Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1998 Apr 15;101(8):1693–1698. doi: 10.1172/JCI1020

MIP-1alpha as a critical macrophage chemoattractant in murine wound repair.

L A DiPietro 1, M Burdick 1, Q E Low 1, S L Kunkel 1, R M Strieter 1
PMCID: PMC508751  PMID: 9541500

Abstract

At sites of injury, macrophages secrete growth factors and proteins that promote tissue repair. While this central role of the macrophage has been well studied, the specific stimuli that recruit macrophages into sites of injury are not well understood. This study examines the role of macrophage inflammatory protein 1alpha (MIP-1alpha), a C-C chemokine with monocyte chemoattractant capability, in excisional wound repair. Both MIP-1alpha mRNA and protein were detectable in murine wounds from 12 h through 5 d after injury. MIP-1alpha protein levels peaked 3 d after injury, coinciding with maximum macrophage infiltration. The contribution of MIP-1alpha to monocyte recruitment into wounds was assessed by treating mice with neutralizing anti-MIP-1alpha antiserum before injury. Wounds of mice treated with anti-MIP-1alpha antiserum had significantly fewer macrophages than control (41% decrease, P < 0. 01). This decrease in wound macrophages was paralleled by decreased angiogenic activity and collagen synthesis. When tested in the corneal micropocket assay, wound homogenates from mice treated with anti-MIP-1alpha contained significantly less angiogenic activity than control wound homogenates (27% positive for angiogenic activity versus 91% positive in the control group, P < 0.01). Collagen production was also significantly reduced in the wounds from anti-MIP-1alpha treated animals (29% decrease, P < 0.05). The results demonstrate that MIP-1alpha plays a critical role in macrophage recruitment into wounds, and suggest that appropriate tissue repair is dependent upon this recruitment.

Full Text

The Full Text of this article is available as a PDF (307.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Applequist S. E., Keyna U., Calvin M. R., Beck-Engeser G. B., Raman C., Jäck H. M. Sequence of the rabbit glyceraldehyde-3-phosphate dehydrogenase-encoding cDNA. Gene. 1995 Oct 3;163(2):325–326. doi: 10.1016/0378-1119(95)00386-k. [DOI] [PubMed] [Google Scholar]
  2. Austyn J. M., Gordon S. F4/80, a monoclonal antibody directed specifically against the mouse macrophage. Eur J Immunol. 1981 Oct;11(10):805–815. doi: 10.1002/eji.1830111013. [DOI] [PubMed] [Google Scholar]
  3. Burdick M. D., Kunkel S. L., Lincoln P. M., Wilke C. A., Strieter R. M. Specific ELISAs for the detection of human macrophage inflammatory protein-1 alpha and beta. Immunol Invest. 1993 Aug-Oct;22(6-7):441–449. doi: 10.3109/08820139309063422. [DOI] [PubMed] [Google Scholar]
  4. Clark R. A., Stone R. D., Leung D. Y., Silver I., Hohn D. C., Hunt T. K. Role of macrophages in would healing. Surg Forum. 1976;27(62):16–18. [PubMed] [Google Scholar]
  5. Cook D. N., Beck M. A., Coffman T. M., Kirby S. L., Sheridan J. F., Pragnell I. B., Smithies O. Requirement of MIP-1 alpha for an inflammatory response to viral infection. Science. 1995 Sep 15;269(5230):1583–1585. doi: 10.1126/science.7667639. [DOI] [PubMed] [Google Scholar]
  6. Danon D., Kowatch M. A., Roth G. S. Promotion of wound repair in old mice by local injection of macrophages. Proc Natl Acad Sci U S A. 1989 Mar;86(6):2018–2020. doi: 10.1073/pnas.86.6.2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Davatelis G., Tekamp-Olson P., Wolpe S. D., Hermsen K., Luedke C., Gallegos C., Coit D., Merryweather J., Cerami A. Cloning and characterization of a cDNA for murine macrophage inflammatory protein (MIP), a novel monokine with inflammatory and chemokinetic properties. J Exp Med. 1988 Jun 1;167(6):1939–1944. doi: 10.1084/jem.167.6.1939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. DiPietro L. A., Polverini P. J., Rahbe S. M., Kovacs E. J. Modulation of JE/MCP-1 expression in dermal wound repair. Am J Pathol. 1995 Apr;146(4):868–875. [PMC free article] [PubMed] [Google Scholar]
  9. Fahey T. J., 3rd, Sherry B., Tracey K. J., van Deventer S., Jones W. G., 2nd, Minei J. P., Morgello S., Shires G. T., Cerami A. Cytokine production in a model of wound healing: the appearance of MIP-1, MIP-2, cachectin/TNF and IL-1. Cytokine. 1990 Mar;2(2):92–99. doi: 10.1016/1043-4666(90)90002-b. [DOI] [PubMed] [Google Scholar]
  10. Fahey T. J., 3rd, Tracey K. J., Tekamp-Olson P., Cousens L. S., Jones W. G., Shires G. T., Cerami A., Sherry B. Macrophage inflammatory protein 1 modulates macrophage function. J Immunol. 1992 May 1;148(9):2764–2769. [PubMed] [Google Scholar]
  11. Fukasawa M., Campeau J. D., Yanagihara D. L., Rodgers K. E., Dizerega G. S. Mitogenic and protein synthetic activity of tissue repair cells: control by the postsurgical macrophage. J Invest Surg. 1989;2(2):169–180. doi: 10.3109/08941938909015348. [DOI] [PubMed] [Google Scholar]
  12. Kasama T., Strieter R. M., Lukacs N. W., Lincoln P. M., Burdick M. D., Kunkel S. L. Interleukin-10 expression and chemokine regulation during the evolution of murine type II collagen-induced arthritis. J Clin Invest. 1995 Jun;95(6):2868–2876. doi: 10.1172/JCI117993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Klinger M. H., Wilhelm D., Bubel S., Sticherling M., Schröder J. M., Kühnel W. Immunocytochemical localization of the chemokines RANTES and MIP-1 alpha within human platelets and their release during storage. Int Arch Allergy Immunol. 1995 Aug;107(4):541–546. doi: 10.1159/000237097. [DOI] [PubMed] [Google Scholar]
  14. Kovacs E. J., DiPietro L. A. Fibrogenic cytokines and connective tissue production. FASEB J. 1994 Aug;8(11):854–861. doi: 10.1096/fasebj.8.11.7520879. [DOI] [PubMed] [Google Scholar]
  15. Leibovich S. J., Danon D. Promotion of wound repair in mice by application of glucan. J Reticuloendothel Soc. 1980 Jan;27(1):1–11. [PubMed] [Google Scholar]
  16. Leibovich S. J., Ross R. The role of the macrophage in wound repair. A study with hydrocortisone and antimacrophage serum. Am J Pathol. 1975 Jan;78(1):71–100. [PMC free article] [PubMed] [Google Scholar]
  17. Leibovich S. J., Wiseman D. M. Macrophages, wound repair and angiogenesis. Prog Clin Biol Res. 1988;266:131–145. [PubMed] [Google Scholar]
  18. Lukacs N. W., Kunkel S. L., Strieter R. M., Warmington K., Chensue S. W. The role of macrophage inflammatory protein 1 alpha in Schistosoma mansoni egg-induced granulomatous inflammation. J Exp Med. 1993 Jun 1;177(6):1551–1559. doi: 10.1084/jem.177.6.1551. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mustoe T. A., Pierce G. F., Thomason A., Gramates P., Sporn M. B., Deuel T. F. Accelerated healing of incisional wounds in rats induced by transforming growth factor-beta. Science. 1987 Sep 11;237(4820):1333–1336. doi: 10.1126/science.2442813. [DOI] [PubMed] [Google Scholar]
  20. Nissen N. N., Polverini P. J., Gamelli R. L., DiPietro L. A. Basic fibroblast growth factor mediates angiogenic activity in early surgical wounds. Surgery. 1996 Apr;119(4):457–465. doi: 10.1016/s0039-6060(96)80148-6. [DOI] [PubMed] [Google Scholar]
  21. Polverini P. J., Cotran P. S., Gimbrone M. A., Jr, Unanue E. R. Activated macrophages induce vascular proliferation. Nature. 1977 Oct 27;269(5631):804–806. doi: 10.1038/269804a0. [DOI] [PubMed] [Google Scholar]
  22. Porras-Reyes B. H., Blair H. C., Jeffrey J. J., Mustoe T. A. Collagenase production at the border of granulation tissue in a healing wound: macrophage and mesenchymal collagenase production in vivo. Connect Tissue Res. 1991;27(1):63–71. doi: 10.3109/03008209109006995. [DOI] [PubMed] [Google Scholar]
  23. Shanley T. P., Schmal H., Friedl H. P., Jones M. L., Ward P. A. Role of macrophage inflammatory protein-1 alpha (MIP-1 alpha) in acute lung injury in rats. J Immunol. 1995 May 1;154(9):4793–4802. [PubMed] [Google Scholar]
  24. Smith R. E., Strieter R. M., Phan S. H., Lukacs N. W., Huffnagle G. B., Wilke C. A., Burdick M. D., Lincoln P., Evanoff H., Kunkel S. L. Production and function of murine macrophage inflammatory protein-1 alpha in bleomycin-induced lung injury. J Immunol. 1994 Nov 15;153(10):4704–4712. [PubMed] [Google Scholar]
  25. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  26. Standiford T. J., Kunkel S. L., Basha M. A., Chensue S. W., Lynch J. P., 3rd, Toews G. B., Westwick J., Strieter R. M. Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung. J Clin Invest. 1990 Dec;86(6):1945–1953. doi: 10.1172/JCI114928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Standiford T. J., Kunkel S. L., Lukacs N. W., Greenberger M. J., Danforth J. M., Kunkel R. G., Strieter R. M. Macrophage inflammatory protein-1 alpha mediates lung leukocyte recruitment, lung capillary leak, and early mortality in murine endotoxemia. J Immunol. 1995 Aug 1;155(3):1515–1524. [PubMed] [Google Scholar]
  28. Stricklin G. P., Li L., Nanney L. B. Localization of mRNAs representing interstitial collagenase, 72-kda gelatinase, and TIMP in healing porcine burn wounds. J Invest Dermatol. 1994 Sep;103(3):352–358. doi: 10.1111/1523-1747.ep12394926. [DOI] [PubMed] [Google Scholar]
  29. Strieter R. M., Kunkel S. L., Elner V. M., Martonyi C. L., Koch A. E., Polverini P. J., Elner S. G. Interleukin-8. A corneal factor that induces neovascularization. Am J Pathol. 1992 Dec;141(6):1279–1284. [PMC free article] [PubMed] [Google Scholar]
  30. VanOtteren G. M., Standiford T. J., Kunkel S. L., Danforth J. M., Burdick M. D., Abruzzo L. V., Strieter R. M. Expression and regulation of macrophage inflammatory protein-1 alpha by murine alveolar and peritoneal macrophages. Am J Respir Cell Mol Biol. 1994 Jan;10(1):8–15. doi: 10.1165/ajrcmb.10.1.8292385. [DOI] [PubMed] [Google Scholar]
  31. WOESSNER J. F., Jr The determination of hydroxyproline in tissue and protein samples containing small proportions of this imino acid. Arch Biochem Biophys. 1961 May;93:440–447. doi: 10.1016/0003-9861(61)90291-0. [DOI] [PubMed] [Google Scholar]
  32. Wang C., Tammi M., Guo H., Tammi R. Hyaluronan distribution in the normal epithelium of esophagus, stomach, and colon and their cancers. Am J Pathol. 1996 Jun;148(6):1861–1869. [PMC free article] [PubMed] [Google Scholar]
  33. Whitby D. J., Ferguson M. W. Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol. 1991 Sep;147(1):207–215. doi: 10.1016/s0012-1606(05)80018-1. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES