Lung disease causes significant morbidity and mortality, and is exacerbated by environmental injury, e.g. through lipopolysaccharide (LPS) or ozone (O3) exposure. 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 prototypic receptor for flagellin, is expressed in alveolar macrophages, and regulates immune responses to environmental injury. We demonstrate that TLR5 physically associates with TLR4 and LPS, biases TLR4 signaling towards the MyD88 pathway, and impacts the in vivo response to LPS, hyaluronan and O3. Human carriers of a dominant negative TLR5 allele have decreased inflammatory response to O3 exposure in vivo and LPS exposure in vitro. Our results suggest an updated paradigm for LPS sensing and innate immunity and demonstrate a novel role for TLR5 in environmental lung injury.
Hussain, Salik and Johnson, Collin G. and Sciurba, Joseph and Meng, Xianglin and Stober, Vandy P. and Liu, Caini and Rice, Annette B. and Cyphert-Daly, Jaime M. and Bulek, Katarzyna and Qian, Wen and Solis, Alma and Sakamachi, Yosuke and Trempus, Carol S. and Aloor, Jim J. and Gowdy, Kym M. and Foster, W. Michael and Hollingsworth, John W. and Tighe, Robert M. and Li, Xiaoxia and Fessler, Michael B. and Garantziotis, Stavros, TLR5 Participates in the TLR4 Receptor Complex and Biases Towards MyD88-Dependent Signaling in Environmental Lung Injury (March 13, 2019). Available at SSRN: https://ssrn.com/abstract=3351826 or http://dx.doi.org/10.2139/ssrn.3351826
This version of the paper has not been formally peer reviewed.
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