Lymphangiogenesis in chronic inflammation in the testis

Abstract

SummaryLymphangiogenesis occurs in various organs under inflammatory conditions. Recently, it was demonstrated that activated macrophages play an important role in the process of lymphangiogenesis. However, lymphangiogenesis during testicular inflammation has not yet been studied. Here, we investigated lymphangiogenesis in experimental autoimmune orchitis, a immunologic male infertility model, in mice. Histological changes were observed using immunohistochemical staining with the monoclonal antibodies against F4/80 (mature macrophage marker), lymph vessel endothelium HA‐receptor 1 (LYVE‐1) (lymphatic endothelial cells marker) and CD31 (endothelial cells marker). The expression of angiogenesis and lymphangiogenesis factors, such as vascular endothelial growth factor (VEGF)‐A, VEGF‐C, VEGF‐D and TNF‐α, which are secreted by activated macrophages, were examined using real‐time RT‐PCR. The results showed that lymphangiogenesis occurred along the undersurface of the tunica albuginea but not into the interstitium proper between the seminiferous tubules (STs) during the orchitis. It was noted that some F4/80‐positive macrophages expressed LYVE‐1 at the undersurface of the tunica albuginea and also in the testicular interstitium proper. RT‐PCR analysis revealed that the expressions of VEGF‐A, VEGF‐D and TNF‐α were significantly increased but that of VEGF‐C remained unchanged in the inflammatory testes. This study suggests that testicular macrophages are involved in the specific lymphangiogenesis in the chronic inflammation.

Macrophages: An Inflammatory Link Between Angiogenesis and Lymphangiogenesis

“… Cd11b+ macrophages were shown to form lymphatic‐like structures in vitro in Matrigel that were positive for LYVE‐1 and podoplanin. In an experimental autoimmune orchitis (EAO) model, a model for studying chronic inflammation of the testes, F4/80+ macrophages were found to migrate toward and get incorporated into the lymphatic capillary walls and, intriguingly, not the walls of blood capillaries . In a mouse model of tail lymphedema, Shimizu et al .…”

Lymphangiogenesis guidance by paracrine and pericellular factors

“…Inflammation-associated lymphangiogenesis is induced by inflammatory cytokines such as TNFα and IL-1 (which stimulate target cells), and leukocytes (e.g., macrophages) can produce substantial amounts of VEGF-C (Enholm et al 1997;Matsui et al 2003;Kataru et al 2009;Kim et al 2009). Macrophages and other bone marrow-derived cells have also been reported to intercalate in between the LECs at a very low rate during the formation of lymphatic vessels and, in some cases, have been detected to express the LEC markers LYVE1 and PROX1 (Maruyama et al 2005;Religa et al 2005;Jiang et al 2008;Zumsteg et al 2009;Lee et al 2010;Hall et al 2012;Hirai et al 2013). However, there is no lineage tracing evidence that these cells would directly contribute to expansion of lymphatic vessels in inflammation.…”

Inflammation-associated lymphangiogenesis: a double-edged sword?

“…[15][16][17][18][19][20]. Macrophage transdifferentiation was reported in an experimental orchitis model (15), LPS-induced peritonitis model (19), corneal injury model (16), and in a human transplanted kidney (17). Interestingly, under normal conditions the lymphatic endothelial progenitor cells appear only in minute quantities, but inflammatory stimuli lead to remarkable increases (18).…”

“…Although this remains the mainstream theory, some recent evidence suggests that circulating progenitor cells might be incorporated directly into the growing lymphatic vessels and transdifferentiate into LECs (lymphovasculogenesis; Figure 1 and refs. [15][16][17][18][19][20]. Macrophage transdifferentiation was reported in an experimental orchitis model (15), LPS-induced peritonitis model (19), corneal injury model (16), and in a human transplanted kidney (17).…”