Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing

Kazuichi Maruyama, Jun Asai, Masaaki Ii, Tina Thorne, Douglas W. Losordo, Patricia A. D'Amore

Research output: Contribution to journalArticlepeer-review

319 Citations (Scopus)

Abstract

Impaired wound healing is a common complication of diabetes. Although it is well known that both macrophages and blood vessels are critical to wound repair, the role of wound-associated lymphatic vessels has not been well investigated. We report that both the presence of activated macrophages and the formation of lymphatic vessels are rate-limiting to the healing of diabetic wounds. We have previously shown that macrophages contribute to the lymphatic vessels that form during the acute phase of corneal wound healing. We now demonstrate that this is a general phenomenon; cells that co-stain for the macrophage marker F4/80 and the lymphatic markers LYVE-1 (lymphatic vascular endothelium hyaluronate receptor) and podoplanin contribute to lymphatic vessels in full-thickness wounds. LYVE-1-positive lymphatic vessels and CD31-positive blood vessels were significantly reduced in corneal wound healing in diabetic mice (db/db) (P < 0.02) compared with control (db/+) mice. Glucose treatment of control macrophages led to the down-regulation of the lymphatic-specific receptor VEGFR3 and its ligands, vascular endothelial growth factor-C and -D (VEGF-C, -D). Interleukin-1β stimulation rescued diabetic macrophage function; application of interleukin-1β-treated db/db-derived macrophages to wounds in db/db mice induced lymphatic vessel formation and accelerated wound healing. These observations suggest a potential therapeutic approach for healing wounds in diabetic patients.

Original languageEnglish
Pages (from-to)1178-1191
Number of pages14
JournalAmerican Journal of Pathology
Volume170
Issue number4
DOIs
Publication statusPublished - 2007 Apr

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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