Circulating FABP5 released by dying macrophages function as a DAMP to exacerbate septic inflammation

Area of Science:

• Immunology
• Molecular Biology
• Sepsis Pathophysiology

Background:

• Damage-associated molecular patterns (DAMPs) can trigger excessive immune responses.
• Fatty Acid-Binding Protein 5 (FABP5) is known for fatty acid transport but its role in sepsis is unclear.
• Elevated FABP5 is linked to adverse sepsis outcomes.

Purpose of the Study:

• Investigate the role of FABP5 in sepsis.
• Determine the source and mechanism of FABP5's action in sepsis.
• Evaluate FABP5 as a therapeutic target in sepsis.

Main Methods:

• Measured circulating FABP5 levels in sepsis patients.
• Investigated FABP5 origin from macrophage pyroptosis.
• Examined FABP5 interaction with Toll-like receptor 4 (TLR4) and downstream signaling pathways (NF-κB, MAPK).
• Assessed the therapeutic potential of blocking circulating FABP5 in a mouse sepsis model.

Main Results:

• Circulating FABP5 levels were elevated in sepsis patients and correlated with poor outcomes.
• FABP5 originated from macrophage pyroptosis in late-stage sepsis.
• Circulating FABP5 activated TLR4, inducing secondary inflammation via NF-κB and MAPK pathways.
• Reduced, intracellular FABP5 suppressed macrophage pyroptosis, while oxidized, extracellular FABP5 promoted it.
• Blocking circulating FABP5 improved survival in mice with sepsis.

Conclusions:

• Circulating FABP5 acts as a DAMP in sepsis, exacerbating inflammation through TLR4 activation.
• FABP5 presents a potential therapeutic target for sepsis treatment.
• Strategies to reduce circulating FABP5 levels may improve sepsis outcomes.