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TLR5 Participates in the TLR4 Receptor Complex and Biases Towards MyD88-Dependent Signaling in Environmental Lung Injury

51 Pages Posted: 14 Mar 2019 Publication Status: Review Complete

See all articles by Salik Hussain

Salik Hussain

National Institute of Environmental Health Sciences (NIEHS)

Collin G. Johnson

National Institute of Environmental Health Sciences (NIEHS)

Joseph Sciurba

National Institute of Environmental Health Sciences (NIEHS)

Xianglin Meng

National Institute of Environmental Health Sciences (NIEHS)

Vandy P. Stober

National Institute of Environmental Health Sciences (NIEHS)

Caini Liu

Cleveland Clinic Foundation - Lerner Research Institute

Annette B. Rice

National Institute of Environmental Health Sciences (NIEHS)

Jaime M. Cyphert-Daly

National Institute of Environmental Health Sciences (NIEHS)

Katarzyna Bulek

Cleveland Clinic Foundation - Lerner Research Institute

Wen Qian

Cleveland Clinic Foundation - Lerner Research Institute

Alma Solis

National Institute of Environmental Health Sciences (NIEHS)

Yosuke Sakamachi

National Institute of Environmental Health Sciences (NIEHS)

Carol S. Trempus

National Institute of Environmental Health Sciences (NIEHS)

Jim J. Aloor

East Carolina University - School of Medicine

Kym M. Gowdy

East Carolina University - School of Medicine

W. Michael Foster

Duke University - Medical Center

John W. Hollingsworth

Duke University - Medical Center

Robert M. Tighe

Duke University - Medical Center

Xiaoxia Li

Cleveland Clinic Foundation - Lerner Research Institute

Michael B. Fessler

National Institute of Environmental Health Sciences (NIEHS)

Stavros Garantziotis

National Institute of Environmental Health Sciences (NIEHS)

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Abstract

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.

Suggested Citation

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.

Salik Hussain

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Collin G. Johnson

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Joseph Sciurba

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Xianglin Meng

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Vandy P. Stober

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Caini Liu

Cleveland Clinic Foundation - Lerner Research Institute

9500 Euclid Avenue
Cleveland, OH 44195
United States

Annette B. Rice

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Jaime M. Cyphert-Daly

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Katarzyna Bulek

Cleveland Clinic Foundation - Lerner Research Institute

9500 Euclid Avenue
Cleveland, OH 44195
United States

Wen Qian

Cleveland Clinic Foundation - Lerner Research Institute

9500 Euclid Avenue
Cleveland, OH 44195
United States

Alma Solis

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Yosuke Sakamachi

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Carol S. Trempus

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Jim J. Aloor

East Carolina University - School of Medicine

600 Moye Boulevard
Greenville, NC 27858
United States

Kym M. Gowdy

East Carolina University - School of Medicine

600 Moye Boulevard
Greenville, NC 27858
United States

W. Michael Foster

Duke University - Medical Center

100 Fuqua Drive
Durham, NC 27715
United States

John W. Hollingsworth

Duke University - Medical Center

100 Fuqua Drive
Durham, NC 27715
United States

Robert M. Tighe

Duke University - Medical Center

100 Fuqua Drive
Durham, NC 27715
United States

Xiaoxia Li

Cleveland Clinic Foundation - Lerner Research Institute

9500 Euclid Avenue
Cleveland, OH 44195
United States

Michael B. Fessler

National Institute of Environmental Health Sciences (NIEHS)

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

Stavros Garantziotis (Contact Author)

National Institute of Environmental Health Sciences (NIEHS) ( email )

P.O. Box 12233, Mail Drop NH 06
Changping District
Research Triangle Park, NC Changping District 27709
United States

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