Ubiquitin immunoreactivity in cerebrospinal fluid after traumatic brain injury: Clinical and experimental findings

Majetschak, Matthias; King, David R.; Krehmeier, Ulrich; Busby, Lissette T; Thomé, Claudius; Vajkoczy, Susanne; Proctor, Kenneth G.

doi:10.1097/01.ccm.0000169883.41245.23

Cited by 43 publications

(48 citation statements)

References 19 publications

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“…The observation that i.v. AMD3100 did not affect ubiquitin plasma levels further supports the assumption that the majority of extracellular ubiquitin originates from its passive release from cells and tissues undergoing physiological turnover or damage (16)(17)(18)37,56).…”

Section: Discussionsupporting

confidence: 54%

Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

Bach

Saini

Baker

et al. 2012

Mol Med

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CXC chemokine receptor (CXCR)-4 agonists have been shown to attenuate inflammation and organ injury in various disease models, including trauma/hemorrhage. The pathophysiological role of CXCR4 during the early response to tissue injury, however, remains unknown. Therefore, we investigated the effects of AMD3100, a drug that antagonizes binding of stromal cell-derived factor (SDF)-1α and ubiquitin to CXCR4 during the initial response to polytrauma in pigs. Fifteen minutes before polytrauma (femur fractures/lung contusion; control: sham), 350 nmol/kg AMD3100, equimolar AMD3100 and ubiquitin (350 nmol/kg each) or vehicle were administered intravenously. After a 60-min shock period, fluid resuscitation was performed for 360 min. Ubiquitin binding to peripheral blood mononuclear cells was significantly reduced after intravenous AMD3100. SDF-1α plasma levels increased transiently >10-fold with AMD3100 in all animals. In injured animals, AMD3100 increased fluid requirements to maintain hemodynamics and enhanced increases in peripheral blood granulocytes, lymphocytes and monocytes, compared with its effects in uninjured animals. Cytokine release from leukocytes in response to Toll-like receptor (TLR)-2 and TLR-4 activation was increased after in vitro AMD3100 treatment of normal whole blood and after in vivo AMD3100 administration in animals subjected to polytrauma. Coadministration of AMD3100/ubiquitin reduced lactate levels, prevented AMD3100-induced increases in fluid requirements and sensitization of the tumor necrosis factor (TNF)-α and interleukin (IL)-6 release upon TLR-2/4 activation, but did not attenuate increases in leukocyte counts and SDF-1α plasma levels. Our findings suggest that CXCR4 controls leukocyte mobilization after trauma, regulates leukocyte reactivity toward inflammatory stimuli and mediates protective effects during the early phase of trauma-induced inflammation.

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Section: Discussionsupporting

confidence: 54%

Initial Assessment of the Role of CXC Chemokine Receptor 4 after Polytrauma

Bach

Saini

Baker

et al. 2012

Mol Med

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“…Previous studies suggested that the majority of extracellular ubiquitin originates from damaged cells and tissues, and we identified erythrocytes as a major source (12,13,48). Although mature erythrocytes contain high amounts of ubiquitin, they have lost substantial amounts of enzymes of the ubiquitin proteasome pathway (4,49).…”

Section: Discussionmentioning

confidence: 99%

CXC Chemokine Receptor 4 Is a Cell Surface Receptor for Extracellular Ubiquitin

Saini

Marchese

Majetschak

2010

Journal of Biological Chemistry

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152

204

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Ubiquitin is one of the most highly conserved proteins in eukaryotes and plays major biological roles as a post-translational protein modifier. Ubiquitin is also a natural constituent of plasma, and several lines of evidence suggest that extracellular ubiquitin is an immune modulator with anti-inflammatory properties. In addition, ubiquitin treatment has been shown to limit inflammation and reduce organ injury in various disease models and species in vivo. However, its mechanism of action is unknown. Here we show that extracellular ubiquitin is a natural CXC chemokine receptor 4 (CXCR4 and CD184) agonist. Extracellular ubiquitin promotes intracellular Ca 2؉ flux and reduces cAMP levels through a G protein-coupled receptor that signals via a G␣ i/o protein in THP1 cells. Toll-like receptor 4 stimulation reduces ubiquitin-binding sites, which enabled identification of four G␣ i/o PCRs as ubiquitin receptor candidates. Overexpression of candidate genes in HEK293 cells, gene silencing in THP1 cells, competition binding, and signaling studies with the CXCR4 agonist stromal cell-derived factor-1␣ (chemokine (CXC motif) ligand 12) and inhibitor AMD3100 identify CXCR4 as a functional ubiquitin receptor. Our finding uncovers a fundamentally new aspect of the role of ubiquitin in biology, has implications for the understanding of CXCR4-mediated events, and is expected to facilitate development of new therapeutic avenues for a variety of diseases.

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“…Hemolysis was estimated spectrophotometrically by measuring plasma absorption at 414 nm with an enzyme-linked immunosorbent assay (ELISA) plate reader (Quant, Bio-Tek Instruments, Winooski, VT) against standard curves of hemolyzed pRBCs. Hemolysis was induced in vitro by a freeze-thaw cycle followed by centrifugation at 20,000 g for 30 min [23].…”

Section: Methodsmentioning

confidence: 99%

“…Its intracellular concentration in RBCs is 10 -20 ng Ub/10 6 cells and the ubiquitin amount per blood volume is 1,000-to 10,000-fold higher in erythrocytes than in any other blood cell type [19 -23]. Recently, hemolysis was identified as one potential source of extracellular Ub in vivo [23]. Ub has well-defined intracellular roles in protein degradation and posttranslational modification [24 -26].…”

Section: Introductionmentioning

confidence: 99%