RT Journal Article
SR Electronic
T1 TLR5 participates in the TLR4 receptor complex and biases towards MyD88-dependent signaling in environmental lung injury
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 792705
DO 10.1101/792705
A1 Salik Hussain
A1 Collin G Johnson
A1 Joseph Sciurba
A1 Xianglin Meng
A1 Vandy P Stober
A1 Caini Liu
A1 Jaime M Cyphert-Daly
A1 Katarzyna Bulek
A1 Wen Qian
A1 Alma Solis
A1 Yosuke Sakamachi
A1 Carol S Trempus
A1 Jim J Aloor
A1 Kym M Gowdy
A1 W. Michael Foster
A1 John W Hollingsworth
A1 Robert M Tighe
A1 Xiaoxia Li
A1 Michael B Fessler
A1 Stavros Garantziotis
YR 2019
UL http://biorxiv.org/content/early/2019/10/03/792705.abstract
AB Lung disease causes significant morbidity and mortality, and is exacerbated by environmental injury, e.g. 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.