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S100A8/A9 is an important host defence mediator in neuropathic foot ulcers in patients with type 2 diabetes mellitus

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Abstract

Chronic wounds and in particular diabetic foot ulcers (DFUs) are a growing clinical challenge, but the underlying molecular pathophysiological mechanisms are unclear. Recently, we reported reduced levels of the immunomodulating and antimicrobial S100A8/A9 in non-healing venous leg ulcers (VLUs), while another study found increased S100A8/A9 in DFUs. To clarify these apparently contradictory findings, we compared S100A8/A9 as well as an inducer, lipopolysaccharide (LPS) and selected innate immune response mediators in wound fluids from non-healing DFUs and VLUs with healing wounds. Wound fluids were collected from neuropathic DFUs (n = 6) and VLUs (n = 9) of median 2-year duration, and split-thickness skin graft donor site wounds (n = 10) by standardized method. None of the patients had ischaemic extremities or clinically infected wounds. LPS was determined by limulus amoebocyte lysate test, and S100A8/A9, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-10 and vascular endothelial growth factor (VEGF) by immunospecific quantitative assays. LPS levels were median 8.7 (interquartile range 5.4–21.2) ng/ml in DFUs compared with 121 (22–2000) ng/ml in VLUs. S100A8/A9 was higher (p = 0.020) in DFUs [718 (634-811) µg/ml] than in VLUs [303 (252–533) µg/ml]. Neither G-CSF nor IL-10 wound fluid levels differed significantly between the chronic wound groups. VEGF levels correlated with LPS (r = 0.758, p = 0.011, n = 10) and were higher (p = 0.024) in VLU wound fluids. LPS (p < 0.0001), S100A8/A9 (p = 0.005), G-CSF (p = 0.003), IL-10 (p = 0.003) and VEGF (p = 0.005) were increased in chronic wound fluids combined compared with the sterile donor site wound fluids. The protein alterations in the wounds were not reflected in the patients’ sera. Low S100A8/A9 levels may contribute to poor wound healing in colonized chronic wounds with striking difference between DFUs and VLUs.

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Acknowledgments

Hanne Vogensen, Lone Haase and Rebekka Nielsen collected the sera and wound fluids.

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Authors and Affiliations

  1. Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark

    Hannah Trøstrup, Lars Christophersen, Niels Høiby & Claus Moser

  2. Copenhagen Wound Healing Center, University of Copenhagen, Copenhagen, Denmark

    Per Holstein, Bo Jørgensen, Tonny Karlsmark & Magnus S. Ågren

  3. Institute for International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark

    Niels Høiby

  4. Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark

    Magnus S. Ågren

  5. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Magnus S. Ågren

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  1. Hannah Trøstrup
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Correspondence to Magnus S. Ågren.

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Trøstrup, H., Holstein, P., Christophersen, L. et al. S100A8/A9 is an important host defence mediator in neuropathic foot ulcers in patients with type 2 diabetes mellitus. Arch Dermatol Res 308, 347–355 (2016). https://doi.org/10.1007/s00403-016-1646-7

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