The Proangiogenic Capacity of Polymorphonuclear Neutrophils Delineated by Microarray Technique and by Measurement of Neovascularization in Wounded Skin of CD18-Deficient Mice

Abstract

Growing evidence supports the concept that polymorphonuclear neutrophils (PMN) are critically involved in inflammation-mediated angiogenesis which is important for wound healing and repair. We employed an oligonucleotide microarray technique to gain further insight into the molecular mechanisms underlying the proangiogenic potential of human PMN. In addition to 18 known angiogenesis-relevant genes, we detected the expression of 10 novel genes, namely midkine, erb-B2, ets-1, transforming growth factor receptor-β₂ and -β₃, thrombospondin, tissue inhibitor of metalloproteinase 2, ephrin A2, ephrin B2 and restin in human PMN freshly isolated from the circulation. Gene expression was confirmed by the RT-PCR technique. In vivo evidence for the role of PMN in neovascularization was provided by studying neovascularization in a skin model of wound healing using CD18-deficient mice which lack PMN infiltration to sites of lesion. In CD18-deficient animals, neovascularization was found to be significantly compromised when compared with wild-type control animals which showed profound neovascularization within the granulation tissue during the wound healing process. Thus, PMN infiltration seems to facilitate inflammation-mediated angiogenesis which may be a consequence of the broad spectrum of proangiogenic factors expressed by these cells.

Clinical relevance of circulating midkine in ulcerative colitis

“…Midkine expression has been found in epithelial cells of intestinal mucosa and endothelial cells of gut blood vessels (8). Also, immune cells infiltrating inflamed tissue (14), such as lymphocytes (15), neutrophiles (16), and macrophages (17), may contribute to increased concentration of midkine. Platelets, which can selectively scavenge angiogenic factors and release them upon activation (18), may be another possible source of this cytokine.…”

Neutrophils Are a Key Component of the Antitumor Efficacy of Topical Chemotherapy with Ingenol-3-Angelate

“…Neutrophil extravasation into inflamed sites is severely impaired in CD18-deficient mice (23,30,31), whereas Ab and some T cell responses remain intact (32). B16 tumors grew faster in CD18-deficient mice compared with C57BL/6 mice (Fig.…”

Inflammation, inflammatory cells and angiogenesis: decisions and indecisions

“…Enhanced release of VEGF by neutrophils is associated with the excessive angiogenesis in endometriosis [27,28]. Deletion of CD18, which results in defective neutrophil recruitment, slows angiogenesis in wound healing models in vivo [29]. Neutrophils are associated with angiogenesis in the Matrigel sponge model in vivo induced by the HIV viral transactivator protein tat [30], where the neutrophils morphologically appeared to be leading the vessel invasion into the gels (Fig.…”

“…Multiple neutrophil subsets have been defined with differing cytokine production profiles and surface markers [41], these are likely only a glimpse into the wide range of potential effects of neutrophils. In addition to VEGFA, neutrophils have been shown to make a wide range of angiogenic molecules [29,33,42] and an equally wide range of anti-tumor and antiangiogenic molecules [40,42,43]. The key appears to lie within the response of these cells to the signals from the microenvironment.…”