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European Journal of Medical Research
Published in: European Journal of Medical Research 1/2018

Open Access 01-12-2018 | Research

Chemokine ligand–receptor interactions critically regulate cutaneous wound healing

Authors: Erich Bünemann, Norman-Philipp Hoff, Bettina Alexandra Buhren, Ulrike Wiesner, Stephan Meller, Edwin Bölke, Anja Müller-Homey, Robert Kubitza, Thomas Ruzicka, Albert Zlotnik, Bernhard Homey, Peter Arne Gerber

Published in: European Journal of Medical Research | Issue 1/2018

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Abstract

Background

Wound healing represents a dynamic process involving directional migration of different cell types. Chemokines, a family of chemoattractive proteins, have been suggested to be key players in cell-to-cell communication and essential for directed migration of structural cells. Today, the role of the chemokine network in cutaneous wound healing is not fully understood. Unraveling the chemokine-driven communication pathways in this complex process could possibly lead to new therapeutic strategies in wound healing disorders.

Methods

We performed a systematic, comprehensive time-course analysis of the expression and function of a broad variety of cytokines, growth factors, adhesion molecules, matrixmetalloproteinases and chemokines in a murine cutaneous wound healing model.

Results

Strikingly, chemokines were found to be among the most highly regulated genes and their expression was found to coincide with the expression of their matching receptors. Accordingly, we could show that resting and activated human primary keratinocytes (CCR3, CCR4, CCR6, CXCR1, CXCR3), dermal fibroblasts (CCR3, CCR4, CCR10) and dermal microvascular endothelial cells (CCR3, CCR4, CCR6, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3) express a distinct and functionally active repertoire of chemokine receptors. Furthermore, chemokine ligand–receptor interactions markedly improved the wound repair of structural skin cells in vitro.

Conclusion

Taken together, we here present the most comprehensive analysis of mediators critically involved in acute cutaneous wound healing. Our findings suggest therapeutic approaches for the management of wound closure by targeting the chemokine network.
Appendix
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Literature
1.
2.
Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol. 2001;69:513–21.PubMed
3.
Engelhardt E, Toksoy A, Goebeler M, Debus S, Brocker EB, et al. Chemokines IL-8, GROalpha, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am J Pathol. 1998;153:1849–60.CrossRefPubMedPubMedCentral
4.
Leibovich SJ, Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975;78:71–100.PubMedPubMedCentral
5.
Leibovich SJ, Wiseman DM. Macrophages, wound repair and angiogenesis. Prog Clin Biol Res. 1988;266:131–45.PubMed
6.
DiPietro LA. Wound healing: the role of the macrophage and other immune cells. Shock. 1995;4:233–40.CrossRefPubMed
7.
8.
DiPietro LA, Burdick M, Low QE, Kunkel SL, Strieter RM. MIP-1 alpha as a critical macrophage chemoattractant in murine wound repair. J Clin Invest. 1998;101:1693–8.CrossRefPubMedPubMedCentral
9.
DiPietro LA, Polverini PJ, Rahbe SM, Kovacs EJ. Modulation of JE/MCP-1 expression in dermal wound repair. Am J Pathol. 1995;146:868–75.PubMedPubMedCentral
10.
DiPietro LA, Reintjes MG, Low QE, Levi B, Gamelli RL. Modulation of macrophage recruitment into wounds by monocyte chemoattractant protein-1. Wound Repair Regen. 2001;9:28–33.CrossRefPubMed
11.
Fedyk ER, Jones D, Critchley HO, Phipps RP, Blieden TM, et al. Expression of stromal-derived factor-1 is decreased by IL-1 and TNF and in dermal wound healing. J Immunol. 2001;166:5749–54.CrossRefPubMed
12.
13.
Luster AD, Cardiff RD, MacLean JA, Crowe K, Granstein RD. Delayed wound healing and disorganized neovascularization in transgenic mice expressing the IP-10 chemokine. Proc Assoc Am Physicians. 1998;110:183–96.PubMed
14.
Rennekampff HO, Hansbrough JF, Woods V Jr, Dore C, Kiessig V, Schroder JM. Role of melanoma growth stimulatory activity (MGSA/gro) on keratinocyte function in wound healing. Arch Dermatol Res. 1997;289:204–12.CrossRefPubMed
15.
Weber KS, Nelson PJ, Grone HJ, Weber C. Expression of CCR2 by endothelial cells : implications for MCP-1 mediated wound injury repair and In vivo inflammatory activation of endothelium. Arterioscler Thromb Vasc Biol. 1999;19:2085–93.CrossRefPubMed
16.
Gerber PA, Hippe A, Buhren BA, Müller A, Homey B. Chemokines in tumor-associated angiogenesis. Biol Chem. 2009;390:1213–23.CrossRefPubMed
17.
18.
Martins-Green M, Petreaca M, Wang L. Chemokines and their receptors are key players in the orchestra that regulates wound healing. Adv Wound Care (New Rochelle). 2013;2:327–47.CrossRef
19.
Rossi D, Zlotnik A. The biology of chemokines and their receptors. Annu Rev Immunol. 2000;18:217–42.CrossRefPubMed
20.
21.
Muller A, Homey B, Soto H, Ge N, Catron D, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410:50–6.CrossRefPubMed
22.
Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity. Immunity. 2000;12:121–7.CrossRefPubMed
23.
Homey B, Dieu-Nosjean MC, Wiesenborn A, Massacrier C, Pin JJ, et al. Up-regulation of macrophage inflammatory protein-3 alpha/CCL20 and CC chemokine receptor 6 in psoriasis. J Immunol. 2000;164:6621–32.CrossRefPubMed
24.
Homey B, Wang W, Soto H, Buchanan ME, Wiesenborn A, et al. Cutting edge: the orphan chemokine receptor G protein-coupled receptor-2 (GPR-2, CCR10) binds the skin-associated chemokine CCL27 (CTACK/ALP/ILC). J Immunol. 2000;164:3465–70.CrossRefPubMed
25.
Hurst SD, Muchamuel T, Gorman DM, Gilbert JM, Clifford T, et al. New IL-17 family members promote Th1 or Th2 responses in the lung: in vivo function of the novel cytokine IL-25. J Immunol. 2002;169:443–53.CrossRefPubMed
26.
Vanbervliet B, Homey B, Durand I, Massacrier C, Ait-Yahia S, et al. Sequential involvement of CCR2 and CCR6 ligands for immature dendritic cell recruitment: possible role at inflamed epithelial surfaces. Eur J Immunol. 2002;32:231–42.CrossRefPubMed
27.
Lindhout E, Vissers JL, Hartgers FC, Huijbens RJ, Scharenborg NM, et al. The dendritic cell-specific CC-chemokine DC-CK1 is expressed by germinal center dendritic cells and attracts CD38-negative mantle zone B lymphocytes. J Immunol. 2001;166:3284–9.CrossRefPubMed
28.
Mrazek F, Sekerova V, Drabek J, Kolek V, du Bois RM, et al. Expression of the chemokine PARC mRNA in bronchoalveolar cells of patients with sarcoidosis. Immunol Lett. 2002;84:17–22.CrossRefPubMed
29.
Pardo A, Smith KM, Abrams J, Coffman R, Bustos M, et al. CCL18/DC-CK-1/PARC up-regulation in hypersensitivity pneumonitis. J Leukoc Biol. 2001;70:610–6.PubMed
30.
Zheng L, Martins-Green M. Molecular mechanisms of thrombin-induced interleukin-8 (IL-8/CXCL8) expression in THP-1-derived and primary human macrophages. J Leukoc Biol. 2007;82:619–29.CrossRefPubMed
31.
Charbonnier AS, Kohrgruber N, Kriehuber E, Stingl G, Rot A, et al. Macrophage inflammatory protein 3 alpha is involved in the constitutive trafficking of epidermal langerhans cells. J Exp Med. 1999;190:1755–68.CrossRefPubMedPubMedCentral
32.
Yamamoto T, Eckes B, Mauch C, Hartmann K, Krieg T. Monocyte chemoattractant protein-1 enhances gene expression and synthesis of matrix metalloproteinase-1 in human fibroblasts by an autocrine IL-1 alpha loop. J Immunol. 2000;164:6174–9.CrossRefPubMed
33.
Sholley MM, Gimbrone MA Jr, Cotran RS. Cellular migration and replication in endothelial regeneration: a study using irradiated endothelial cultures. Lab Invest. 1977;36:18–25.PubMed
34.
Addison CL, Daniel TO, Burdick MD, Liu H, Ehlert JE, et al. The CXC chemokine receptor 2, CXCR2, is the putative receptor for ELR+ CXC chemokine-induced angiogenic activity. J Immunol. 2000;165:5269–77.CrossRefPubMed
35.
Bernardini G, Spinetti G, Ribatti D, Camarda G, Morbidelli L, et al. I-309 binds to and activates endothelial cell functions and acts as an angiogenic molecule in vivo. Blood. 2000;96:4039–45.PubMed
36.
Feil C, Augustin HG. Endothelial cells differentially express functional CXC-chemokine receptor-4 (CXCR-4/fusin) under the control of autocrine activity and exogenous cytokines. Biochem Biophys Res Commun. 1998;247:38–45.CrossRefPubMed
37.
Haque NS, Fallon JT, Taubman MB, Harpel PC. The chemokine receptor CCR8 mediates human endothelial cell chemotaxis induced by I-309 and Kaposi sarcoma herpesvirus-encoded vMIP-I and by lipoprotein(a)-stimulated endothelial cell conditioned medium. Blood. 2001;97:39–45.CrossRefPubMed
38.
Murdoch C, Monk PN, Finn A. Cxc chemokine receptor expression on human endothelial cells. Cytokine. 1999;11:704–12.CrossRefPubMed
39.
Salcedo R, Wasserman K, Young HA, Grimm MC, Howard OM, et al. Vascular endothelial growth factor and basic fibroblast growth factor induce expression of CXCR4 on human endothelial cells: in vivo neovascularization induced by stromal-derived factor-1alpha. Am J Pathol. 1999;154:1125–35.CrossRefPubMedPubMedCentral
40.
41.
dos Santos JS, Monte-Alto-Costa A. Female, but not male, mice show delayed cutaneous wound healing following aspirin administration. Clin Exp Pharmacol Physiol. 2013;40:90–6.CrossRefPubMed
Metadata
Title
Chemokine ligand–receptor interactions critically regulate cutaneous wound healing
Authors
Erich Bünemann
Norman-Philipp Hoff
Bettina Alexandra Buhren
Ulrike Wiesner
Stephan Meller
Edwin Bölke
Anja Müller-Homey
Robert Kubitza
Thomas Ruzicka
Albert Zlotnik
Bernhard Homey
Peter Arne Gerber
Publication date
01-12-2018
Publisher
BioMed Central
Published in
European Journal of Medical Research / Issue 1/2018
Electronic ISSN: 2047-783X
DOI
https://doi.org/10.1186/s40001-017-0299-0

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