Macrophage-Mediated Tissue Vascularization: Similarities and Differences Between Cornea and Skin

Abstract

Macrophages are critical mediators of tissue vascularization both in health and disease. In multiple tissues, macrophages have been identified as important regulators of both blood and lymphatic vessel growth, specifically following tissue injury and in pathological inflammatory responses. In development, macrophages have also been implicated in limiting vascular growth. Hence, macrophages provide an important therapeutic target to modulate tissue vascularization in the clinic. However, the molecular mechanisms how macrophages mediate tissue vascularization are still not entirely resolved. Furthermore, mechanisms might also vary among different tissues. Here we review the role of macrophages in tissue vascularization with a focus on their role in blood and lymphatic vessel formation in the barrier tissues cornea and skin. Comparing mechanisms of macrophage-mediated hem- and lymphangiogenesis in the angiogenically privileged cornea and the physiologically vascularized skin provides an opportunity to highlight similarities but also tissue-specific differences, and to understand how macrophage-mediated hem- and lymphangiogenesis can be exploited for the treatment of disease, including corneal wound healing after injury, graft rejection after corneal transplantation or pathological vascularization of the skin.

Keywords: angiogenesis; cornea; lymphangiogenesis; macrophages; monocytes; skin.

Figure 1

Macrophages in corneal neovascular disease. (A) The naive cornea is devoid of blood and lymphatic vessels. Few immune cells including macrophages are present in the peripheral cornea and to a lesser extent in the central cornea. (B) An acute incisional injury (left) leads to the ingrowth of lymphatic, but not blood vessels. A chronic injury (suture placement, right) leads to the ingrowth of blood and lymphatic vessels. Corneal neovascularization in both injury models critically depends on the presence of corneal macrophages. (C) Bacterial keratitis (left) leads to ingrowth of blood vessels in the early and late stage of infection, whereas lymphatic vessels only appear in the late stage of infection. Both are critically dependent on the presence of corneal macrophages. HSV-1 keratitis (right) leads to the ingrowth of blood and lymphatic vessels independently of the presence of corneal macrophages. (D) The low-risk corneal transplantation setting (left) without pre-existent corneal neovascularization usually does not result in graft rejection, whereas the high-risk corneal transplantation setting (right) with pre-existent blood and lymphatic vessels is likely to result in graft rejection. Macrophage depletion significantly improves graft survival. All settings (B–D) result in the accumulation of corneal macrophages.