The dynamic and complex role of mast cells in allergic disease

Mast cells (MCs) are found widely distributed in tissues and contribute to regulation of inflammatory responses and ongoing modulation of the tissues. Although MCs are important in a variety of processes, including innate immunity, their role in allergic disease has received increasing attention in the past decade. MCs are located throughout the human body and, upon allergen exposure, they are stimulated via the immunoglobulin E (IgE) receptor (Fc(epsilon)RI) to release several pro-inflammatory mediators such as tumor necrosis factor (TNF), reactive oxygen species such as nitric oxide (NO), proteases, and lipid-derived mediators. However, we now recognize that MCs can be activated by a variety of mechanisms and that mediator release is a consequence of several intra- and extracellular signals. Some of these mechanisms, such as Fc receptor aggregation and proteinase-activated receptor (PAR)-mediated activation facilitate and augment local inflammatory responses. Other mechanisms, such as interferon gamma (IFN-gamma) induction of NO, may inhibit MC function and downregulate inflammatory responses. Increased understanding of these complex pathways has encouraged the development of therapies for allergic inflammation that target specific MC functions and mediators. Some novel strategies include oligonucleotides that induce or inhibit the production of specific mediators. Such approaches may yield useful therapies for allergic individuals in the near future.     

Endogenous protein and enzyme fragments induce immunoglobulin E‐independent activation of mast cells via a G protein‐coupled receptor,MRGPRX2

Mast cells play a central role in inflammatory and allergic reactions by releasing inflammatory mediators through 2 main pathways, immunoglobulin E‐dependent and E‐independent activation. In the latter pathway, mast cells are activated by a diverse range of basic molecules (collectively known as basic secretagogues) through Mas‐related G protein‐coupled receptors (MRGPR s). In addition to the known basic secretagogues, here, we discovered several endogenous protein and enzyme fragments (such as chaperonin‐10 fragment) that act as bioactive peptides and induce immunoglobulin E‐independent mast cell activation via MRGPRX 2 (previously known as MrgX2), leading to the degranulation of mast cells. We discuss the possibility that MRGPRX 2 responds various as‐yet‐unidentified endogenous ligands that have specific characteristics, and propose that MRGPRX 2 plays an important role in regulating inflammatory responses to endogenous harmful stimuli, such as protein breakdown products released from damaged or dying cells.     

Potential therapeutic use of IL-37: a key suppressor of innate immunity and allergic immune responses mediated by mast cells

The host response to either exogenous or endogenous insults produces a series of changes, characterized by alterations in immunological functions and generation of mediators called cytokines which include the interleukin-1 (IL-1) family members. IL-1 acts as a hormone mediating the host responses to infection and inflammation. Blocking inflammatory IL-1 family members can be effective against inflammatory disorders, including allergies. IL-37, (formerly IL-1 family member 7), emerges as an inhibitor of innate and adaptive immunity by reducing circulating and organ cytokine levels. IL-37, mainly expressed in dendritic cells, monocytes, and plasma cells after TIR ligand activation, inhibits inflammatory cytokines and augments the level of anti-inflammatory IL-10. IL-37 is involved in allergic reaction and its expression in dendritic cells causes tollerogenicity and inhibits inflammatory response. Mast cells (MCs) are ubiquitous in the body, reside in numerous mucosal tissues, and are mediators of allergic reaction, and innate and adaptive immunity. MCs are important regulators of cytokine generation in the course of inflammatory responses and allergy, and are implicated in the pathophysiology of allergic asthma. Cysteine protease caspase-1 activation leads to the cleavage of pro-form of IL-1 into active mature IL-1 which is present in stimulated and unstimulated inflammatory MCs. Inflammatory cytokine inhibition, along with the augmentation of anti-inflammatory IL-10 by IL-37, is certainly beneficial and improves the pathogenesis of allergic disorders. However, in these studies, the exact mechanism(s) of IL-37-induced anti-inflammatory and anti-allergic activity along with its side effect(s) remain to be determined.     

Significance of mast cells in spermatogenesis,implantation, pregnancy,and abortion: Cross talk and molecular mechanisms

Both subsets of MCs including MC_TC (tryptase‐positive, chymase‐positive) and MC_T (tryptase‐positive, chymase‐negative) are present in the testis and epididymis. Increased number of MCs, higher levels of MC‐released tryptase in testis and seminal plasma of males with fertility problems, and promoting sperm motility in individuals with oligozoospermia after using MC blockers provide evidence that MCs may play a role in male infertility/subfertility disturbances. MC‐released tryptase and histamine contribute to the fibrosis and may disrupt spermatogenesis. MCs not only influence the process of spermatogenesis but also have effects on the function of other testis‐residing cells. MC‐derived histamine may influence the steroidogenesis of Leydig cells by acting through H1R and H2R receptors. Additionally, the interaction between MC‐released ATP and P2X receptors expressed on the peritubular cells may induce the production of the pro‐inflammatory mediators by peritubular cells. Further investigations showed that MCs may be involved in the pathology of female infertility during implantation, pregnancy, and abortion. In the uterus, MC_T subtype is abundant in myometrium and adjacent basal layer while MC_TC subtype is distributed in all layers. MCs in response to hormones mainly estradiol and progesterone become activated and release a wide range of mediators including histamine, VEGF, proteases, and metalloproteinases (MMPs) that have a role in different stages of pregnancy. An increasing influx of MCs to the cervix during the pregnancy occurs that helps to the physiologic cervical ripening. While MMPs degrade the extracellular matrix (ECM), VEGF modulates neovascularization and histamine influences the embryo implantation. MC‐derived histamine may have a positive effect during implantation due to its participation in tissue remodeling. MC proteases including tryptase and chymase activate the precursors of MMP2 and MMP9 to mediate ECM degradation during the physiologic menstrual cycle. There is a line of evidence that MCs have a role in abortion by releasing TNF‐α.     

肥大细胞在细菌和病毒感染中的作用

自1878年发现肥大细胞以来，人们对肥大细胞在过敏性疾病中的作用进行了广泛而深入的研究，但对肥大细胞的生理功能却了解不多。从无脊椎动物的昆虫到人类，肥大细胞在生物体的长期进化中能得以保留，说明这种细胞具有不可替代的重要作用。肥大细胞广泛分布于皮肤、呼吸道和胃肠道等易与外界接触的部位，并位于血管周围。这就使得肥大细胞不仅能时刻监视病原菌的入侵，而且肥大细胞所释放的介质和细胞因子也能迅速作用于血管内皮细胞和血液中的炎性细胞，并经血液分布到全身各组织器官中。有关肥大细胞在宿主抵御病原微生物中的作用已引起人们的关注。本综述主要介绍肥大细胞在细菌感染时，对宿主的保护和损伤作用、对细菌识别的分子机制以及肥大细胞与病毒感染等方面的研究进展。     

Mast cells in the pathogenesis of rheumatic diseases and as potential targets for anti-rheumatic therapy

Summary:  Increasing evidence suggests that mast cells (MCs), in addition to acute allergic reactions, are involved in the pathogenesis of chronic inflammatory diseases and in particular in rheumatoid arthritis (RA). MCs reside in connective tissues and in synovial tissue of joints. They produce an array of proinflammatory mediators, tissue destructive proteases, and cytokines, most prominently tumor necrosis factor-α, which is one of the key cytokines in the pathogenesis of RA. MCs may also participate in the development of secondary or amyloid A amyloidosis, as the partial degradation of the serum amyloid A (SAA) protein by MCs leads to the generation of a highly amyloidogenic N-terminal fragment of SAA. MCs may contribute to the pathogenesis of connective tissue diseases, scleroderma, vasculitic syndromes, and systemic lupus erythematosus, although the data available are limited. Inhibition of the most important growth factor receptor of human MCs, c-Kit, by the selective tyrosine kinase inhibitor imatinib mesylate, induces apoptosis of synovial tissue MCs. As MCs are long-lived cells, induction of their apoptosis could be a feasible approach to inhibit their functions. Preliminary findings suggest that a drug that inhibits c-Kit could have anti-rheumatic activity in the treatment of patients with RA and spondyloarthropathies.     

Prevention of F‐actin assembly switches the response to SCF from chemotaxis to degranulation in human mast cells

Following antigen/IgE‐mediated aggregation of high affinity IgE‐receptors (FcεRI), mast cells (MCs) degranulate and release inflammatory mediators leading to the induction of allergic reactions including anaphylaxis. Migration of MCs to resident tissues and sites of inflammation is regulated by tissue chemotactic factors such as stem cell factor (SCF (KIT ligand)). Despite inducing similar early signaling events to antigen, chemotactic factors, including SCF, produce minimal degranulation in the absence of other stimuli. We therefore investigated whether processes regulating MC chemotaxis are rate limiting for MC mediator release. To investigate this issue, we disrupted actin polymerization, a requirement for MC chemotaxis, with latrunculin B and cytochalasin B, then examined chemotaxis and mediator release in human (hu)MCs induced by antigen or SCF. As expected, such disruption minimally affected early signaling pathways, but attenuated SCF‐induced human mast cell chemotaxis. In contrast, SCF, in the absence of other stimuli, induced substantial degranulation in a concentration‐dependent manner following actin disassembly. It also moderately enhanced antigen‐mediated human mast cell degranulation which was further enhanced in the presence of SCF. These observations suggest that processes regulating cell migration limit MC degranulation as a consequence of cytoskeletal reorganization.     

An overview of mast cell pattern recognition receptors

Background

Mast cells (MCs) are long-lived immune cells of the connective tissue which play a key role in development and amplification of inflammatory process initiated inter alia by allergic reactions or microbial infections. They reside in strategic locations in the body that are notably exposed to deleterious factors disturbing homeostasis, which enables them to become one of the first-line defense strategy. MCs have developed a wide range of various mechanisms to deal with invading intruders and harmful endogenic factors. Those include storage and synthesis with a subsequent release of inflammatory mediators, forming of MC-extracellular traps, and phagocytosis.

Findings

Particularly, important role in microbial sensing is achieved due to the presence of different pattern recognition receptors (PRRs). The best-described receptors are Toll-like receptors activated by different pathogen- and damage-associated molecular patterns. However, MCs express also C-type lectin receptors specialized in antifungal defense, NOD-like receptors detecting bacterial peptidoglycans, and RIG-like receptors relevant in viral sensing.

Conclusion

This review will focus on the current knowledge of PRRs expressed within different types of MCs.

     

Mast cell chymase modulates IL-33 levels and controls allergic sensitization in dust-mite induced airway inflammation

Mast cells (MCs) are major effector cells contributing to allergic conditions. When activated, they can release large amounts of active proteases, including chymase from their secretory granules. Here we assessed the role of the chymase mouse mast cell protease 4 (mMCP-4) in allergic airway inflammation induced by house-dust mite (HDM) extract. mMCP-4^−/− mice demonstrated elevated airway reactivity and eosinophilia compared with wild-type (WT) animals, suggesting a protective role for mMCP-4 during the late inflammatory phase of the disease. However, mMCP-4 also contributed to the sensitization phase, as indicated by higher levels of serum immunoglobulin E in mMCP-4^−/− vs. WT mice and higher levels of cytokines secreted by HDM-restimulated mMCP-4^−/− vs. WT splenocytes. In line with a contribution of mMCP-4 in the early stages of disease, HDM extract directly induced chymase secretion from MCs. The elevated airway and inflammatory responses of mMCP-4^−/− mice were associated with a profound increase in the levels of interleukin (IL)-33 in the lung tissue. Moreover, WT MCs degraded IL-33 more efficiently than did MCs lacking mMCP-4. Together, our findings identify a protective role of a MC chymase in a physiologically relevant model for airway inflammation and suggest that chymase-mediated regulation of IL-33 can account for this protective function.     

Allergic disease and autoimmune effectors pathways

Allergy and autoimmunity result from dysregulation of the immune system. Until recently, it was generally accepted that the mechanisms that govern these disease processes are quite disparate; however, new discoveries suggest possible common pathogenetic effector pathways. This review illustrates the concomitant presentation of these conditions and the potential relationship or common mechanism in some cases, by looking at the key elements that regulate the immune response in both allergic and autoimmunite conditions: mast cells, antibodies, T cells, cytokines, and genetic determinants. The parallel appearance of allergic and autoimmune conditions in the some patients may reveal that such aberrations of the immune system have a common pathophysiologic mechanism. Mast cells, which play a key role in allergic reactions, and the wealth of inflammatory mediators they express, make it likely that they have profound effects on many autoimmune processes. Activation of protein kinases by inflammatory cytokines and environmental stresses may contribute to both allergic and autoimmune diseases. The presence of autoantibodies in some allergic conditions suggests an autoimmune basis for these conditions. Because of the central role T cells play in immune reactivity, the T-cell receptor (TCR) loci have long been considered important candidates for common disease susceptibility within the immune system such as asthma, atopy, and autoimmunity. Immunomodulation is the key to a successful treatment of allergic and autoimmune conditions.     

Presence of SNAP-23 and syntaxin 4 in mouse and hamster peritoneal mast cells

Mast cells (MCs) play a crucial role in inflammatory reactions. Their presence and number in the peritoneal cavity is important to overcome and enhance resistance to peritoneal infection. When MCs are activated they release a variety of biological mediators from their granules, such as histamine, that contribute to the appropriate and rapid local immune response. Granular content is released using a process of compound exocytosis, also termed degranulation. SNAP-23 and syntaxin 4 are plasma membrane proteins involved in degranulation of rat MCs. Their presence, however, has not been studied in MCs of other rodent species. The aim of the present study was to investigate using immunocytochemistry whether SNAP-23 and syntaxin 4 are present in peritoneal MCs of the mouse and hamster. In addition, the diameter, percentage and histamine content of these cells were also analyzed. Our results demonstrate that SNAP-23 and syntaxin 4 are present in the mouse and hamster peritoneal MCs, suggesting that proteins involved in the secretory process in MCs are conserved among species. Likewise, we conclude that peritoneal MCs of mouse and hamster are heterogeneous in size, percentage and histamine content.     

Activated mast cells synthesize and release soluble ST2‐a decoy receptor for IL‐33

IL‐33 released from damaged cells plays a central role in allergic inflammation by acting through its membrane‐bound receptor, ST2 receptor (ST2L). IL‐33 activity can be neutralized by the soluble spliced variant of ST2 (sST2) that has been associated with allergic inflammation but its source is not well defined. We investigated whether mast cells (MCs) are a significant source of sST2 following activation through FcεRI or ST2. We find that antigen and IL‐33 induce substantial production and release of sST2 from human and mouse MCs in culture and do so synergistically when added together or in combination with stem cell factor. Moreover, increases in circulating sST2 during anaphylaxis in mice were dependent on the presence of MCs. Human MCs activated via FcεRI failed to generate IL‐33 and IL‐33 produced by mouse bone marrow‐derived MCs was retained within the cells. Therefore, FcεRI‐mediated sST2 production is independent of MC‐derived IL‐33 acting in an autocrine manner. These results are consistent with the conclusion that both mouse and human MCs when activated are a significant inducible source of sST2 but not IL‐33 and thus have the ability to modulate the biologic impact of IL‐33 produced locally by other cell types during allergic inflammation.     

Mast cells and autoimmunity

Mast cells (MCs) are major effector cells in allergic diseases. Recently, it has become evident that the contribution of MCs extends far beyond their accepted role in allergic disease, and that they play a more extensive role in a variety of non-allergic immune processes such as the innate immunity response. These cells have a key role in both the induction and elicitation of several autoimmune conditions. Targeting MC development, maturation or activation may be of value in future prevention and treatment of autoimmune conditions.     

Non-IgE mediated mast cell activation

Mast cells (MCs) are innate immune cells that are scattered in tissues throughout the organism being particularly abundant at sites exposed to the environment such as the skin and mucosal surfaces. Generally known for their role in IgE-mediated allergies, they have also important functions in the maintenance of tissue integrity by constantly sensing their microenvironment for signals by inflammatory triggers that can comprise infectious agents, toxins, hormones, alarmins, metabolic states, etc. When triggered their main function is to release a whole set of inflammatory mediators, cytokines, chemokines, and lipid products. This allows them to organize the ensuing innate immune and inflammatory response in tight coordination with resident tissue cells, other rapidly recruited immune effector cells as well as the endocrine and exocrine systems of the body. To complete these tasks, MCs are endowed with a large repertoire of receptors allowing them to respond to multiple stimuli or directly interact with other cells. Here we review some of the receptors expressed on MCs (ie, receptors for Immunoglobulins, pattern recognition receptors, nuclear receptors, receptors for alarmins, and a variety of other receptors) and discuss their functional implication in the immune and inflammatory response focusing on non-IgE-mediated activation mechanisms.     

Eosinophils in Allergic Diseases: Immuno-Pharmacological Regulation

Eosinophils (EOS) are cells that have excited great interest among researchers because of their involvement in many phenomena, and particularly those of defence against parasitic infestations and of modulation of allergic inflammatory reactions. The ontogenesis, morphology and functions of EOS are described, and especially the receptors and chemical mediators they synthesize. Particular attention is paid to the EOS role as a central element in allergic inflammation processes, able to maintain the inflammatory state by producing specific cytokines and to cause tissue damage by producing free radicals. The cell's role in the defence against parasitic infestations is also considered. Finally, emphasis is placed on EOS capacity for immunopharmacological regulation by means both of active secretion of regulating substances and of modulation of other substances, able to inhibit certain phases of allergic inflammation.     

Novel Strategies to Target Mast Cells in Disease

Mast cells (MCs) are versatile effector cells of the immune system, characterized by a large content of secretory granules containing a variety of inflammatory mediators. They are implicated in the host protection toward various external insults, but are mostly well known for their detrimental impact on a variety of pathological conditions, including allergic disorders such as asthma and a range of additional disease settings. Based on this, there is currently a large demand for therapeutic regimens that can dampen the detrimental impact of MCs in these respective pathological conditions. This can be accomplished by several strategies, including targeting of individual mediators released by MCs, blockade of receptors for MC-released compounds, inhibition of MC activation, limiting mast cell growth or by inducing mast cell apoptosis. Here, we review the currently available and emerging regimens to interfere with harmful mast cell activities in asthma and other pathological settings and discuss the advantages and limitations of such strategies.     

Positive and negative regulatory mechanisms in high-affinity IgE receptor-mediated mast cell activation

Mast cells are important effector cells in allergic inflammatory reactions. The aggregation of the high-affinity IgE receptor (FcεRI) on the surface of mast cells initiates a complex cascade of signaling events that ultimately leads to the release of various mediators involved in allergic inflammation and anaphylactic reactions. The release of these mediators is tightly controlled by signaling pathways that are propagated through the cell by specific phosphorylation and dephosphorylation events. These events are controlled by protein kinases and protein phosphatases which either positively or negatively regulate the propagation of the signal through the cell. This review summarizes the role of both positive and negative regulators of FcεRI-induced mast cell activation.     

Eosinophils in Allergic Diseases: Immuno-Pharmacological Regulation

Abstract

Eosinophils (EOS) are cells that have excited great interest among researchers because of their involvement in many phenomena, and particularly those of defence against parasitic infestations and of modulation of allergic inflammatory reactions. The ontogenesis, morphology and functions of EOS are described, and especially the receptors and chemical mediators they synthesize. Particular attention is paid to the EOS role as a central element in allergic inflammation processes, able to maintain the inflammatory state by producing specific cytokines and to cause tissue damage by producing free radicals. The cell's role in the defence against parasitic infestations is also considered. Finally, emphasis is placed on EOS capacity for immunopharmacological regulation by means both of active secretion of regulating substances and of modulation of other substances, able to inhibit certain phases of allergic inflammation.     

Effects of H1 antihistamines on adhesion molecules: a possible rationale for long-term treatment

Our knowledge of the mechanisms underlying the allergic reaction has increased rapidly and has revealed a complex network of cells, mediators and cytokines. The intercellular adhesion system (and the ICAM-1 molecule in particular) appeared to play a pivotal role in the accumulation of inflammatory cells at the site of allergic reaction. The new antihistamines have been demonstrated to be capable of affecting several phenomena of the allergic inflammation, including mediator release, cellular activation and adhesion molecule expression. Taking into consideration the central role of adhesion molecules, the modulation of their expression may represent an important therapeutic target. The nasal and the conjunctival challenges represent two useful models for the in vivo study of the antiallergic activity of drugs, as they allow investigation of a wide variety of parameters: inflammatory infiltrate, ICAM-1 expression, concentration of soluble mediators.     

The significance and technical aspects of quantitative measurements of inflammatory mediators in allergic rhinitis

The pathophysiology of allergic rhinitis induced by various inhalant allergens through an IgE mediated mechanism, has been well demonstrated. The participation of many important inflammatory cells and mediators released by these cells in the human nasal allergic reaction provides insight into the relationship between the responsiveness to allergen exposure and nasal symptoms of allergic rhinitis. This paper summarizes our previous studies on some important mediators in the nasal secretions of atopic patients during different phases after nasal allergen challenge and during natural allergen exposure. The microsuction technique proves to be an especially useful and reliable nasal sampling method permitting quantitative analysis of important mediators such as histamine, tryptase, leukotriene C4 and eosinophil cationic protein in nasal secretions. The measurement of these mediators during allergic reactions provides accurate data on the activity of some important inflammatory cells (i.e., mast cells, basophils, and eosinophils) and their responses to therapy.