The essential role of mast cells in orchestrating inflammation (2007)

Mast cells (MCs) are distributed in virtually all organs and vascularized tissues. They are present in the skin, the entire gastrointestinal tract, and the airways, where they are in close contact with the outside environment. They are also normal residents of the brain, peritoneum, synovium, hair follicles, and many other organs. This diverse distribution, recognized long ago, is associated with the heterogeneity of the MCs. MCs were divided into two general categories: the connective tissue MCs and the mucosal MCs. These two categories highlighted the fact that MCs residing in mucosal surfaces and in connective tissues were clearly different. The observed differences were based initially on histological staining and later on differences in the intracellular proteoglycans and proteases. However, it is clear now that the heterogeneity of MCs is much more complex, and their environments play a bigger role than anticipated in shaping the different characteristics of MCs. Our current knowledge on MC progenitors and development will be reviewed in an article of this issue of Immunological Review on MCs, which also discusses the various factors involved in MC constitutive homing and trafficking to sites of inflammation 1. MCs have long been known to participate in the inflammatory process. This knowledge was based on the fact that MCs are present in and recruited to the sites of inflammation. For example, they were observed long ago in the lesions of patients with Crohn’s disease and in the synovium of patients with rheumatoid arthritis. However, the participation level of MCs in the inflammatory processes leading to these diseases and the importance of their role were not fully appreciated until very recently. It is becoming clear that MCs are essential for promoting inflammation; they are not simple participants. There is evidence that they orchestrate the inflammatory reactions. What is this evidence? In my view, the first key experiment to point in that direction is the one performed by Dr Melissa Brown’s group 2, using the experimental allergic encephalomyelitis (EAE) mouse model, arguably the best model of multiple sclerosis (MS). After immunization with the components of myelin, the mice develop a disease with central nervous system demyelination, which resembles human MS. In that experiment, Dr Brown’s group takes advantage of a mouse strain (W/Wv mice) that is deficient in MCs to show that these mice have a significant reduction in disease incidence and severity following immunization with myelin components. Importantly, the induction and severity of the disease were restored after reconstitution of the MC population. This experiment shows that MCs play a necessary role in organizing the inflammatory response that leads to the disease. More recently, a similar experiment was performed to show the essential role of MCs in arthritis 3. Unlike wildtype animals, MC-deficient mice were resistant to the arthritis induced after injection of arthritogenic serum. Similar to what was observed in the EAE model experiment, reconstitution of the MC-deficient mice by infusion of MCs was sufficient to restore the arthritis. These two experiments show that MCs are capable of orchestrating inflammation in vastly different contexts, the brain and the joints. In other words, in the absence of MCs, inflammation and the development of the disease appear to be fundamentally affected. In a number of very recent general reviews on inflammation and inflammatory diseases, MCs were either not mentioned at all or listed as simple participants. Maybe this absence of recognition is in part because of the well-publicized role of MCs in allergic diseases, which may have somewhat overshadowed their other potential roles in other contexts. Or, the omission may simply be because of the fact that inflammatory lesions do not contain MCs in great numbers when compared with, for example the numbers of lymphocytes and neutrophils in those lesions. Violins, violas, trumpets, and so on are necessary to an orchestra, but only one conductor directs the music they make. Following this analogy, the MCs are few, but they are essential in promoting the inflammatory response. It seems very timely to advertise the central role of MCs as the conductor of the orchestra, while underlining the fact that many other cells are of course necessary for the inflammatory response. This issue of Immunological Reviews is devoted substantially to emphasizing this fundamental role of MCs and to point to new therapeutic options that such a role may permit. A number of reviews address the role of MCs in diseases associated classically with inflammation, including rheumatoid arthritis, MS, inflammatory kidney diseases, and conjunctivitis, and they discuss the mechanisms by which MCs are thought to trigger and orchestrate the inflammatory reactions in these very different contexts 3-9. Two articles discuss the role of MCs in atherosclerosis and cardiovascular diseases, both of which have been shown recently to contain a crucial inflammatory component 10, 11. Other articles review in great detail the mediators used by MCs to produce inflammatory responses, such as tryptases and proteases 12, 13, eicosanoids 14, and reactive oxygen species and nitric oxide 15. The roles of immunoglobulin G receptors and the counterregulation by other receptors are also analyzed 16-18. Additional reviews are devoted to MC-specific events: the early signaling pathways that include the tyrosine kinases and lipid mediators 19, the impact of the structure of the ligand on signaling 20, the network of transcription factors 21, and the mechanisms of endocytosis and exocytosis 22. MCs also play a protective role in innate immunity and an anti-inflammatory role in certain circumstances 23, 24. This beneficial role of MCs is discussed and analyzed in several reviews 6, 8, 12, 14, 15, 23, 24. The at once protective and proinflammatory role of MCs appears to be contradictory. This is not necessarily the case, as discussed below. Nevertheless, the apparent contradiction is a very important factor to take into consideration when asking the question of whether MCs could be a good therapeutic target. My own answer to that question is a probable yes. What are the arguments? One argument is based on the position of the MCs within our overall immune system. MCs are positioned in the evolutionary tree as an ancient cell. Analysis of primitive organisms indicates that MCs’ existence preceded lymphocytes and other cells of the immune system (R. Stevens, personal communication). Thus, evolution has built up a useful immune network of redundant mechanisms, MCs probably being one of the first. Today, there is no question that MCs are somehow involved in the immune response, for example against parasites, although in this case, it is not the body’s only defense mechanism. The real question, then, is whether MCs are still necessary and essential as a protective shield in our Westernized societies, which show the highest prevalence for many inflammatory diseases such as asthma and MS. One could hypothesize precisely that because MCs are no longer needed to play a protective role, they now are dominant in orchestrating the inflammatory reactions leading to these diseases. In this scenario, MCs have become oversensitive to stimuli that would not have been capable to trigger an inflammatory cascade in the context of MCs fulfilling their protective role. This hypothesis would fit very well with the ‘hygiene hypothesis’ that has been proposed to support the increased incidence of atopy, eczema, asthma, MS, type I diabetes, inflammatory bowel diseases, and other inflammatory and autoimmune diseases 25, 26 in modern Western societies. In the hygiene hypothesis, it is the absence of stimuli from infectious agents that is thought to lead the immune system to overreact to small or harmless factors and even to attack ‘self’-cells. I propose here that MCs are at the center of the hygiene hypothesis. This argument that MCs could be a determining factor in explaining the hygiene hypothesis has not yet been tested, and studies are needed to prove or disprove this point. However, it provides a framework to support a therapeutic strategy to target MCs in inflammatory diseases. Another argument that supports MCs as good therapeutic targets comes from the clinical data obtained with some tyrosine kinase inhibitors, which are known to be potent MC inhibitors. One such a drug, imatinib mesylate, was designed primarily to inhibit the BCR-abl tyrosine kinase, and it is now the treatment of choice for chronic myelogenous leukemia. However, imatinib is also an inhibitor of the c-kit tyrosine kinase and of some of its mutations. As such, it is being used in gastrointestinal stromal tumors, a cancer in which juxtamembranous mutations of c-kit are considered the primary oncogenic event. It is also used off-label in many patients with c-kit-expressing solid tumors and has been used in treatment of rheumatoid arthritis. Through c-kit inhibition, imatinib is an inhibitor of MC survival and activation and is an inducer of MC apoptosis, both in vitro and in vivo. However, although many thousands of patients are being exposed chronically to the drug, side effects such as infections, which could be considered secondary to an immune deficit engendered by MC inhibition, have not been reported associated with the drug. This point is particularly remarkable because many of these patients are immunocompromised because of their disease status and treatment with other drugs. Thus, MC targeting in the context of c-kit inhibition does not appear to lead to immunodeficiency or to loss of immune protection. In this article, I argue that MCs play an essential role in ‘orchestrating’ the inflammatory responses that are common in many inflammatory diseases. As such and in spite of their protective roles in some circumstances, MCs represent an attractive therapeutic target for the treatment of these diseases.