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

  title={Regulation of lung injury and repair by Toll-like receptors and hyaluronan},
  author={Dianhua Jiang and Jiurong Liang and Juan Fan and Shuang Yu and Suping Chen and Yi Luo and Glenn D. Prestwich and Marcella M. Mascarenhas and Hari G. Garg and Deborah A. Quinn and Robert J. Homer and Daniel R. Goldstein and Richard J. Bucala and Patty J. Lee and Ruslan Medzhitov and Paul W. Noble},
  journal={Nature Medicine},
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… 

Matrix regulation of lung injury, inflammation, and repair: the role of innate immunity.

It is found that Toll-like receptors 2 and 4 (TLR2 and TLR4) are responsible for macrophage inflammatory gene expression in response to hyaluronan fragments, and they have a protective role against lung injury on alveolar epithelial cells.

The role of Toll-like receptors in non-infectious lung injury

It is identified that host matrix component HA and TLR interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from acute lung injury.

Hyaluronan in tissue injury and repair.

The interactions between the endogenous matrix component hyaluronan and its signaling receptors initiate inflammatory responses, maintain structural cell integrity, and promote recovery from tissue injury.

TLR4 promotes fibrosis but attenuates tubular damage in progressive renal injury.

TLR4 attenuates tubular damage but promotes renal fibrosis by modulating the susceptibility of renal cells to TGF-beta, suggesting that TLR4 signaling may be a therapeutic target for the prevention of renal Fibrosis.

Differential toll-like receptor activation in lung ischemia reperfusion injury.

The Role of Toll-Like Receptor 2 in Inflammation and Fibrosis during Progressive Renal Injury

It is found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury and that the absence ofTLR2 does not affect the development of chronic renal Injury and fibrosis.

Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice

Evidence is provided that expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for A EC2 renewal, repair of lung injury and limiting the extent of fibrosis.

Hyaluronan Signaling during Ozone-Induced Lung Injury Requires TLR4, MyD88, and TIRAP

The findings support that ozone-induced airway hyperresponsiveness is dependent on the HA-TLR4-MyD88-TIRAP signaling pathway.

TLR5 participates in the TLR4 receptor complex and biases towards MyD88-dependent signaling in environmental lung injury

It is demonstrated 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, and suggests an updated paradigm for TLR4/TLR5 signaling.



Hyaluronan Fragments Stimulate Endothelial Recognition of Injury through TLR4*

Observations suggest that endogenous components of the extracellular matrix can stimulate endothelia to trigger recognition of injury in the initial stages of the wound defense and repair response.

Resolution of Lung Inflammation by CD44

CD44-deficient mice succumb to unremitting inflammation following noninfectious lung injury, characterized by impaired clearance of apoptotic neutrophils, persistent accumulation of hyaluronan fragments at the site of tissue injury, and impaired activation of transforming growth factor–β1.

Regulation of hyaluronan-induced chemokine gene expression by IL-10 and IFN-gamma in mouse macrophages.

A previously unrecognized role for IL-10 and IFN-gamma are identified as regulators of ECM-induced macrophage expression of inflammatory chemokines in primary mouse macrophages.

Induction of IL-12 and chemokines by hyaluronan requires adhesion-dependent priming of resident but not elicited macrophages.

The results provide further evidence of the potential importance of CD44/LMW-HA interactions in regulating the immune response at sites of inflammation and demonstrate that the state of differentiation of macrophages may determine their sensitivities to matrix components.

γδ T cell–induced hyaluronan production by epithelial cells regulates inflammation

It is shown that γδ T cells are required for hyaluronan deposition in the extracellular matrix (ECM) and subsequent macrophage infiltration into wound sites and a new perspective on T cell regulation of ECM molecules is provided.

Oligosaccharides of Hyaluronan Activate Dendritic Cells via Toll-like Receptor 4

This is the first report that polysaccharide degradation products of the extracellular matrix produced during inflammation might serve as an endogenous ligand for the TLR-4 complex on DCs.

Expression of functional toll-like receptor-2 and -4 on alveolar epithelial cells.

It is shown that human primary ATII cells express mRNA and protein for both TLR-2 andTLR-4, which can be modulated by incubation with LPS and tumor necrosis factor, which suggests that ATII have the potential to contribute significantly to the host defense of the human alveolus against bacteria.

Hyaluronan fragments activate an NF-kappa B/I-kappa B alpha autoregulatory loop in murine macrophages

Activation of the NF-kappa B/I- kappa B system in macrophages by ECM fragments may be an important mechanism for propagating the tissue inflammatory response.

Protection from lethal apoptosis in lipopolysaccharide-induced acute lung injury in mice by a caspase inhibitor.

Low molecular weight hyaluronan from stretched lung enhances interleukin-8 expression.

Results indicated that de novo synthesis of LMW HA was induced in lung fibroblasts by stretch via tyrosine kinase signaling pathways, and may play a role in augmenting induction of proinflammatory cytokines in VILI.