TLR5 participates in the TLR4 receptor complex and promotes MyD88-dependent signaling in environmental lung injury.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Hussain, S; Johnson, CG; Sciurba, J; Meng, X; Stober, VP; Liu, C; Cyphert-Daly, JM; Bulek, K; Qian, W; Solis, A; Sakamachi, Y; Trempus, CS; Aloor, JJ; Gowdy, KM; Foster, WM; Hollingsworth, JW; Tighe, RM; Li, X; Fessler, MB; Garantziotis, S

Published Date

  • January 28, 2020

Published In

Volume / Issue

  • 9 /

PubMed ID

  • 31989925

Pubmed Central ID

  • PMC7032926

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/eLife.50458


  • eng

Conference Location

  • England