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Regulation of lung injury and repair by Toll-like receptors and hyaluronan

Nature Medicine volume 11, pages 1173–1179 (2005)Cite this article

Abstract

Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88−/− and Tlr4−/−Tlr2−/− mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell–specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell–surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-κB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.

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Figure 1: Hyaluronan fragments stimulate chemokine expression through both TLR4 and TLR2.
Figure 2: Impaired lung inflammatory cell recruitment but increased lung injury in the absence of TLR2 and TLR4.
Figure 3: TLRs and hyaluronan regulate lung cell apoptosis.
Figure 4: Blockade of hyaluronan function in vivo impairs lung inflammatory cell recruitment but worsens lung injury.
Figure 5: Overexpression of high-molecular-mass hyaluronan ameliorates lung injury in CC10-HAS2 transgenic mice.
Figure 6: Cell-surface hyaluronan protects epithelial cells from apoptosis through NF-κB.

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Acknowledgements

The authors wish to thank S. Akira (University of Osaka, Japan) for providing MyD88- and TLR-deficient mice, and J.A. McDonald (Mayo Clinic, Scottsdale, Arizona) for providing mouse Has2 cDNA. This work was supported by US National Institutes of Health grants HL57486 and AI52487 (to P.W.N.). G.D.P. acknowledges funding by a Department of Defense for a Breast Cancer Idea Award and by the Center for Cell Signaling at the University of Utah. The authors would like to acknowledge the contributions of J. Hodge (Yale University School of Medicine) for constructive comments.

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Authors and Affiliations

  1. Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Dianhua Jiang, Jiurong Liang, Juan Fan, Shuang Yu, Patty J Lee & Paul W Noble

  2. Department of Pathology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Suping Chen & Robert J Homer

  3. Department of Medicinal Chemistry, The University of Utah, 50 North Medical Center Drive, Salt Lake City, 84132, Utah, USA

    Yi Luo & Glenn D Prestwich

  4. Department of Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, 55 Fruit Street, Boston, 02114, Massachusetts, USA

    Marcella M Mascarenhas, Hari G Garg & Deborah A Quinn

  5. Section of Cardiology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Daniel R Goldstein

  6. Section of Rheumatology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Richard Bucala

  7. Howard Hughes Medical Institute, Section of Immunobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, 06520, Connecticut, USA

    Ruslan Medzhitov

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Supplementary information

Supplementary Fig. 1

Hyaluronan fragment–induced chemokine expression is TLR2-, TLR4- and MyD88-dependent. (PDF 69 kb)

Supplementary Fig. 2

Hyaluronan fragment–induced chemokine expression is independent of TLR1, TLR3, TLR5 and TLR9. (PDF 64 kb)

Supplementary Fig. 3

Human hyaluronan fragment–induced chemokine expression is TLR2-, TLR4- and MyD88-dependent. (PDF 50 kb)

Supplementary Fig. 4

Specificity of hyaluronan-induced chemokine expression. (PDF 102 kb)

Supplementary Fig. 5

Effect of KC on inflammatory responses to bleomycin lung injury. (PDF 45 kb)

Supplementary Fig. 6

Impaired KC induction by bleomycin in Tlr2−/−Tlr4−/− epithelial cells. (PDF 37 kb)

Supplementary Fig. 7

Tlr2−/−Tlr4−/− mice are more susceptible to hyperoxia. (PDF 46 kb)

Supplementary Fig. 8

Effect of hyaluronan-blocking peptide on survival of mice with bleomycin injury. (PDF 44 kb)

Supplementary Methods (PDF 37 kb)

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Jiang, D., Liang, J., Fan, J. et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med 11, 1173–1179 (2005). https://doi.org/10.1038/nm1315

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