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Quantification of Monocyte Chemotactic Activity In Vivo and Characterization of Blood Monocyte Derived Macrophages
Published on: August 12, 2019
Injury-induced MRP8/MRP14 stimulates IP-10/CXCL10 in monocytes/macrophages
Juan Wang1, Yoram Vodovotz2, Liyan Fan3
1State Key Laboratory of Organ Failure Research, Key Laboratory of Transcriptomics and Proteomics, Ministry of Education of China, Key Laboratory of Proteomics of Guangdong Province, Southern Medical University, Guangzhou, China; Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA;
Abstract:
Trauma/hemorrhagic shock is associated with morbidity and mortality due to dysregulated inflammation, which is driven in part by monocytes/macrophages stimulated by injury-induced release of damage-associated molecular pattern (DAMP) molecules. MRP8/MRP14 is an endogenous DAMP involved in various inflammatory diseases, though its mechanism of action is unclear. Circulating MRP8/MRP14 levels in human blunt trauma nonsurvivors were significantly lower than those of survivors (P < 0.001). Human monocytic THP-1 cells stimulated with MRP8/MRP14 expressed the chemokine IFN-γ inducible protein 10 (IP-10)/CXCL10. Circulating IP-10 levels in human blunt trauma patients were correlated positively with MRP8/MRP14 levels (r = 0.396, P < 0.001), and were significantly lower in trauma nonsurvivors than in survivors (P < 0.001). We therefore sought to determine the mechanisms by which MRP8/MRP14 stimulates IP-10 in monocytes/macrophages, and found that induction of IP-10 by MRP8/MRP14 required Toll-like receptor 4 and TRIF but not MyD88. Full induction of IP-10 by MRP8/MRP14 required synergy between the transcription factors NF-κB and IFN regulatory factor 3 (IRF3). The receptor for IP-10 is CXCR3, and MRP8/MRP14-induced chemotaxis of CXCR3(+) cells was dependent on the production of IP-10 in monocytes/macrophages. Furthermore, in vivo study with a mouse trauma/hemorrhagic shock model showed that administration of neutralizing antibody against MRP8 prevented activation of NF-κB and IRF3 as well as IP-10 production. Thus, the current study identified a novel signaling mechanism that controls IP-10 expression in monocytes/macrophages by MRP8/MRP14, which may play an important role in injury-induced inflammation.
Insights
Damage-associated molecular pattern MRP8/MRP14 is lower in trauma non-survivors. This study reveals MRP8/MRP14 signaling via Toll-like receptor 4 and TRIF drives IP-10 production, impacting inflammation.
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.
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