United States
Carol S Trempus
National Institute of Environmental Health Sciences, Research Triangle Park, United States
Jim J Aloor
National Institute of Environmental Health Sciences, Research Triangle Park, United States; East Carolina University Brody School of Medicine, Greenville, United States
Kym M Gowdy
National Institute of Environmental Health Sciences, Research Triangle Park, United States; East Carolina University Brody School of Medicine, Greenville, United States
W Michael Foster
Duke University Medical Center, Durham, United States
John W Hollingsworth
Duke University Medical Center, Durham, United States
Robert M Tighe
Duke University Medical Center, Durham, United States
Lung disease causes significant morbidity and mortality, and is exacerbated by environmental injury, for example through lipopolysaccharide (LPS) or ozone (O3). Toll-like receptors (TLRs) orchestrate immune responses to injury by recognizing pathogen- or danger-associated molecular patterns. TLR4, the prototypic receptor for LPS, also mediates inflammation after O3, triggered by endogenous hyaluronan. Regulation of TLR4 signaling is incompletely understood. TLR5, the flagellin receptor, is expressed in alveolar macrophages, and regulates immune responses to environmental injury. Using in vivo animal models of TLR4-mediated inflammations (LPS, O3, hyaluronan), we show that TLR5 impacts the in vivo response to LPS, hyaluronan and O3. We demonstrate that immune cells of human carriers of a dominant negative TLR5 allele have decreased inflammatory response to O3 exposure ex vivo and LPS exposure in vitro. Using primary murine macrophages, we find that TLR5 physically associates with TLR4 and biases TLR4 signaling towards the MyD88 pathway. Our results suggest an updated paradigm for TLR4/TLR5 signaling.
