Skip to main content
Erschienen in: European Journal of Trauma and Emergency Surgery 1/2020

30.08.2018 | Original Article

Increased extracellular ubiquitin in surgical wound fluid provides a chemotactic signal for myeloid dendritic cells

verfasst von: Maximilian Leiblein, Norbert Ponelies, Theresa Johnson, Julian Marzi, Kerstin Kontradowitz, Emanuel Geiger, Ingo Marzi, Dirk Henrich

Erschienen in: European Journal of Trauma and Emergency Surgery | Ausgabe 1/2020

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Myeloid dendritic cells (MDC) decline significantly after multiple traumas which might be due to an increased migration into injured regions. Ubiquitin is released from dying cells and is increased in serum after trauma. Ubiquitin can bind to the chemokine receptor CXCR4. Thus, we hypothesized that elevated ubiquitin provides a chemotactic signal for MDC to injured regions.

Methods

Surgical wound fluid (SWF) and serum from patients with mono-trauma (n = 20) were used to simulate the humoral situation in injured tissue. MDC were identified by flow cytometry. Chemotaxis was measured using transwell migration assays. Ubiquitin and CXCL12 (natural CXCR4 ligand) were determined by ELISA.

Results

MDC express CXCR4 and fluorescence-labeled ubiquitin binds to MDC. Ubiquitin exerts a dose-dependent chemotactic effect (fourfold at 100 ng/mL, p < 0.05). Ubiquitin concentration was sixfold higher in SWF (p < 0.05), whereas CXCL12 was increased in serum. MDC migration towards SWF was significantly reduced (− 40%, p < 0.05), if ubiquitin was neutralized by specific antibodies.

Conclusions

Ubiquitin is increased in SWF and exerts a significant chemotactic effect on MDC. This mechanism might play a role in attraction of immune cells to injured regions and might contribute to the decline of circulating MDC in multiple traumas.
Literatur
1.
Zurück zum Zitat Bastian D, Tamburstuen MV, Lyngstadaas SP, Reikerås O. Local and systemic chemokine patterns in a human musculoskeletal trauma model. Inflamm Res. 2009;58:483–9 (Birkhäuser, Basel). CrossRefPubMed Bastian D, Tamburstuen MV, Lyngstadaas SP, Reikerås O. Local and systemic chemokine patterns in a human musculoskeletal trauma model. Inflamm Res. 2009;58:483–9 (Birkhäuser, Basel). CrossRefPubMed
2.
Zurück zum Zitat Hietbrink F, Koenderman L, Rijkers G, Leenen L. Trauma: the role of the innate immune system. World J Emerg Surg BioMed Central. 2006;1:15. CrossRef Hietbrink F, Koenderman L, Rijkers G, Leenen L. Trauma: the role of the innate immune system. World J Emerg Surg BioMed Central. 2006;1:15. CrossRef
3.
Zurück zum Zitat Flohé SB, Flohé S, Schade FU. Invited review: deterioration of the immune system after trauma: signals and cellular mechanisms. Innate Immun. 2008;14:333–44 (London: SAGE Publications). CrossRefPubMed Flohé SB, Flohé S, Schade FU. Invited review: deterioration of the immune system after trauma: signals and cellular mechanisms. Innate Immun. 2008;14:333–44 (London: SAGE Publications). CrossRefPubMed
4.
Zurück zum Zitat Lenz A, Franklin GA, Cheadle WG. Systemic inflammation after trauma. Injury. 2007;38:1336–45. CrossRefPubMed Lenz A, Franklin GA, Cheadle WG. Systemic inflammation after trauma. Injury. 2007;38:1336–45. CrossRefPubMed
6.
Zurück zum Zitat Aldrian S, Koenig F, Weninger P, Vécsei V, Nau T. Characteristics of polytrauma patients between 1992 and 2002: what is changing? Injury. 2007;38:1059–64. CrossRefPubMed Aldrian S, Koenig F, Weninger P, Vécsei V, Nau T. Characteristics of polytrauma patients between 1992 and 2002: what is changing? Injury. 2007;38:1059–64. CrossRefPubMed
7.
Zurück zum Zitat Biberthaler P, Bogner V, Baker HV, López MC, Neth P, Kanz K-G, et al. Genome-wide monocytic mRNA expression in polytrauma patients for identification of clinical outcome. Shock. 2005;24:11–9. CrossRefPubMed Biberthaler P, Bogner V, Baker HV, López MC, Neth P, Kanz K-G, et al. Genome-wide monocytic mRNA expression in polytrauma patients for identification of clinical outcome. Shock. 2005;24:11–9. CrossRefPubMed
8.
Zurück zum Zitat Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol. 2003;3:984–93 (Nature Publishing Group). CrossRefPubMed Kapsenberg ML. Dendritic-cell control of pathogen-driven T-cell polarization. Nat Rev Immunol. 2003;3:984–93 (Nature Publishing Group). CrossRefPubMed
9.
Zurück zum Zitat Mazzoni A, Segal DM. Controlling the toll road to dendritic cell polarization. J Leukoc Biol. 2004;75:721–30. CrossRefPubMed Mazzoni A, Segal DM. Controlling the toll road to dendritic cell polarization. J Leukoc Biol. 2004;75:721–30. CrossRefPubMed
10.
Zurück zum Zitat Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, et al. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol. 2000;165:6037–46. CrossRefPubMed Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S, et al. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol. 2000;165:6037–46. CrossRefPubMed
12.
Zurück zum Zitat Grimaldi D, Louis S, Pène F, Sirgo G, Rousseau C, Claessens YE, et al. Profound and persistent decrease of circulating dendritic cells is associated with ICU-acquired infection in patients with septic shock. Intensive Care Med. 2011;37:1438–46 (Springer). CrossRefPubMed Grimaldi D, Louis S, Pène F, Sirgo G, Rousseau C, Claessens YE, et al. Profound and persistent decrease of circulating dendritic cells is associated with ICU-acquired infection in patients with septic shock. Intensive Care Med. 2011;37:1438–46 (Springer). CrossRefPubMed
13.
Zurück zum Zitat Guisset O, Dilhuydy M-S, Thiébaut R, Lefèvre J, Camou F, Sarrat A, et al. Decrease in circulating dendritic cells predicts fatal outcome in septic shock. Intensive Care Med. 2007;33:148–52. CrossRefPubMed Guisset O, Dilhuydy M-S, Thiébaut R, Lefèvre J, Camou F, Sarrat A, et al. Decrease in circulating dendritic cells predicts fatal outcome in septic shock. Intensive Care Med. 2007;33:148–52. CrossRefPubMed
14.
Zurück zum Zitat Riccardi F, Porta Della MG, Rovati B, Casazza A, Radolovich D, De Amici M, et al. Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis. Cytom B Clin Cytom. 2011;80:14–21 (Wiley). CrossRef Riccardi F, Porta Della MG, Rovati B, Casazza A, Radolovich D, De Amici M, et al. Flow cytometric analysis of peripheral blood dendritic cells in patients with severe sepsis. Cytom B Clin Cytom. 2011;80:14–21 (Wiley). CrossRef
15.
Zurück zum Zitat Henrich D, Maier M, Relja B, Trendafilov P, Schiessling S, Wirth M, et al. Significant decline of peripheral myeloid dendritic cells following multiple trauma. J Surg Res. 2009;154:239–45. CrossRefPubMed Henrich D, Maier M, Relja B, Trendafilov P, Schiessling S, Wirth M, et al. Significant decline of peripheral myeloid dendritic cells following multiple trauma. J Surg Res. 2009;154:239–45. CrossRefPubMed
16.
Zurück zum Zitat Maier M, Geiger EV, Henrich D, Ebrahimi R, Wutzler S, Lehnert M, et al. Apoptosis differs in dendritic cell subsets early after severe trauma. Hum Immunol. 2009;70:803–8. CrossRefPubMed Maier M, Geiger EV, Henrich D, Ebrahimi R, Wutzler S, Lehnert M, et al. Apoptosis differs in dendritic cell subsets early after severe trauma. Hum Immunol. 2009;70:803–8. CrossRefPubMed
17.
Zurück zum Zitat Pastille E, Didovic S, Brauckmann D, Rani M, Agrawal H, Schade FU, et al. Modulation of dendritic cell differentiation in the bone marrow mediates sustained immunosuppression after polymicrobial sepsis. J Immunol. 2011;186:977–86 (American Association of Immunologists). CrossRefPubMed Pastille E, Didovic S, Brauckmann D, Rani M, Agrawal H, Schade FU, et al. Modulation of dendritic cell differentiation in the bone marrow mediates sustained immunosuppression after polymicrobial sepsis. J Immunol. 2011;186:977–86 (American Association of Immunologists). CrossRefPubMed
18.
Zurück zum Zitat Wirsdörfer F, Bangen JM, Pastille E, Schmitz D, Flohé S, Schumak B, et al. Dendritic cell-like cells accumulate in regenerating murine skeletal muscle after injury and boost adaptive immune responses only upon a microbial challenge. In: Kovats S, editor. PLoS One. 2016;11:e0155870. Wirsdörfer F, Bangen JM, Pastille E, Schmitz D, Flohé S, Schumak B, et al. Dendritic cell-like cells accumulate in regenerating murine skeletal muscle after injury and boost adaptive immune responses only upon a microbial challenge. In: Kovats S, editor. PLoS One. 2016;11:e0155870.
19.
Zurück zum Zitat Vecchi A, Massimiliano L, Ramponi S, Luini W, Bernasconi S, Bonecchi R, et al. Differential responsiveness to constitutive vs. inducible chemokines of immature and mature mouse dendritic cells. J Leukoc Biol. 1999;66:489–94. CrossRefPubMed Vecchi A, Massimiliano L, Ramponi S, Luini W, Bernasconi S, Bonecchi R, et al. Differential responsiveness to constitutive vs. inducible chemokines of immature and mature mouse dendritic cells. J Leukoc Biol. 1999;66:489–94. CrossRefPubMed
20.
Zurück zum Zitat Saini V, Marchese A, Tang W-J, Majetschak M. Structural determinants of ubiquitin-CXC chemokine receptor 4 interaction. J Biol Chem Am Soc Biochem Mol Biol. 2011;286:44145–52. Saini V, Marchese A, Tang W-J, Majetschak M. Structural determinants of ubiquitin-CXC chemokine receptor 4 interaction. J Biol Chem Am Soc Biochem Mol Biol. 2011;286:44145–52.
21.
Zurück zum Zitat Wilkinson KD. Protein ubiquitination: a regulatory post-translational modification. Anticancer Drug Des. 1987;2:211–29. PubMed Wilkinson KD. Protein ubiquitination: a regulatory post-translational modification. Anticancer Drug Des. 1987;2:211–29. PubMed
22.
Zurück zum Zitat Majetschak M, Zedler S, Hostmann A, Sorell LT, Patel MB, Novar LT, et al. Systemic ubiquitin release after blunt trauma and burns: association with injury severity, posttraumatic complications, and survival. J Trauma. 2008;64:586–96 (discussion 596–8). CrossRefPubMed Majetschak M, Zedler S, Hostmann A, Sorell LT, Patel MB, Novar LT, et al. Systemic ubiquitin release after blunt trauma and burns: association with injury severity, posttraumatic complications, and survival. J Trauma. 2008;64:586–96 (discussion 596–8). CrossRefPubMed
23.
Zurück zum Zitat Penna G, Vulcano M, Sozzani S, Adorini L. Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells. Hum Immunol. 2002;63:1164–71. CrossRefPubMed Penna G, Vulcano M, Sozzani S, Adorini L. Differential migration behavior and chemokine production by myeloid and plasmacytoid dendritic cells. Hum Immunol. 2002;63:1164–71. CrossRefPubMed
24.
Zurück zum Zitat Maier M, Geiger EV, Henrich D, Bendt C, Wutzler S, Lehnert M, et al. Platelet factor 4 is highly upregulated in dendritic cells after severe trauma. Mol Med. 2009;15:384–91. CrossRefPubMedPubMedCentral Maier M, Geiger EV, Henrich D, Bendt C, Wutzler S, Lehnert M, et al. Platelet factor 4 is highly upregulated in dendritic cells after severe trauma. Mol Med. 2009;15:384–91. CrossRefPubMedPubMedCentral
25.
Zurück zum Zitat Marzi J. Wirkung von Ubiquitin auf die Migration regenerativer Zellen. Bachelor thesis. Johann Wolfgang Goethe University, Frankfurt; 2012. Marzi J. Wirkung von Ubiquitin auf die Migration regenerativer Zellen. Bachelor thesis. Johann Wolfgang Goethe University, Frankfurt; 2012.
26.
Zurück zum Zitat Yager DR, Kulina RA, Gilman LA. Wound fluids: a window into the wound environment? Int J Low Extrem Wounds. 2007;6:262–72. CrossRefPubMed Yager DR, Kulina RA, Gilman LA. Wound fluids: a window into the wound environment? Int J Low Extrem Wounds. 2007;6:262–72. CrossRefPubMed
27.
Zurück zum Zitat Powerski MJ, Henrich D, Sander A, Wastl D, Ludwig K, Marzi I. CD133+ CD34+ stem cells are mobilized after musculoskeletal surgery and target endothelium activated by surgical wound fluid. Langenbecks Arch Surg. 2011;396:379–87. CrossRefPubMed Powerski MJ, Henrich D, Sander A, Wastl D, Ludwig K, Marzi I. CD133+ CD34+ stem cells are mobilized after musculoskeletal surgery and target endothelium activated by surgical wound fluid. Langenbecks Arch Surg. 2011;396:379–87. CrossRefPubMed
28.
Zurück zum Zitat Janusz Powerski M, Henrich D, Wastl D, Sander A, Marzi I. Surgical wound fluid from elderly patients shows a dramatically reduced potential to stimulate in-vitro recruitment and differentiation of endothelial progenitor cells: role of VEGF-165 and TGF-β1. Wounds. 2010;22:204–11. PubMed Janusz Powerski M, Henrich D, Wastl D, Sander A, Marzi I. Surgical wound fluid from elderly patients shows a dramatically reduced potential to stimulate in-vitro recruitment and differentiation of endothelial progenitor cells: role of VEGF-165 and TGF-β1. Wounds. 2010;22:204–11. PubMed
29.
Zurück zum Zitat Baker EA, Leaper DJ. Proteinases, their inhibitors, and cytokine profiles in acute wound fluid. Wound Repair Regen. 2000;8:392–8. CrossRefPubMed Baker EA, Leaper DJ. Proteinases, their inhibitors, and cytokine profiles in acute wound fluid. Wound Repair Regen. 2000;8:392–8. CrossRefPubMed
30.
Zurück zum Zitat Baker TA, Davis CS, Bach HH, Romero J, Burnham EL, Kovacs EJ, et al. Ubiquitin and stromal cell-derived factor-1α in bronchoalveolar lavage fluid after burn and inhalation injury. J Burn Care Res. 2012;33:57–64. CrossRefPubMed Baker TA, Davis CS, Bach HH, Romero J, Burnham EL, Kovacs EJ, et al. Ubiquitin and stromal cell-derived factor-1α in bronchoalveolar lavage fluid after burn and inhalation injury. J Burn Care Res. 2012;33:57–64. CrossRefPubMed
31.
Zurück zum Zitat Haas AL, Wilkinson KD. The large scale purification of ubiquitin from human erythrocytes. Prep Biochem. 1985;15:49–60. PubMed Haas AL, Wilkinson KD. The large scale purification of ubiquitin from human erythrocytes. Prep Biochem. 1985;15:49–60. PubMed
32.
Zurück zum Zitat Sowemimo-Coker SO. Red blood cell hemolysis during processing. Transfus Med Rev. 2002;16:46–60. CrossRefPubMed Sowemimo-Coker SO. Red blood cell hemolysis during processing. Transfus Med Rev. 2002;16:46–60. CrossRefPubMed
33.
Zurück zum Zitat Hicke L, Schubert HL, Hill CP. Ubiquitin-binding domains. Nat Rev Mol Cell Biol. 2005;6:610–21 (Nature Publishing Group). CrossRefPubMed Hicke L, Schubert HL, Hill CP. Ubiquitin-binding domains. Nat Rev Mol Cell Biol. 2005;6:610–21 (Nature Publishing Group). CrossRefPubMed
35.
Zurück zum Zitat Saini V, Staren DM, Ziarek JJ, Nashaat ZN, Campbell EM, Volkman BF, et al. The CXC chemokine receptor 4 ligands ubiquitin and stromal cell-derived factor-1α function through distinct receptor interactions. J Biol Chem. 2011;286:33466–77 (American Society for Biochemistry Molecular Biology). CrossRefPubMedPubMedCentral Saini V, Staren DM, Ziarek JJ, Nashaat ZN, Campbell EM, Volkman BF, et al. The CXC chemokine receptor 4 ligands ubiquitin and stromal cell-derived factor-1α function through distinct receptor interactions. J Biol Chem. 2011;286:33466–77 (American Society for Biochemistry Molecular Biology). CrossRefPubMedPubMedCentral
36.
Zurück zum Zitat Ratajczak MZ, Suszynska M. Emerging strategies to enhance homing and engraftment of hematopoietic stem cells. Stem Cell Rev Rep. 2016;12:121–8 (Springer). CrossRefPubMed Ratajczak MZ, Suszynska M. Emerging strategies to enhance homing and engraftment of hematopoietic stem cells. Stem Cell Rev Rep. 2016;12:121–8 (Springer). CrossRefPubMed
37.
Zurück zum Zitat Tu TC, Nagano M, Yamashita T, Hamada H, Ohneda K, Kimura K, et al. A chemokine receptor, CXCR4, which is regulated by hypoxia-inducible factor 2α, is crucial for functional endothelial progenitor cells migration to ischemic tissue and wound repair. Stem Cells Dev. 2016;25:266–76 (Mary Ann Liebert, Inc, Rochelle). CrossRefPubMed Tu TC, Nagano M, Yamashita T, Hamada H, Ohneda K, Kimura K, et al. A chemokine receptor, CXCR4, which is regulated by hypoxia-inducible factor 2α, is crucial for functional endothelial progenitor cells migration to ischemic tissue and wound repair. Stem Cells Dev. 2016;25:266–76 (Mary Ann Liebert, Inc, Rochelle). CrossRefPubMed
38.
Zurück zum Zitat Cao Y, Li C, Zhang Q, Wang Y, Xia R. Extracellular ubiquitin enhances the suppressive effects of regulatory T cells on effector T cell responses. Clin Lab. 2014;60:1983–91. PubMed Cao Y, Li C, Zhang Q, Wang Y, Xia R. Extracellular ubiquitin enhances the suppressive effects of regulatory T cells on effector T cell responses. Clin Lab. 2014;60:1983–91. PubMed
39.
Zurück zum Zitat Majetschak M, Krehmeier U, Bardenheuer M, Denz C, Quintel M, Voggenreiter G, et al. Extracellular ubiquitin inhibits the TNF-alpha response to endotoxin in peripheral blood mononuclear cells and regulates endotoxin hyporesponsiveness in critical illness. Blood. 2003;101:1882–90 (American Society of Hematology). CrossRefPubMed Majetschak M, Krehmeier U, Bardenheuer M, Denz C, Quintel M, Voggenreiter G, et al. Extracellular ubiquitin inhibits the TNF-alpha response to endotoxin in peripheral blood mononuclear cells and regulates endotoxin hyporesponsiveness in critical illness. Blood. 2003;101:1882–90 (American Society of Hematology). CrossRefPubMed
40.
Zurück zum Zitat Earle SA, El-Haddad A, Patel MB, Ruiz P, Pham SM, Majetschak M. Prolongation of skin graft survival by exogenous ubiquitin. Transplantation. 2006;82:1544–6. CrossRefPubMed Earle SA, El-Haddad A, Patel MB, Ruiz P, Pham SM, Majetschak M. Prolongation of skin graft survival by exogenous ubiquitin. Transplantation. 2006;82:1544–6. CrossRefPubMed
41.
Zurück zum Zitat Singh M, Roginskaya M, Dalal S, Menon B, Kaverina E, Boluyt MO, et al. Extracellular ubiquitin inhibits beta-AR-stimulated apoptosis in cardiac myocytes: role of GSK-3beta and mitochondrial pathways. Cardiovasc Res. 2010;86:20–8. CrossRefPubMed Singh M, Roginskaya M, Dalal S, Menon B, Kaverina E, Boluyt MO, et al. Extracellular ubiquitin inhibits beta-AR-stimulated apoptosis in cardiac myocytes: role of GSK-3beta and mitochondrial pathways. Cardiovasc Res. 2010;86:20–8. CrossRefPubMed
42.
Zurück zum Zitat Majetschak M. Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules. J Leukoc Biol. 2011;89:205–19. CrossRefPubMed Majetschak M. Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules. J Leukoc Biol. 2011;89:205–19. CrossRefPubMed
43.
Zurück zum Zitat Sozzani S, Luini W, Borsatti A, Polentarutti N, Zhou D, Piemonti L, et al. Receptor expression and responsiveness of human dendritic cells to a defined set of CC and CXC chemokines. J Immunol. 1997;159:1993–2000. PubMed Sozzani S, Luini W, Borsatti A, Polentarutti N, Zhou D, Piemonti L, et al. Receptor expression and responsiveness of human dendritic cells to a defined set of CC and CXC chemokines. J Immunol. 1997;159:1993–2000. PubMed
44.
Zurück zum Zitat Olweus J, BitMansour A, Warnke R, Thompson PA, Carballido J, Picker LJ, et al. Dendritic cell ontogeny: a human dendritic cell lineage of myeloid origin. Proc Natl Acad Sci USA 1997;94:12551–6. CrossRefPubMedPubMedCentral Olweus J, BitMansour A, Warnke R, Thompson PA, Carballido J, Picker LJ, et al. Dendritic cell ontogeny: a human dendritic cell lineage of myeloid origin. Proc Natl Acad Sci USA 1997;94:12551–6. CrossRefPubMedPubMedCentral
Metadaten
Titel
Increased extracellular ubiquitin in surgical wound fluid provides a chemotactic signal for myeloid dendritic cells
verfasst von
Maximilian Leiblein
Norbert Ponelies
Theresa Johnson
Julian Marzi
Kerstin Kontradowitz
Emanuel Geiger
Ingo Marzi
Dirk Henrich
Publikationsdatum
30.08.2018
Verlag
Springer Berlin Heidelberg
Erschienen in
European Journal of Trauma and Emergency Surgery / Ausgabe 1/2020
Print ISSN: 1863-9933
Elektronische ISSN: 1863-9941
DOI
https://doi.org/10.1007/s00068-018-1001-0

Weitere Artikel der Ausgabe 1/2020

European Journal of Trauma and Emergency Surgery 1/2020 Zur Ausgabe

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie. Erweitert durch Fallbeispiele, DICOM-Daten, Videos und Abbildungen. » Jetzt entdecken

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.