Journal
ELIFE
Volume 9, Issue -, Pages -Publisher
ELIFE SCIENCES PUBLICATIONS LTD
DOI: 10.7554/eLife.50458
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Funding
- National Institute of Environmental Health Sciences [Z01ES102605, Z01ES102005]
- NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES [ZICES102546, ZIAES102005, ZIAES102605] Funding Source: NIH RePORTER
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Lung disease causes significant morbidity and mortality, and is exacerbated by environmental injury, for example through lipopolysaccharide (LPS) or ozone (O-3). 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 O-3, 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, O-3, hyaluronan), we show that TLR5 impacts the in vivo response to LPS, hyaluronan and O-3. We demonstrate that immune cells of human carriers of a dominant negative TLR5 allele have decreased inflammatory response to O-3 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.
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