cAMP ameliorates inflammation by modulation of macrophage receptor for advanced glycation end-products.

Abstract

Clarification of the roles of PAMPs (pathogen-associated molecular patterns) and DAMPs (damage-associated molecular patterns) is indispensable for therapeutic strategies against various inflammatory diseases. RAGE (receptor for advanced glycation end-products) is one of the PRRs (pattern recognition receptors) and has been implicated in autoimmune and inflammatory diseases. Effective remedies targeting RAGE are required for the diseases. In the present study, we show that cAMP-induced modulation of the RAGE isoform in macrophages can control the inflammatory state in both in vitro and in vivo experimental conditions. The RAGE ligand S100B stimulated MCP-1 (monocyte chemoattractant protein-1) secretion from peritoneal macrophages, but cAMP elevation suppressed it by converting the RAGE isoform from a membrane-bound into a soluble form. This shedding is the result of ectodomain cleavage of mRAGE (membrane-bound RAGE) by MMP9 (matrix metalloproteinase 9). Furthermore, forskolin significantly inhibited peritoneal macrophage accumulation in a mouse S100B-induced peritonitis model. These results suggest that cAMP serves as a negative regulator of ligand-RAGE signalling and macrophage recruitment by mRAGE down-regulation and formation of decoys as soluble receptors. The present study should deepen our understanding of the pathogenesis of RAGE-mediated tissue derangement and provide new clues for overcoming RAGE-related inflammatory diseases.

• Authors: So Motoyoshi, Yasuhiko Yamamoto, Seiichi Munesue, Hirobumi Igawa, Ai Harashima, Hidehito Saito, Dong Han, Takuo Watanabe, Hiroshi Sato, Hiroshi Yamamoto
• Journal: The Biochemical journal (Biochem J) Vol. 463 Issue 1 Pg. 75-82 (Oct 01 2014) ISSN: 1470-8728 [Electronic] England
• PMID: 24995813 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ccl2 protein, mouse
• Chemokine CCL2
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic
• S100 Calcium Binding Protein beta Subunit
• S100b protein, mouse
• Cyclic AMP
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Chemokine CCL2 (genetics, metabolism)
• Cyclic AMP (genetics, metabolism)
• Inflammation (genetics, metabolism, pathology)
• Macrophages, Peritoneal (metabolism, pathology)
• Matrix Metalloproteinase 9 (genetics, metabolism)
• Mice
• Mice, Knockout
• Protein Structure, Tertiary
• Proteolysis
• Receptor for Advanced Glycation End Products
• Receptors, Immunologic (genetics, metabolism)
• S100 Calcium Binding Protein beta Subunit (genetics, metabolism)
• Signal Transduction