Mast cells as cellular sensors in inflammation and immunity

Abstract

Mast cells are localized in tissues. Intense research on these cells over the years has demonstrated their role as effector cells in the maintenance of tissue integrity following injury produced by infectious agents, toxins, metabolic states, etc. After stimulation they release a sophisticated array of inflammatory mediators, cytokines, and growth factors to orchestrate an inflammatory response. These mediators can directly initiate tissue responses on resident cells, but they have also been shown to regulate other infiltrating immune cell functions. Research in recent years has revealed that the outcome of mast cell actions is not always detrimental for the host but can also limit disease development. In addition, mast cell functions highly depend on the physiological context in the organism. Depending on the genetic background, strength of the injurious event, the particular microenvironment, mast cells direct responses ranging from pro- to anti-inflammatory. It appears that they have evolved as cellular sensors to discern their environment in order to initiate an appropriate physiological response either aimed to favor inflammation for repair or at the contrary limit the inflammatory process to prevent further damage. Like every sophisticated machinery, its dysregulation leads to pathology. Given the broad distribution of mast cells in tissues this also explains their implication in many inflammatory diseases.

Keywords: immunity; inflammation; mast cells.

Figure 1

Immediate hypersensitivity responses to inactivate endo- or exogenous venoms. While IgE-dependent hypersensitivity reactions have been known for long to initiate allergic responses, recent research has unveiled that this type of response can also be activated by certain endogenous or exogenous toxins, which cause the mast cells to release granule-stored proteases, which in a feed-back mechanism can inactivate these toxins through proteolytic cleavage. Thus endogenously produced highly active pharmacological peptides such as endothelin-1 and neurotensin can be cleaved with mast cell-released carboxypeptidase A and neurolysin, respectively. Similarly certain snake venoms such as sarafotoxins, which bear homology to endothelin-1 can also be cleaved by CPA. Interestingly, while honeybee venom has been shown in some cases to cause IgE-dependent deadly anaphylactic reactions, mast cell released products also serve to inactivate this venom and limit its toxicity.

Figure 2

Mast cells function as cellular sensors. Mast cells are components of the innate and adaptive immune surveillance system in tissues. Following an injurious event, mast cells become activated and release a whole array of pro-inflammatory mediators. Their activation will promote a tissue inflammatory response characterized by the cellular cross-talk with tissue resident cells and other tissue infiltrating cells through released products or direct cell–cell contact. Mast cell activation is controlled by multiple additional factors that highly depend on a given genetic background and the local environment. Studies in recent years have revealed that mast cells are able to differentially control this response by initiating either a pro- or anti-inflammatory program destined for tissue repair and conditioned by the nature of the initial injurious event (strength, type, etc., for explanation see text). Mast cells can therefore be viewed as cellular sensors that direct tissue responses in inflammation and immunity as a function of the stimulus and physiological/pathological context. Dysregulation of this sensor function by chronic stimulation or defective control mechanisms can promote pathology and lead to inflammatory and auto-immune diseases.