Injury-induced MRP8/MRP14 stimulates IP-10/CXCL10 in monocytes/macrophages

Area of Science:

• Immunology
• Molecular Biology
• Trauma Research

Background:

• Trauma and hemorrhagic shock induce inflammation, increasing morbidity and mortality.
• Monocytes/macrophages, stimulated by damage-associated molecular patterns (DAMPs), drive this inflammation.
• The DAMP MRP8/MRP14's role in trauma-induced inflammation requires clarification.

Purpose of the Study:

• To elucidate the signaling mechanisms by which MRP8/MRP14 stimulates IP-10 production in monocytes/macrophages.
• To investigate the role of MRP8/MRP14 and IP-10 in trauma/hemorrhagic shock outcomes.

Main Methods:

• Measured circulating MRP8/MRP14 and IP-10 levels in human blunt trauma patients.
• Stimulated human monocytic THP-1 cells with MRP8/MRP14 to assess IP-10 expression.
• Investigated signaling pathways (TLR4, TRIF, MyD88, NF-κB, IRF3) involved in MRP8/MRP14-induced IP-10 production.
• Assessed MRP8/MRP14-induced chemotaxis of CXCR3(+) cells.
• Utilized a mouse trauma/hemorrhagic shock model with anti-MRP8 antibody treatment.

Main Results:

• Lower circulating MRP8/MRP14 and IP-10 levels were observed in trauma non-survivors compared to survivors.
• MRP8/MRP14 stimulation of THP-1 cells induced IP-10 expression.
• IP-10 induction required Toll-like receptor 4 (TLR4) and TRIF, synergizing NF-κB and IRF3 transcription factors.
• MRP8/MRP14-induced chemotaxis of CXCR3(+) cells depended on monocyte-derived IP-10.
• In vivo, anti-MRP8 antibody administration reduced NF-κB/IRF3 activation and IP-10 production in a mouse model.

Conclusions:

• Identified a novel signaling pathway where MRP8/MRP14 activates TLR4/TRIF, leading to NF-κB and IRF3-dependent IP-10 production in monocytes/macrophages.
• This MRP8/MRP14-IP-10 axis plays a significant role in regulating inflammation following trauma/hemorrhagic shock.
• Targeting MRP8/MRP14 may offer a therapeutic strategy for mitigating injury-induced inflammation.