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

Dianhua Jiang¹, Jiurong Liang¹, Juan Fan¹, Shuang Yu¹, Suping Chen², Yi Luo³, Glenn D Prestwich³, Marcella M Mascarenhas⁴, Hari G Garg⁴, Deborah A Quinn⁴, Robert J Homer², Daniel R Goldstein⁵, Richard Bucala⁶, Patty J Lee¹, Ruslan Medzhitov⁷ & Paul W Noble¹

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

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

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

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

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

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

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

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-B. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.

	Top