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, 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
Abstract
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.
Trial registration: ClinicalTrials.gov NCT01087307 NCT00341237 NCT00574158.
Keywords: TLR4; TLR5; human; human biology; immunology; inflammation; innate immune receptors; medicine; mouse.
Conflict of interest statement
SH, CJ, JS, XM, VS, CL, JC, KB, WQ, AS, YS, CT, JA, KG, WF, JH, RT, XL, MF, SG No competing interests declared
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