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.
- Stavros Garantziotis
- Michael B Fessler
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: Mice were given access to water and chow ad libitum, and were maintained at a 12-hour dark-light cycle. All experiments are approved by the NIEHS Institutional Animal Care and Use Committee.
Human subjects: All subjects signed informed consent and all clinical research protocols were approved by the IRBs at Duke University Medical Center and the National Institute of Environmental Health Sciences, as applicable. The study described herein is using data collected as part of several clinical or translational studies (NCT01087307, NCT00341237, NCT00574158) and were approved by NIEHS and Duke IRBs (Protocol IRB approvals # 10-E-0063, 04-E-0053, 12496-CP-004)
- Jos WM van der Meer, Radboud University Medical Centre, Netherlands
- Received: July 23, 2019
- Accepted: January 24, 2020
- Accepted Manuscript published: January 28, 2020 (version 1)
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