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

Area of Science:

• Immunology
• Cellular and Molecular Biology
• G protein-coupled receptors (GPCRs)

Background:

• G2A, a G protein-coupled receptor (GPCR), is highly expressed in immune cells.
• The role of G2A in immune response, particularly during sepsis, requires further elucidation.

Purpose of the Study:

• To investigate the role of G2A in the host defense mechanism against sepsis.
• To explore the underlying molecular mechanisms, including cAMP signaling and inflammatory responses, associated with G2A deficiency in sepsis.

Main Methods:

• Utilized a murine model of sepsis (cecal ligation and puncture) in G2A knockout (G2A^-/-) and wild-type (G2A^+/+) mice.
• Assessed lethality, plasma cytokine levels, bacterial clearance, and macrophage function (phagocytosis, cAMP, PGE2, nitrite, ROS).
• Investigated the interaction between G2A and adenosine receptor type 2b (A2bAR) using coexpression studies and specific agonists.

Main Results:

• G2A^-/- mice exhibited increased lethality, elevated plasma cytokines, and impaired bacterial clearance during sepsis.
• Impaired bacterial clearance in G2A^-/- mice was linked to increased IL-10 levels and prostaglandin E2 (PGE2) production, suggesting a disturbed prostaglandin system.
• G2A deficiency led to impaired phagocytosis and cAMP signaling in response to LPS/C5a stimulation, with increased PGE2, nitrite, and reactive oxygen species (ROS) production.
• G2A and A2bAR physically interact and synergistically enhance cAMP signaling in a ligand-independent manner; this interaction is crucial for the anti-septic effects of lysophosphatidylcholine.

Conclusions:

• G2A plays a critical role in regulating Kupffer cell function and host defense during sepsis.
• Impaired cAMP signaling due to G2A deficiency, potentially exacerbated by a lack of interaction with A2bAR, leads to inappropriate Kupffer cell activation and contributes to sepsis severity.
• Targeting the G2A-A2bAR interaction could offer a therapeutic strategy for sepsis management.