Hyaluronan fragments promote inflammation by down-regulating the anti-inflammatory A2a receptor.

Abstract

The tissue microenvironment plays a critical role in regulating inflammation. Chronic inflammation leads to an influx of inflammatory cells and mediators, extracellular matrix turnover, and increased extracellular adenosine. Low molecular weight (LMW) fragments of hyaluronan (HA), a matrix component, play a critical role in lung inflammation and fibrosis by inducing inflammatory gene expression at the injury site. Adenosine, a crucial negative regulator of inflammation, protects tissues from immune destruction via the adenosine A2a receptor (A2aR). Therefore, these two extracellular products of inflammation play opposing roles in regulating immune responses. As such, we wanted to determine the effect of LMW HA on A2aR function. In this article, we demonstrate that LMW HA causes a rapid, significant, and sustained down-regulation of the A2aR. CD44 was found to be necessary for LMW HA to down-modulate the A2aR as was protein kinase C signaling. We also demonstrate that LMW HA induces A2aR down-regulation during inflammation in vivo, and that this down-regulation can be blocked by treatment with an HA-blocking peptide. Because adenosine plays a critical role in limiting inflammation, our data provide a novel mechanism whereby LMW HA itself may further augment inflammation. By defining the pro- and anti-inflammatory properties of extracellular matrix components, we will be better able to identify specific pharmacologic targets as potential therapies.

• Authors: Samuel L Collins, Katharine E Black, Yee Chan-Li, Young-Hoon Ahn, Philip A Cole, Jonathan D Powell, Maureen R Horton
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 45 Issue 4 Pg. 675-83 (Oct 2011) ISSN: 1535-4989 [Electronic] United States
• PMID: 21257926 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Anti-Inflammatory Agents
• Cd44 protein, mouse
• Hyaluronan Receptors
• Inflammation Mediators
• Lipopolysaccharides
• Myd88 protein, mouse
• Myeloid Differentiation Factor 88
• Peptide Fragments
• Peptides
• Protein Kinase Inhibitors
• RNA, Messenger
• Receptor, Adenosine A2A
• Tlr2 protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 4
• Hyaluronic Acid
• Protein Kinase C

Topics

• Animals
• Anti-Inflammatory Agents (pharmacology)
• Cell Line
• Disease Models, Animal
• Down-Regulation
• Hyaluronan Receptors (genetics, metabolism)
• Hyaluronic Acid (antagonists & inhibitors, metabolism)
• Inflammation Mediators (metabolism)
• Lipopolysaccharides
• Macrophages, Alveolar (drug effects, immunology, metabolism)
• Macrophages, Peritoneal (drug effects, immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Myeloid Differentiation Factor 88 (genetics, metabolism)
• Peptide Fragments (antagonists & inhibitors, metabolism)
• Peptides (pharmacology)
• Pneumonia (genetics, immunology, metabolism, prevention & control)
• Protein Kinase C (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• RNA, Messenger (metabolism)
• Receptor, Adenosine A2A (genetics, metabolism)
• Time Factors
• Toll-Like Receptor 2 (genetics, metabolism)
• Toll-Like Receptor 4 (genetics, metabolism)