Endothelial cells in the eyes of an immunologist

Abstract

Endothelial cell activation in the process of tumor angiogenesis and in various aspects of vascular biology has been extensively studied. However, endothelial cells also function in other capacities, including in immune regulation. Compared to the more traditional immune regulatory populations (Th1, Th2, Treg, etc.), endothelial cells have received far less credit as being immune regulators. Their regulatory capacity is multifaceted. They are critical in both limiting and facilitating the trafficking of various immune cell populations, including T cells and dendritic cells, out of the vasculature and into tissue. They also can be induced to stimulate immune reactivity or to be immune inhibitory. In each of these parameters (trafficking, immune stimulation and immune inhibition), their role can be physiological, whereby they have an active role in maintaining health. Alternatively, their role can be pathological, whereby they contribute to disease. In theory, endothelial cells are in an ideal location to recruit cells that can mediate immune reactivity to tumor tissue. Furthermore, they can activate the immune cells as they transmigrate across the endothelium into the tumor. However, what is seen is the absence of these protective effects of endothelial cells and, instead, the endothelial cells succumb to the defense mechanisms of the tumor, resulting in their acquisition of a tumor-protective role. To understand the immune regulatory potential of endothelial cells in protecting the host versus the tumor, it is useful to better understand the other circumstances in which endothelial cells modulate immune reactivities. Which of the multitude of immune regulatory roles that endothelial cells can take on seems to rely on the type of stimulus that they are encountering. It also depends on the extent to which they can be manipulated by potential dangers to succumb and contribute toward attack on the host. This review will explore the physiological and pathological roles of endothelial cells as they regulate immune trafficking, immune stimulation and immune inhibition in a variety of conditions and will then apply this information to their role in the tumor environment. Strategies to harness the immune regulatory potential of endothelial cells are starting to emerge in the non-tumor setting. Results from such efforts are expected to be applicable to being able to skew endothelial cells from having a tumor-protective role to a host-protective role.

Fig. 1

Endothelial cell regulation of immune cell trafficking. Endothelial cells (EC) can form a barrier that prevents transmigration of immune cells, thereby protecting tissue from immune injury. This is particularly important in protecting the blood–brain barrier or in maintaining immune privilege. However, depending on their state of activity, endothelial cells can also recruit immune cells through their expression of adhesion molecules and chemokine. This often occurs in response to exposure to pathogens, such as bacteria or viruses where recruitment of innate immune response is the first line of defense against the invading organism. Whether immune cell transmigration is prevented or facilitated depends on the state of endothelial cell activity and the endothelial cell stimuli

Fig. 2

Endothelial cells as immune stimulatory cells. Activation of endothelial cells by various pathogens can stimulate release of cytokines and chemokines, leading to recruitment of immune cells. If uncontrolled, this first line of immunological defense against invading pathogens can result in injury. For example, excessive inflammation induced by endothelial cells can result in a cytokine storm, which can contribute to tissue damage. In recognition of the injury that can result from uncontrolled endothelial cells stimulation of immune reactivity, various pharmacological approaches are being tested to limit this excessive inflammation

Fig. 3

Endothelial cells as immune suppressive cells. Through a variety of approaches, both cell contact–dependent and cell contact–independent, endothelial cells can inhibit immune reactivity. The physiological benefit of this immune suppressive capability of endothelial cells is that it limits excessive inflammation that could otherwise lead to tissue injury. However, the immune inhibitory activity of endothelia cells can also be induced by pathogens to as a protective strategy from immune destruction. Furthermore, it can prevent the normal immunological processes that maintain health, such as in the tightly regulated recruitment of monocytes to limit amyloid accumulation that otherwise occurs in Alzheimer’s disease

Fig. 4

Immune inhibitory endothelial cells in the tumor environment. The intimate proximity of endothelial cells to immune cells attempting to transmigrate into tumor tissue or regional lymph nodes places them in a precarious position of being able to either promote or prevent immune reactivity to tumor. Through multiple means, tumors have developed schemes by which to manipulate the endothelial cells to take on a role that prevents immune reactivity to tumor and, thus, facilitates tumor development. These means include downregulation of endothelial cell adhesion molecules that otherwise facilitate immune cell trafficking into tissue, or inducing endothelial cells that either tolerize T cells or skew various immune cell populations into inhibitory cells