Connexin-43-dependent ATP release mediates macrophage activation during sepsis

Area of Science:

• Immunology
• Cell Biology
• Sepsis Pathophysiology

Background:

• Bacterial translocation into sterile sites from perforated organs causes peritonitis and sepsis.
• Macrophage activation via extracellular ATP and purinergic signaling is crucial for sepsis outcome.
• Mechanisms of ATP release from macrophages remain largely unknown.

Purpose of the Study:

• To investigate the role of Connexin-43 hemichannels in macrophage ATP release during sepsis.
• To determine the impact of Connexin-43-mediated signaling on sepsis survival.
• To evaluate therapeutic strategies targeting Connexin-43 in sepsis.

Main Methods:

• Utilized Toll-like receptor (TLR) agonists and a murine peritonitis/sepsis model (CLP).
• Assessed Connexin-43 expression in human and murine macrophages.
• Generated conditional knockout mice (Lyz2cre/creGja1flox/flox) to delete Connexin-43 specifically in macrophages.
• Employed pharmacological blockade of Connexin-43 hemichannels.

Main Results:

• TLR-2 and TLR-4 agonists induce ATP release through Connexin-43 hemichannels in macrophages, correlating with poor sepsis survival.
• Connexin-43 is upregulated on macrophages in human peritonitis patients and in murine models.
• Macrophage-specific deletion or pharmacological inhibition of Connexin-43 reduced pro-inflammatory cytokine release and improved survival in sepsis models.

Conclusions:

• Connexin-43 hemichannels mediate ATP release from macrophages, contributing to sepsis pathogenesis.
• Targeting macrophage Connexin-43-dependent ATP signaling represents a promising therapeutic approach to improve sepsis outcomes.