Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis

Abstract

The lymphatic system provides important functions for tissue fluid homeostasis and immune response. Lymphangiogenesis, the formation of new lymphatics, comprises a series of complex cellular events in vitro or in vivo, e.g., proliferation, differentiation, and sprouting. Recent evidence has implied that macrophages act as a direct structural contributor to lymphatic endothelial walls or secret VEGF-C/-D and VEGF-A to initiate lymphangiogenesis in inflamed or tumor tissues. Bone marrow-derived macrophages are versatile cells that express different functional programs in response to exposure to microenvironmental signals, and can be identified by specific expression of a number of proteins, F4/80, CD11b, and CD68. Several causative factors, e.g., NF-κB, IL-1β, TNF-α, SDF-1, M-CSF, especially TonEBP/VEGF-C signaling, may be actively involved in macrophage-induced lymphangiogenesis. Alteration of macrophage phenotype and function has a profound effect on the development and progression of inflammation and malignancy, and macrophage depletion for controlling lymphangiogenesis may provide a novel approach for prevention and treatment of lymphatic-associated diseases.

Cellular phenotypes and spatio‐temporal patterns of lymphatic vessel development in embryonic mouse hearts

“…It is expressed on a variety of adult macrophage subsets, microglial cells in the brain, and also on a subpopulation of dendritic cells (Leenen et al 1994;Van den Berg and Kraal 2005;Lewis and Pollard, 2006). Conversely, CD11b is implicated in various adhesive interactions of myeloid cells (macrophages, monocytes, and granulocytes) (Ji, 2012) and belongs to a family of integrins (Arnaout, 1990). It is found also on natural killer (NK) cells and certain subpopulations of B lymphocytes (Flotte et al 1983;Gahmberg et al, 1998;Liu et al, 2004;Solovjov et al, 2005), but not on dendritic cells.…”

“…However, it is possible, that composition of additional surface antigens differs among these Lyve-1 þ cells, depending on the type of tissue/organ and/or the stage of development. Macrophages have been previously suggested to transdifferentiate into lymphatic endothelial cells during inflammatory reactions and during tumor progression (Maruyama et al, 2005(Maruyama et al, , 2007Religa et al, 2005;Ji, 2012). The debate on macrophages contributing to the genesis of lymphatic vessels has been broadened by a study by Gordon et al (2010), which indicates that Lyve-1-expressing macrophages are intimately involved in vessel wall of developing lymphatic sacs and embryonic lymphatic vessels in mice.…”

“…However, neither their detailed phenotypes nor time of occurrence have been characterized precisely. Recent studies indicate that Lyve-1 is also expressed on the surface of a subset of macrophages, which have been proposed to contribute to inflammation-induced lymphangiogenesis (Cursiefen et al, 2004;Religa et al, 2005;Maruyama et al, 2005Maruyama et al, , 2007Schledzewski et al, 2006;Albrecht and Christofori, 2011;Ji, 2012;SchulteMerker et al, 2011). These cells have been reported to be present in the mesenchyme of dermatomes and the mediastinum of the developing embryos and found to express also CD31 (¼PECAM1, platelet endothelial cell adhesion molecule-1) and Prox-1 antigens (Buttler et al, 2006(Buttler et al, , 2008.…”

Are Macrophages in Tumors Good Targets for Novel Therapeutic Approaches?

“…Inhibition of M-CSF has been shown to suppress tumor lymphangiogenesis since it plays a role in VEGF-A/C secretion. Interestingly, endothelial nitric oxide synthase (eNOS) and IL-6 also regulate lymphangiogenesis (Ji, 2011) (Fig. 3).…”

Endometriosis with an aberrant immunophenotype: Challenging differential diagnosis of glandular lesions in the pelvic lymph nodes

“…These data are consistent with results published by Ruiz et al who also found significantly higher CXCR4 expression in endometriotic lesions compared to normal endometrium 33 . In 2012 Ji published that macrophages act as a direct structure contributor to lymphatic endothelial walls or secrete a vascular endothelial growth factor (VEGF) to initiate lymphangiogenesis in inflamed or tumor tissues 34 . This finding, together with the fact that endometriosis is an inflammatory disorder with an increased concentration of macrophages, indicates the possible role of macrophages in the process of lymph node involvement by endometriosis.…”