Viewpoint 5

Abstract

While all of the cells in question, i.e. lymphocytes, dendritic cells (DCs) and keratinocytes, undeniably contribute to the control of skin immunity, one at least equally important cell is missing from the equation: the mast cell (MC). The most likely reason for this is that MCs are generally viewed only as pathology promoting effector cells, which are limited in their functions to the induction of inflammation in disease settings including allergic disorders, urticaria and mastocytosis. There is, however, a rapidly growing body of evidence showing that MCs can do much more than that (1). In fact, MCs are now viewed as initiators and controllers of innate immunity (2), modulators of adaptive immune responses (3) and regulators of tissue homeostasis (4). Although most of our knowledge about the role of MCs in the coordination and control of innate and acquired immune responses is derived from organs other than the skin, we hypothesize that these findings are very likely to be (at least in part) applicable also to the skin immune system and that, in the end, MCs may be key controllers of skin immunity under physiological circumstances (Fig. 1). Mast cells modulate innate and acquired immune responses. Ten years ago, it was reported that, using a murine model of septic peritonitis, MCs are critical effector cells in eliciting protective responses against bacteria (5,6). Since then, a lot of effort has been put into the characterization of the mechanisms by which MCs promote optimal innate immune responses to bacteria. These investigations further highlighted the importance of MC activation at sites of bacterial infections. For example, it has been shown that several very different mechanisms can lead to the activation of MCs and their subsequent release of potent mediators that promote resistance to bacterial infection. MCs not only express functional receptors for the detection of bacteria (e.g. CD48) (7) or bacterial products [e.g. Toll-like receptors (TLRs) 2, 4, 6 and 9] (2), but can also be activated by mediators that are produced or upregulated during bacterial infections, e.g. complement components (8,9) or endothelin-1 (10). The activation of MCs by these substances results in the release of a wide array of mediators with diverse functions. The most important mediator in this setting is tumor necrosis factor (TNF)-α (5), which is stored in MC granules and released immediately upon activation (11). MC-derived TNF-α then results in the recruitment of circulating leucocytes and the subsequent clearance of bacteria. Another mechanism by which MCs contribute to optimal survival after bacterial infection is by limiting the toxicity of endothelin-1, an endogenous toxic mediator, which is upregulated during septic peritonitis (10). Furthermore, MCs may even be directly involved in killing bacteria: it has been shown that they express antimicrobial peptides (12) and can even phagocytose and kill bacteria (13). While most of the in vivo work was done using models of bacterial infections of the peritoneum, recent publications have shown that the concept also proves to be true in other anatomical sites such as the middle ear (14) and the lung (15). In addition, MCs may also play an important role in controlling viral infections, as MCs express functional TLR3 and can upregulate and release antiviral cytokines and chemokines such as RANTES upon contact with Dengue or Newcastle disease virus (16,17). The role of MCs in immune responses is, however, not restricted to innate immunity. MCs have long been known to be beneficial in acquired immunity to parasites of the gut (18) and the skin (19). This is not the only reason why MCs are considered to potently influence the development, intensity, duration and outcome of adaptive immune responses (3). MCs express CD40 ligand and they regulate immunoglobulin production by B cells (20,21) as well as T-cell-mediated immune responses. For example, MC-derived TNF-α and costimulatory molecules from the B7 and the TNF/TNFR families expressed by MCs can enhance proliferation and cytokine production of T cells (22,23). Moreover, leukotriene B4 from activated MCs has been shown to induce chemotaxis of effector T cells (24) and histamine, which is abundant in MCs, can potently modulate T-cell-mediated immune responses (25). Of particular interest, especially in the context of skin immunity, is the ability of MCs to influence the maturation and function of DCs. It has been known for some time that MCs or MC products can influence DC functions in vitro. For example, MC-derived TNF-α has been shown to promote the maturation of DCs by upregulating α6 integrins (26). But it was not until recently that several independent reports unveiled the in vivo importance of MC/DC interactions (27–30). Most of these investigations have been conducted in mouse skin, where MC exosomes have been shown to induce the maturation of DCs by upregulating expression of MHC class II, CD80, CD86 and CD40 (27). Furthermore, MC mediators importantly control the migration of DCs to local lymph nodes, an essential step in efficient antigen presentation and elicitation of an immune response. For example, MC-derived histamine promotes the migration of DCs after IgE mediated activation of skin MCs (29) and Suto et al. (30) reported that the migration of DCs to local lymph nodes after contact hypersensitivity to FITC is dependent on TNF-α released by MCs. We have no doubt that the recent advances in our understanding of the physiological functions of MCs in the control of skin immunity in the mouse are only the tip of the iceberg we are about to discover during the years to come. Even though one has to be careful in extrapolating findings from murine to other systems, we suspect that much of what we see in mice holds true for humans. This view is supported by the fact that human skin MCs also express a huge array of potent immunomodulatory mediators (31) and by the very similar anatomical distribution of murine and human skin MCs, which exhibit the highest density at sites of frequent contact with pathogens (32), i.e. an ideal position for sentinels of the immune system. Will our current and future research efforts show that it is MCs that really control skin immune responses under physiological conditions? We do not know, but we would not be surprised. What we are sure of is that the skin immunity equation cannot be solved without the MC factor.