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Erschienen in: Knee Surgery, Sports Traumatology, Arthroscopy 9/2015

01.09.2015 | Experimental Study

Chemokine expression of CCL2, CCL3, CCL5 and CXCL10 during early inflammatory tendon healing precedes nerve regeneration: an immunohistochemical study in the rat

verfasst von: A. Stålman, D. Bring, P. W. Ackermann

Erschienen in: Knee Surgery, Sports Traumatology, Arthroscopy | Ausgabe 9/2015

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Abstract

Purpose

Chemokines are major promoters of repair and may regulate nerve ingrowth that is essential in tendon healing. The purpose of this study was to assess the temporal occurrence of different chemokines during Achilles tendon healing in relation to sensory nerve regeneration. Chemokine presence in tendon healing has not been studied previously.

Methods

Chemokine expression, nerve regeneration, angiogenesis and inflammatory cell occurrence during healing of Achilles tendon rupture in the rat were studied by immunohistochemistry and histology including semiquantitative assessment. Markers for chemokines (CCL5, CCL2, CCL3, CXCL10), nerves (PGP-9.5) and sensory neuropeptide substance P (SP) were analysed at different time points (1 day–16 weeks) post-rupture.

Results

In intact tendons (controls) immunoreactivity to all chemokines, PGP-9.5 and SP were confined to the tendon surroundings. After rupture, there was rapid increase in the tendon proper of the chemokines studied, all exhibiting their peak expression at week 1. Subsequently, at weeks 2–6, emerging inflammatory cells and maximum sprouting of PGP-/SP-positive nerves were observed close to newly formed blood vessels within the tendon proper, while chemokine expression already decreased. During weeks 6–8, PGP-/SP-positive nerves withdrew from the rupture site and relocated together with the chemokines in the surrounding tendon.

Conclusions

Early chemokine expression in the healing tendon precedes ingrowth of new nerves, angiogenesis and emergence of inflammatory cells. The fine-tuned temporal and spatial appearance of chemokines suggests a chemoattractant role for inflammatory cell migration and possibly also a role in angiogenesis and neurogenesis. Chemokines may thus exhibit vital targets for biological modulation of tendon repair.

Level of evidence

III.
Literatur
2.
Zurück zum Zitat Ackermann PW, Ahmed M, Kreicbergs A (2002) Early nerve regeneration after Achilles tendon rupture-a prerequisite for healing? A study in the rat. J Orthop Res 20(4):849–856CrossRefPubMed Ackermann PW, Ahmed M, Kreicbergs A (2002) Early nerve regeneration after Achilles tendon rupture-a prerequisite for healing? A study in the rat. J Orthop Res 20(4):849–856CrossRefPubMed
3.
Zurück zum Zitat Ackermann PW, Domeij-Arverud E, Leclerc P, Amoudroz P, Nader GA (2013) Anti-inflammatory cytokine profile in early human tendon repair. Knee Surg Sports Traumatol Arthrosc 21(8):1801–1806CrossRefPubMed Ackermann PW, Domeij-Arverud E, Leclerc P, Amoudroz P, Nader GA (2013) Anti-inflammatory cytokine profile in early human tendon repair. Knee Surg Sports Traumatol Arthrosc 21(8):1801–1806CrossRefPubMed
4.
Zurück zum Zitat Ackermann PW, Li J, Lundeberg T, Kreicbergs A (2003) Neuronal plasticity in relation to nociception and healing of rat Achilles tendon. J Orthop Res 21(3):432–441 CrossRefPubMed Ackermann PW, Li J, Lundeberg T, Kreicbergs A (2003) Neuronal plasticity in relation to nociception and healing of rat Achilles tendon. J Orthop Res 21(3):432–441 CrossRefPubMed
5.
Zurück zum Zitat Ackermann PW, Salo PT, Hart DA (2009) Neuronal pathways in tendon healing. Front Biosci 14:5165–5187CrossRef Ackermann PW, Salo PT, Hart DA (2009) Neuronal pathways in tendon healing. Front Biosci 14:5165–5187CrossRef
6.
Zurück zum Zitat Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, Kleinman HK, Reaman GH, Tosato G (1995) Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 182(1):155–162CrossRefPubMed Angiolillo AL, Sgadari C, Taub DD, Liao F, Farber JM, Maheshwari S, Kleinman HK, Reaman GH, Tosato G (1995) Human interferon-inducible protein 10 is a potent inhibitor of angiogenesis in vivo. J Exp Med 182(1):155–162CrossRefPubMed
7.
Zurück zum Zitat Baggiolini M, Dewald B, Moser B (1997) Human chemokines: an update. Annu Rev Immunol 15:675–705CrossRefPubMed Baggiolini M, Dewald B, Moser B (1997) Human chemokines: an update. Annu Rev Immunol 15:675–705CrossRefPubMed
8.
Zurück zum Zitat Behm B, Babilas P, Landthaler M, Schremi S (2012) Cytokines, chemokines and growth factors in wound healing. J Eur Acad Dermatol Venereol 26(7):812–820CrossRefPubMed Behm B, Babilas P, Landthaler M, Schremi S (2012) Cytokines, chemokines and growth factors in wound healing. J Eur Acad Dermatol Venereol 26(7):812–820CrossRefPubMed
9.
Zurück zum Zitat Bring DK, Heidgren ML, Kreicbergs A, Ackermann PW (2005) Increase in sensory neuropeptides surrounding the Achilles tendon in rats with adjuvant arthritis. J Orthop Res 23(2):294–301CrossRefPubMed Bring DK, Heidgren ML, Kreicbergs A, Ackermann PW (2005) Increase in sensory neuropeptides surrounding the Achilles tendon in rats with adjuvant arthritis. J Orthop Res 23(2):294–301CrossRefPubMed
10.
Zurück zum Zitat Burssens P, Steyaert A, Forsyth R, van Ovost EJ, Depaepe Y, Verdonk R (2005) Exogenously administered substance P and neutral endopeptidase inhibitors stimulate fibroblast proliferation, angiogenesis and collagen organization during Achilles tendon healing. Foot Ankle Int 26(10):832–839PubMed Burssens P, Steyaert A, Forsyth R, van Ovost EJ, Depaepe Y, Verdonk R (2005) Exogenously administered substance P and neutral endopeptidase inhibitors stimulate fibroblast proliferation, angiogenesis and collagen organization during Achilles tendon healing. Foot Ankle Int 26(10):832–839PubMed
11.
Zurück zum Zitat Carlsson O, Schizas N, Li J, Ackermann PW (2011) Substance P injections enhance tissue proliferation and regulate sensory nerve ingrowth in rat tendon repair. Scand J Med Sci Sports 21(4):562–569CrossRefPubMed Carlsson O, Schizas N, Li J, Ackermann PW (2011) Substance P injections enhance tissue proliferation and regulate sensory nerve ingrowth in rat tendon repair. Scand J Med Sci Sports 21(4):562–569CrossRefPubMed
12.
Zurück zum Zitat Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354(6):610–621CrossRefPubMed Charo IF, Ransohoff RM (2006) The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med 354(6):610–621CrossRefPubMed
13.
Zurück zum Zitat DiPietro LA, Burdick M, Low QE, Kunkel SL, Strieter RM (1998) MIP-1alpha as a critical macrophage chemoattractant in murine wound repair. J Clin Invest 101(8):1693–1698PubMedCentralCrossRefPubMed DiPietro LA, Burdick M, Low QE, Kunkel SL, Strieter RM (1998) MIP-1alpha as a critical macrophage chemoattractant in murine wound repair. J Clin Invest 101(8):1693–1698PubMedCentralCrossRefPubMed
14.
Zurück zum Zitat Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5):1029–1039PubMedCentralPubMed Dvorak HF, Brown LF, Detmar M, Dvorak AM (1995) Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis. Am J Pathol 146(5):1029–1039PubMedCentralPubMed
15.
Zurück zum Zitat Frank S, Kämpfer H, Wetzler C, Stallmeyer B, Pfellschifter J (2000) Large induction of the chemotactic cytokine RANTES during cutaneous wound repair: a regulatory role for nitric oxide in keratinocyte-derived RANTES expression. Biochem J 347(Pt 1):265–273PubMedCentralCrossRefPubMed Frank S, Kämpfer H, Wetzler C, Stallmeyer B, Pfellschifter J (2000) Large induction of the chemotactic cytokine RANTES during cutaneous wound repair: a regulatory role for nitric oxide in keratinocyte-derived RANTES expression. Biochem J 347(Pt 1):265–273PubMedCentralCrossRefPubMed
16.
Zurück zum Zitat Glaser J, Gonzalez R, Sadr E, Keirstead HS (2006) Neutralization of the chemokine CXCL10 reduces apoptosis and increases axon sprouting after spinal cord injury. J Neurosci Res 84(4):724–734CrossRefPubMed Glaser J, Gonzalez R, Sadr E, Keirstead HS (2006) Neutralization of the chemokine CXCL10 reduces apoptosis and increases axon sprouting after spinal cord injury. J Neurosci Res 84(4):724–734CrossRefPubMed
17.
Zurück zum Zitat Hong HS, Lee J, Lee E, Kwon YS, Lee E, Ahn W, Jiang MH, Kim JC, Son Y (2009) A new role of substance P as an injury-inducible messenger for mobilization of CD29(+) stromal-like cells. Nat Med 15(4):425–435CrossRefPubMed Hong HS, Lee J, Lee E, Kwon YS, Lee E, Ahn W, Jiang MH, Kim JC, Son Y (2009) A new role of substance P as an injury-inducible messenger for mobilization of CD29(+) stromal-like cells. Nat Med 15(4):425–435CrossRefPubMed
18.
Zurück zum Zitat Kalehua AN, Nagel JE, Whelchel LM, Gides JJ, Pyle RS, Smith RJ, Kusiak JW, Taub DD (2004) Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 are involved in both excitotoxin-induced neurodegeneration and regeneration. Exp Cell Res 297(1):197–211CrossRefPubMed Kalehua AN, Nagel JE, Whelchel LM, Gides JJ, Pyle RS, Smith RJ, Kusiak JW, Taub DD (2004) Monocyte chemoattractant protein-1 and macrophage inflammatory protein-2 are involved in both excitotoxin-induced neurodegeneration and regeneration. Exp Cell Res 297(1):197–211CrossRefPubMed
19.
Zurück zum Zitat Low QE, Drugea IA, Duffner LA, Quinn DG, Cook DN, Rollins BJ, Kovacs EJ, DiPietro LA (2001) Wound healing in MIP-1alpha(−/−) and MCP-1(−/−) mice. Am J Pathol 159(2):457–463PubMedCentralCrossRefPubMed Low QE, Drugea IA, Duffner LA, Quinn DG, Cook DN, Rollins BJ, Kovacs EJ, DiPietro LA (2001) Wound healing in MIP-1alpha(−/−) and MCP-1(−/−) mice. Am J Pathol 159(2):457–463PubMedCentralCrossRefPubMed
20.
Zurück zum Zitat Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229(2):176–185CrossRefPubMed Mantovani A, Biswas SK, Galdiero MR, Sica A, Locati M (2013) Macrophage plasticity and polarization in tissue repair and remodelling. J Pathol 229(2):176–185CrossRefPubMed
21.
Zurück zum Zitat Nicoletti M, Neri G, Maccauro G, Tripodi D, Varvara G, Saggini A, Patalivo G, Castellani ML, Fulcheri M, Rosati M, Toniato E, Caraffa A, Antinolfi P, Cerulli G, Pandolfi F, Galzio R, Conti P, Theoharides TC (2012) Impact of neuropeptide substance P an inflammatory compound on arachidonic acid compound generation. Int J Immunopathol Pharmacol 25(4):849–857PubMed Nicoletti M, Neri G, Maccauro G, Tripodi D, Varvara G, Saggini A, Patalivo G, Castellani ML, Fulcheri M, Rosati M, Toniato E, Caraffa A, Antinolfi P, Cerulli G, Pandolfi F, Galzio R, Conti P, Theoharides TC (2012) Impact of neuropeptide substance P an inflammatory compound on arachidonic acid compound generation. Int J Immunopathol Pharmacol 25(4):849–857PubMed
22.
Zurück zum Zitat Olsson N, Nilsson-Helander K, Karlsson J, Eriksson BI, Thomee R, Faxen E, Silbernagl KG (2011) Major functional deficits persist 2 years after acute Achilles tendon rupture. Knee Surg Sports Traumatol Arthrosc 19(8):1385–1393CrossRefPubMed Olsson N, Nilsson-Helander K, Karlsson J, Eriksson BI, Thomee R, Faxen E, Silbernagl KG (2011) Major functional deficits persist 2 years after acute Achilles tendon rupture. Knee Surg Sports Traumatol Arthrosc 19(8):1385–1393CrossRefPubMed
23.
Zurück zum Zitat Sharma P, Maffulli N (2005) Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg Am 87(1):187–202CrossRefPubMed Sharma P, Maffulli N (2005) Tendon injury and tendinopathy: healing and repair. J Bone Joint Surg Am 87(1):187–202CrossRefPubMed
24.
Zurück zum Zitat Sharma P, Maffulli N (2006) Biology of tendon injury: healing, modeling and remodeling. J Musculoskelet Neuronal Interact 6(2):181–190PubMed Sharma P, Maffulli N (2006) Biology of tendon injury: healing, modeling and remodeling. J Musculoskelet Neuronal Interact 6(2):181–190PubMed
25.
Zurück zum Zitat Shiraha H, Glading A, Gupta K, Wells A (1999) IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity. J Cell Biol 146(1):243–254PubMedCentralCrossRefPubMed Shiraha H, Glading A, Gupta K, Wells A (1999) IP-10 inhibits epidermal growth factor-induced motility by decreasing epidermal growth factor receptor-mediated calpain activity. J Cell Biol 146(1):243–254PubMedCentralCrossRefPubMed
26.
Zurück zum Zitat Suffee N, Hlawaty H, Meddahl-Pelle A, Maillard L, Louedec L, Haddad O, Martin L, Laguillier C, Richard B, Oudar O, Letourneur D, Charnaux N, Sutton A (2012) RANTES/CCL5-induced pro-angiogenic effects depend on CCR1, CCR5 and glycosaminoglycans. Angiogenesis 15(4):727–744CrossRefPubMed Suffee N, Hlawaty H, Meddahl-Pelle A, Maillard L, Louedec L, Haddad O, Martin L, Laguillier C, Richard B, Oudar O, Letourneur D, Charnaux N, Sutton A (2012) RANTES/CCL5-induced pro-angiogenic effects depend on CCR1, CCR5 and glycosaminoglycans. Angiogenesis 15(4):727–744CrossRefPubMed
27.
Zurück zum Zitat Suffee N, Richard B, Hlawaty H, Oudar O, Charnaux N, Sutton A (2011) Angiogenic properties of the chemokine RANTES/CCL5. Biochem Soc Trans 39(6):1649–1653CrossRefPubMed Suffee N, Richard B, Hlawaty H, Oudar O, Charnaux N, Sutton A (2011) Angiogenic properties of the chemokine RANTES/CCL5. Biochem Soc Trans 39(6):1649–1653CrossRefPubMed
28.
Zurück zum Zitat Taskinen HS, Röyttä M (2000) Increased expression of chemokines (MCP-1, MIP-1alpha, RANTES) after peripheral nerve transection. J Peripher Nerv Syst 5(2):75–81CrossRefPubMed Taskinen HS, Röyttä M (2000) Increased expression of chemokines (MCP-1, MIP-1alpha, RANTES) after peripheral nerve transection. J Peripher Nerv Syst 5(2):75–81CrossRefPubMed
29.
Zurück zum Zitat Tonnesen MG, Feng X, Clark RA (2000) Angiogenesis in wound healing. J Investig Dermatol Symp Proc 5(1):40–46CrossRefPubMed Tonnesen MG, Feng X, Clark RA (2000) Angiogenesis in wound healing. J Investig Dermatol Symp Proc 5(1):40–46CrossRefPubMed
30.
Zurück zum Zitat Wetzler C, Kämpfer H, Stallmeyer B, Pfeilschifter J, Frank S (2000) Large and sustained induction of chemokine during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair. J Invest Dermatol 115(2):245–253CrossRefPubMed Wetzler C, Kämpfer H, Stallmeyer B, Pfeilschifter J, Frank S (2000) Large and sustained induction of chemokine during impaired wound healing in the genetically diabetic mouse: prolonged persistence of neutrophils and macrophages during the late phase of repair. J Invest Dermatol 115(2):245–253CrossRefPubMed
Metadaten
Titel
Chemokine expression of CCL2, CCL3, CCL5 and CXCL10 during early inflammatory tendon healing precedes nerve regeneration: an immunohistochemical study in the rat
verfasst von
A. Stålman
D. Bring
P. W. Ackermann
Publikationsdatum
01.09.2015
Verlag
Springer Berlin Heidelberg
Erschienen in
Knee Surgery, Sports Traumatology, Arthroscopy / Ausgabe 9/2015
Print ISSN: 0942-2056
Elektronische ISSN: 1433-7347
DOI
https://doi.org/10.1007/s00167-014-3010-9

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