A novel opsonic eCIRP inhibitor for lethal sepsis

Area of Science:

• Immunology
• Molecular Biology
• Pathophysiology

Background:

• Sepsis is a life-threatening inflammatory condition driven by damage-associated molecular patterns like extracellular cold-inducible RNA-binding protein (eCIRP).
• Current therapeutic strategies for managing eCIRP-induced inflammation in sepsis are limited.
• The role of Milk fat globule-epidermal growth factor-VIII (MFG-E8) in eCIRP clearance was previously unexplored.

Purpose of the Study:

• To investigate the potential role of MFG-E8 in the clearance of eCIRP.
• To determine if MFG-E8 can attenuate eCIRP-mediated inflammation and sepsis.
• To explore MFG-E8-derived oligopeptides as a potential therapeutic agent.

Main Methods:

• Investigated the binding interaction between MFG-E8 and eCIRP.
• Utilized genetic disruption of MFG-E8 to assess its role in sepsis models.
• Administered MFG-E8-derived oligopeptides to evaluate their therapeutic efficacy in sepsis.

Main Results:

• MFG-E8 directly binds to eCIRP, facilitating its internalization via αvβ3-integrin and subsequent lysosomal degradation.
• Genetic deficiency of MFG-E8 exacerbated eCIRP accumulation and sepsis-induced acute lung injury.
• MFG-E8-derived oligopeptides mimicked MFG-E8's eCIRP-binding activity, attenuated eCIRP-induced inflammation, and protected against lethal sepsis.

Conclusions:

• MFG-E8 plays a crucial role in the clearance of eCIRP, thereby mitigating sepsis-associated inflammation.
• Targeting the MFG-E8/eCIRP interaction presents a novel therapeutic avenue for sepsis treatment.
• MFG-E8-based therapies hold potential for improving outcomes in patients with severe sepsis.