title: Injury-induced MRP8/MRP14 stimulates IP-10/CXCL10 in monocytes/macrophages.
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.
authors.affiliation: State 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;
authors.forename: Juan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Yoram
authors.initials: Y
authors.lastname: Vodovotz
authors.affiliation: University of Pittsburgh School of Arts and Science, Pittsburgh, Pennsylvania, USA; and.
authors.forename: Liyan
authors.initials: L
authors.lastname: Fan
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA;
authors.forename: Yuehua
authors.initials: Y
authors.lastname: Li
authors.affiliation: State 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;
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA;
authors.forename: Rami
authors.initials: R
authors.lastname: Namas
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA;
authors.forename: Derek
authors.initials: D
authors.lastname: Barclay
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA;
authors.forename: Ruben
authors.initials: R
authors.lastname: Zamora
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA;
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wilson
authors.affiliation: State 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; Research and Development, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA; McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA jiang48231@163.com jif7@pitt.edu.
authors.forename: Jie
authors.initials: J
authors.lastname: Fan
authors.affiliation: State 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; jiang48231@163.com jif7@pitt.edu.
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D040501:Calgranulin A / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D040502:Calgranulin B / Q000097:blood / Q000378:metabolism*; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009000:Monocytes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012771:Shock, Hemorrhagic / Q000097:blood / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014947:Wounds and Injuries / Q000097:blood / Q000235:genetics / Q000378:metabolism*
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002118:Calcium; D040501:Calgranulin A; D040502:Calgranulin B; D054357:Chemokine CXCL10; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; C114753:CXCL10 protein, human; C494232:IRF3 protein, human; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse
keywords: IFN regulatory factor 3; Toll-like receptor 4; myeloid-related protein