Decreased Macrophage Number and Activation Lead to Reduced Lymphatic Vessel Formation and Contribute to Impaired Diabetic Wound Healing

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 lymphaticspecific receptor VEGFR3 and its ligands, vascular endothelial growth factor-C and -D (VEGF-C, -D). Interleukin-1␤ stimulation rescued diabetic macrophage function; application of interleukin-1␤-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.

UV light crosslinking regresses mature corneal blood and lymphatic vessels and promotes subsequent high-risk corneal transplant survival

“…Interestingly, macrophages decreased in inflammatory corneas after CXL, which should contribute to the regression of pathologic BVs and LVs in corneas, as macrophages play a key role in the induction of angiogenesis44, 45 and lymphangiogenesis46, 47, 48, 49 under pathological conditions in the cornea and in the maintenance of LVs 50. Furthermore, we also observed significant reduction in CD45 + leukocytes in suture‐induced inflammation in corneas after CXL treatment using riboflavin and UVA.…”

Vasculogenic mimicry by bone marrow macrophages in patients with multiple myeloma

“…Macrophages take part into neovascularization through secreting a wide array of angiogenic growth factors, including VEGF and bFGF (Ribatti et al, 2006), 'drilling' tunnels for new vasculature by producing tubular destruction of the matrix and distributing to form columns and capillary-like structures containing erythrocytes (Moldovan et al, 2000), localizing in microvessels embedded in bundles of fibrillar collagen (Anghelina et al, 2006a), adhering to injured vessel walls, thus accelerating the re-endothelization of the vascular barrier (Fujiyama et al, 2003), and assisting lymphangiogenesis in cornea (Maruyama et al, 2007) and kidney (Kerjaschki et al, 2006). Herein we show that macrophages participate directly in neovessel formation in MM, adding new information on the mechanisms of MM neovascularization and microcirculation.…”

Autacoid 14S,21R-Dihydroxy-Docosahexaenoic Acid Counteracts Diabetic Impairment of Macrophage Prohealing Functions

“…Macrophages play critical roles in wound healing: they engulf apoptotic polymorphonuclear leukocytes (PMNs), tissue debris, and infectious microorganisms; they promote wound healing, including accelerating re-epithelialization by promoting keratinocyte migration from the wound edge to decrease the epithelial gap and increasing the formation of granulation tissue by promoting fibroblasts and endothelial cells moving into wounds to cover the wound bed 2 ; and they enhance angiogenesis, to repair damaged blood vessels and thus to supply sufficient oxygen and nutrients during healing. 2 Macrophage prohealing functions have been confirmed: macrophage transplantation into wounds promotes healing, 3,4 and macrophage depletion results in delayed wound healing. 5,6 The presence of diabetes, however, compromises macrophage functions and so contributes to disrupted wound healing.…”

“…5,6 The presence of diabetes, however, compromises macrophage functions and so contributes to disrupted wound healing. 1,4,7 In addition to amino acid-based cytokines and growth factors, which are known to mediate wound healing and associated angiogenesis, lipid-derived molecules also may be important mediators. Docosahexaenoic acid (DHA), an essential -3 fatty acid, is a relatively abun- dant, endogenous lipid component in blood and in wounded full-thickness skin.…”

“…8,16 Diabetes and the accompanying hyperglycemia and oxidative stress damage DNA, proteins, and lipids in various tissues. These conditions cause cellular and enzymatic dysfunction during the formation of cytokines and eicosanoids associated with cell growth, angiogenesis, and/or inflammation, 4,7,[17][18][19] all of which are at least in part responsible for impairment of macrophage functions in diabetes. 18,19 We have observed that 14S,21R-diHDHA formation was significantly halted in diabetic wounds, compared with nondiabetic wounds in mice, which suggests that diabetic complications dysregulate the generation of DHA-derived lipid mediators.…”