G2A Protects Mice against Sepsis by Modulating Kupffer Cell Activation: Cooperativity with Adenosine Receptor 2b.

Abstract

G2A is a GPCR abundantly expressed in immune cells. G2A-/- mice showed higher lethality, higher plasma cytokines, and an impaired bacterial clearance in response to a murine model of sepsis (cecal ligation and puncture), which were blocked by GdCl3, an inhibitor of Kupffer cells. Anti-IL-10 Ab reversed the impaired bacterial clearance in G2A-/- mice. Indomethacin effectively blocked both the increased i.p. IL-10 levels and the impaired bacterial clearance, indicating that disturbed PG system is the proximal cause of these phenomena. Stimulation with LPS/C5a induced an increase in Escherichia coli phagocytosis and intracellular cAMP levels in G2A+/+ peritoneal macrophages but not G2A-/- cells, which showed more PGE2/nitrite release and intracellular reactive oxygen species levels. Heterologous coexpression of G2A and adenosine receptor type 2b (A2bAR) induced a synergistic increase in cAMP signaling in a ligand-independent manner, with the evidence of physical interaction of G2A with A2bAR. BAY 60-6583, a specific agonist for A2bAR, increased intracellular cAMP levels in Kupffer cells from G2A+/+ but not from G2A-/- mice. Both G2A and A2bAR were required for antiseptic action of lysophosphatidylcholine. These results show inappropriate activation of G2A-/- Kupffer cells to septic insults due to an impaired cAMP signaling possibly by lack of interaction with A2bAR.

• Authors: Hong-Mei Li, Ji Hye Jang, Jun-Sub Jung, Jiseon Shin, Chul O Park, Yeon-Ja Kim, Won-Gyun Ahn, Ju-Suk Nam, Chang-Won Hong, Jongho Lee, Yu-Jin Jung, Jiang-Fan Chen, Katya Ravid, H Thomas Lee, Won-Ki Huh, Janusz H Kabarowski, Dong-Keun Song
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 202 Issue 2 Pg. 527-538 (01 15 2019) ISSN: 1550-6606 [Electronic] United States
• PMID: 30530591 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 by The American Association of Immunologists, Inc.

Chemical References

• Antibodies, Blocking
• Cell Cycle Proteins
• G2A receptor
• Reactive Oxygen Species
• Receptor, Adenosine A2B
• Receptors, G-Protein-Coupled
• Interleukin-10
• Cyclic AMP

Topics

• Animals
• Antibodies, Blocking
• Cell Cycle Proteins (genetics, metabolism)
• Cells, Cultured
• Cyclic AMP (metabolism)
• Disease Models, Animal
• Escherichia coli (physiology)
• Escherichia coli Infections (immunology)
• Humans
• Interleukin-10 (immunology, metabolism)
• Kupffer Cells (immunology)
• Macrophages, Peritoneal (microbiology, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Phagocytosis
• Protein Binding
• Reactive Oxygen Species (metabolism)
• Receptor Cross-Talk
• Receptor, Adenosine A2B (genetics, metabolism)
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Sepsis (genetics, metabolism)
• Signal Transduction