BBA - Molecular Basis of Disease (v.1822, #1)

Special issue on mast cells in inflammation by Wouter J de Jonge; René M van den Wijngaard (1).

Mast cells, angiogenesis, and tumour growth by Domenico Ribatti; Enrico Crivellato (2-8).
Accumulation of mast cells (MCs) in tumours was described by Ehrlich in his doctoral thesis. Since this early account, ample evidence has been provided highlighting participation of MCs to the inflammatory reaction that occurs in many clinical and experimental tumour settings. MCs are bone marrow-derived tissue-homing leukocytes that are endowed with a panoply of releasable mediators and surface receptors. These cells actively take part to innate and acquired immune reactions as well as to a series of fundamental functions such as angiogenesis, tissue repair, and tissue remodelling. The involvement of MCs in tumour development is debated. Although some evidence suggests that MCs can promote tumourigenesis and tumour progression, there are some clinical sets as well as experimental tumour models in which MCs seem to have functions that favour the host. One of the major issues linking MCs to cancer is the ability of these cells to release potent pro-angiogenic factors. This review will focus on the most recent acquisitions about this intriguing field of research. This article is part of a Special Issue entitled: Mast cells in inflammation.►Angiogenesis, tumour growth, and inflammation are closely related. ►Mast cells are in involved in tumour growth and angiogenesis. ►Inhibition of mast cells degranulation may be a therapeutic approach in antiangiogenesis in cancer treatment.
Keywords: Angiogenesis; Antiangiogenesis; Mast cells; Tumour growth;

Role of mast cells in colorectal cancer development, the jury is still out by J. Heijmans; N.V. Büller; V. Muncan; G.R. van den Brink (9-13).
The link between inflammation and colorectal cancer development is becoming increasingly clear. It had long been recognized that patients with inflammatory bowel disease are at an increased risk of colon cancer. Evidence from experimental animals now also implicates the innate immune system in the development of sporadically occurring intestinal adenomas, the precursors to colorectal cancer. Here we discuss the interaction between the immune system and the adenoma to carcinoma sequence with a special emphasis on the role of mast cells which may play a key role in adenoma development. This article is part of a Special Issue entitled: Mast cells in inflammation.► Chronic inflammation predisposes to colorectal cancer formation. ► The role of innate immunity in sporadic colon cancer development is increasingly recognized. ► Mast cells are innate immune cells that may modulate colonic adenoma to carcinoma development. ► We review conflicting studies in mice on the potential role of mast cells in adenoma formation. ► We discuss strengths and weaknesses of the models used.
Keywords: Mast cell; Colon cancer; Innate immune system; Adaptive immune system;

Mast cells and metabolic syndrome by Jie Zhang; Guo-Ping Shi (14-20).
Mast cells are critical effectors in the development of allergic diseases and in many immunoglobulin E-mediated immune responses. These cells exert their physiological and pathological activities by releasing granules containing histamine, cytokines, chemokines, and proteases, including mast cell-specific chymase and tryptase. Like macrophages and T lymphocytes, mast cells are inflammatory cells, and they participate in the pathogenesis of inflammatory diseases such as cardiovascular complications and metabolic disorders. Recent observations suggested that mast cells are involved in insulin resistance and type 2 diabetes. Data from animal models proved the direct participation of mast cells in diet-induced obesity and diabetes. Although the mechanisms by which mast cells participate in these metabolic diseases are not fully understood, established mast cell pathobiology in cardiovascular diseases and effective mast cell inhibitor medications used in pre-formed obesity and diabetes in experimental models offer hope to patients with these common chronic inflammatory diseases. This article is part of a Special Issue entitled: Mast cells in inflammation.►Mast cells are rich sources for inflammatory mediators. ►Mast cells exert their activities by releasing these inflammatory mediators. ►Mast cells are implicated in cardiovascular and metabolic diseases. ►Mast cell inactivation is effective to treat inflammatory diseases in animal models.
Keywords: Mast cell; Metabolic syndrome; Obesity; Diabetes; Hypertension dyslipidemia;

Mast cells and inflammation by Theoharis C. Theoharides; Konstantinos-Dionysios Alysandratos; Asimenia Angelidou; Danae-Anastasia Delivanis; Nikolaos Sismanopoulos; Bodi Zhang; Shahrzad Asadi; Magdalini Vasiadi; Zuyi Weng; Alexandra Miniati; Dimitrios Kalogeromitros (21-33).
Mast cells are well known for their role in allergic and anaphylactic reactions, as well as their involvement in acquired and innate immunity. Increasing evidence now implicates mast cells in inflammatory diseases where they are activated by non-allergic triggers, such as neuropeptides and cytokines, often exerting synergistic effects as in the case of IL-33 and neurotensin. Mast cells can also release pro-inflammatory mediators selectively without degranulation. In particular, IL-1 induces selective release of IL-6, while corticotropin-releasing hormone secreted under stress induces the release of vascular endothelial growth factor. Many inflammatory diseases involve mast cells in cross-talk with T cells, such as atopic dermatitis, psoriasis and multiple sclerosis, which all worsen by stress. How mast cell differential responses are regulated is still unresolved. Preliminary evidence suggests that mitochondrial function and dynamics control mast cell degranulation, but not selective release. Recent findings also indicate that mast cells have immunomodulatory properties. Understanding selective release of mediators could explain how mast cells participate in numerous diverse biologic processes, and how they exert both immunostimulatory and immunosuppressive actions. Unraveling selective mast cell secretion could also help develop unique mast cell inhibitors with novel therapeutic applications. This article is part of a Special Issue entitled: Mast cells in inflammation.► Mast cells release pro-inflammatory mediators selectively without degranulation. ► Mast cells are activated by CRH released under stress. ► Neuropeptide mast cell triggers have synergistic action with cytokines, like IL-33. ► Unique flavonoid combinations can effectively block mast cell secretion. ► Mast cells may serve as new therapeutic targets for psoriasis and multiple sclerosis.
Keywords: Skin inflammation; Mast cell; Multiple sclerosis; Selective release;

Mast cell activation and autism by Theoharis C. Theoharides; Asimenia Angelidou; Konstantinos-Dionysios Alysandratos; Bodi Zhang; Shahrzad Asadi; Konstantinos Francis; Elena Toniato; Dimitrios Kalogeromitros (34-41).
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by varying degrees of dysfunctional communication and social interactions, repetitive and stereotypic behaviors, as well as learning and sensory deficits. Despite the impressive rise in the prevalence of autism during the last two decades, there are few if any clues for its pathogenesis, early detection or treatment. Increasing evidence indicates high brain expression of pro-inflammatory cytokines and the presence of circulating antibodies against brain proteins. A number of papers, mostly based on parental reporting on their children's health problems, suggest that ASD children may present with “allergic-like” problems in the absence of elevated serum IgE and chronic urticaria. These findings suggest non-allergic mast cell activation, probably in response to environmental and stress triggers that could contribute to inflammation. In utero inflammation can lead to preterm labor and has itself been strongly associated with adverse neurodevelopmental outcomes. Premature babies have about four times higher risk of developing ASD and are also more vulnerable to infections, while delayed development of their gut–blood–brain barriers makes exposure to potential neurotoxins likely. Perinatal mast cell activation by infectious, stress-related, environmental or allergic triggers can lead to release of pro-inflammatory and neurotoxic molecules, thus contributing to brain inflammation and ASD pathogenesis, at least in a subgroup of ASD patients. This article is part of a Special Issue entitled: Mast cells in inflammation.►Allergic problems are common in autistic individuals. ►Perinatal mast cell activation may contribute to brain inflammation. ►The peptide neurotensin is increased in serum of autistic individuals.
Keywords: Allergy; Autism; Brain; Inflammation; Mast cells; Stress;

Transcription factors have a key role in mast cell differentiation and response of differentiated mast cells to external stimuli. During differentiation of progenitor cells to mast cells, a role for different GATA transcription factors in combination with PU.1 expression and downregulation of C/EBPα has been described. Notch pathway has been proposed to have a role in mast cell development. The microphthalmia-associated transcription factor expression is upregulated in later stages of mast cells differentiation, but it is not expressed in the closely related basophiles. In differentiated mast cells, there is a role for transcription factors both in determining the specific mast cell phenotype and in the response to immune stimuli such as IgE-Ag. A large number of transcription factors, including AP-1 family proteins, microphthalmia-associated transcription factor and STAT5, are modulated by these stimuli. These transcription factors and related protein modulators form a complex transcription factor network. They can form stimuli regulated specific heterodimers and common inhibitors can move from one protein to another. Transcription factors are the key regulators of mast cell physiology. Modulation of key transcription by such means as the therapeutic siRNA may hopefully allow us to modulate mast cell function, obtaining clinical benefit in a variety of diseases. This article is part of a Special Issue entitled: Mast cells in inflammation.► Mast cell differentiation is dependent upon correct levels of GATA PU.1 and C/EBPα. ► MITF is important for differentiated mast cells. ► This network includes USF2 MITF ATF3, PIAS3,STAT3 and AP-1.
Keywords: Mast cells transcription factor; IgE-Ag; AP-1; MITF;

Plasmodium falciparum, the aetiological agent of human lethal malaria, is responsible for over 2 million deaths per year and malaria episodes may vary considerably in their severity and clinical manifestations. Dysregulated balance of the inflammatory response and a defect in the anti-Plasmodium parasite immune response represent the hallmarks of malaria disease. Among the many possible mechanisms, it is now widely recognized that the production of pro-inflammatory mediators and cytokines and upregulation of endothelial cell adhesion molecules play important roles in malaria pathogenesis. We and others provided evidence that some components of allergic inflammatory response to malaria parasites or elicited by by-products of parasite infection may contribute to malaria pathogenesis. This review provides some clue regarding these mechanisms where mast cells and histamine, an inflammatory mediator generated following IgE-independent or IgE-mediated immune response, were found to play a major role in parasite transmission and malaria pathogenesis, respectively. This article is part of a Special Issue entitled: Mast cells in inflammation.► During Plasmodium parasite transmission via Anopheles mosquito bite, vector saliva induces rapid skin mast cell activation. ► Mosquito saliva-induced mast cell activation results in the down-regulation of antigen-specific immune response. ► Histamine plays a critical role in the development of malaria pathogenesis. ► Allergic inflammatory response may be considered as a risk factor for severe forms of malaria disease.
Keywords: Cerebral malaria; Mast cells; Anopheles; Skin; Histamine; Plasmodium;

New insights into the role of mast cells in autoimmunity: Evidence for a common mechanism of action? by Margaret E. Walker; Julianne K. Hatfield; Melissa A. Brown (57-65).
Mast cells are classically considered innate immune cells that act as first responders in many microbial infections and have long been appreciated as potent contributors to allergic reactions. However, recent advances in the realm of autoimmunity have made it clear that these cells are also involved in the pathogenic responses that exacerbate disease. In the murine models of multiple sclerosis, rheumatoid arthritis and bullous pemphigoid, both the pathogenic role of mast cells and some of their mechanisms of action are shared. Similar to their role in infection and a subset of allergic responses, mast cells are required for the efficient recruitment of neutrophils to sites of inflammation. Although this mast cell-dependent neutrophil response is protective in infection settings, it is postulated that neutrophils promote local vascular permeability and facilitate the entry of inflammatory cells that enhance tissue destruction at target sites. However, there is still much to learn. There is little information regarding mechanisms of mast cell activation in disease. Nor is it known how many mast cell-derived mediators are relevant and whether interactions with other cells are implicated in these diseases including T cells, B cells and astrocytes. Here we review the current state of knowledge about mast cells in autoimmune disease. We also discuss findings regarding newly discovered mast cell actions and factors that modulate mast cell function. We speculate that much of this new information will ultimately contribute to a greater understanding of the full range of mast cell actions in autoimmunity. This article is part of a Special Issue entitled: Mast cells in inflammation.► Mast cells are potent inflammatory cells that are well studied in allergic disease. ► Mast cells also exacerbate autoimmune disease in humans as well as in animal models. ► Mast cells act to recruit neutrophils to sites of autoimmune destruction in many of these diseases. ► Emerging data in mast cell biology offer potential roles for these cells in autoimmunity.
Keywords: Mast cells; Autoimmunity; TNF; Neutrophils; Inflammation;

Intestinal mast cells in gut inflammation and motility disturbances by Benedicte Y. De Winter; Rene M. van den Wijngaard; Wouter J. de Jonge (66-73).
Mast cells may be regarded as prototypes of innate immune cells that can be controlled by neuronal mediators. Their activation has been implicated in many types of neuro-inflammatory responses, and related disturbances of gut motility, via direct or indirect mechanisms that involve several mechanisms relevant to disease pathogenesis such as changes in epithelial barrier function or activation of adaptive or innate immune responses. Here we review the evidence for the involvement of mast cells in the inflammation of the bowel wall caused by bowel manipulation that leads to motility disturbances such as postoperative gastroparesis and ileus. Also in IBD there is substantial evidence for the involvement of mast cells and a mast cell-mediated neuroimmune interaction showing an increased number and an increased degranulation of mast cells. We discuss the potential of mast cell inhibition as a bona fide drug target to relief postoperative ileus. Further research on mast cell-related therapy either by stabilizing the mast cells or by blocking specific mast cell mediators as adjunctive therapy in IBD is encouraged, bearing in mind that several drugs currently used in the treatment of IBD possess properties affecting mast cell activities. This article is part of a Special Issue entitled: Mast cells in inflammation.► Mast cells are prototypes of innate immune cells that can be controlled by neuronal mediators. ► In the bowel, these cells comprise different subtypes that develop in accordance to the cytokine microenvironment. ► Evidence links mast cell activity to epithelial barrier dysfunction or activation of adaptive or innate immune responses. ► Mast cells are involved in the pathogenesis of bowel disorders via the neurogenic cytokine and protease release. ► Mast cell related adjunctive therapy in these pathologies should be considered.
Keywords: Mast cells; Neurogastroenterology; Macrophages; IBD; Ileus; Motility;

Relevance of mast cell–nerve interactions in intestinal nociception by Sophie A. van Diest; Oana I. Stanisor; Guy E. Boeckxstaens; Wouter J. de Jonge; René M. van den Wijngaard (74-84).
Cross-talk between the immune- and nervous-system is considered an important biological process in health and disease. Because mast cells are often strategically placed between nerves and surrounding (immune)-cells they may function as important intermediate cells. This review summarizes the current knowledge on bidirectional interaction between mast cells and nerves and its possible relevance in (inflammation-induced) increased nociception. Our main focus is on mast cell mediators involved in sensitization of TRP channels, thereby contributing to nociception, as well as neuron-released neuropeptides and their effects on mast cell activation. Furthermore we discuss mechanisms involved in physical mast cell–nerve interactions. This article is part of a Special Issue entitled: Mast cells in inflammation.► Mast cell-neuron communication can have major implications in various diseases. ► Mast cell mediators can sensitize neuronal receptors contributing to pain perception. ► Neuropeptides released by activated neurons can modulate mast cell activation. ► This review summarizes current knowledge on mast cell-neuron communication.
Keywords: Mast cell; Sensory afferent; Neuropeptide; TRP channel; Gut; Nociception;

Mast cell–nerve axis with a focus on the human gut by Sabine Buhner; Michael Schemann (85-92).
This paper summarizes the current knowledge on the interactions between intestinal mast cells, enteric neurons and visceral afferents which are part of the gut brain axis. The focus of this review is on the relevance of the mast cell–nerve axis in the human intestine. Similarities and important differences in the organization of the mast cell–nerve axis between human and rodents are discussed. Functionally important human mast cell mediators with neural actions in the human ENS are histamine (H1-4 receptors), proteases (PAR1 receptors), several cytokines and chemokines and probably also serotonin (5-HT3 receptors). On the other hand, mediator release from human intestinal mast cells is modulated by neuropeptides released from enteric and visceral afferent nerves. This article is part of a Special Issue entitled: Mast Cells in Inflammation.► Mast cell–nerve signaling through mast cell mediators. ► Nerve–mast cell signaling through enteric and visceral afferent nerves. ► Pathopyhsiological relevance of mast cell–nerve interactions.
Keywords: Mast cell; Enteric nervous system; Viszeral afferents; Human; Neuro-immune interaction;

The two faces of mast cells in food allergy and allergic asthma: The possible concept of Yin Yang by Aletta D. Kraneveld; Seil Sagar; Johan Garssen; Gert Folkerts (93-99).
The purpose of this review is to discuss the role of mast cells in allergic inflammation. We have focused on inflammation associated with allergic asthma and food allergy. Mast cells are ‘first line of defense’ innate/adaptive immune cells and are widely distributed in tissues in surfaces exposed to the environment. Especially in allergic settings mast cells are extensively studied, as they can be activated to release a wide range of mediators by allergen-IgE specific triggers. In addition, in allergic inflammation mast cells can also be activated non-allergic triggers. Recent studies revealed that mast cells, besides the classical role of pro-inflammatory effector cell, have also emerged as modulators of allergic sensitization and down-regulators of allergic inflammation. Therefore, mast cells can be regarded as ‘Ying Yan’ modulators in allergic responses in intestinal tract and airways. This article is part of a Special Issue entitled: Mast Cells in Inflammation.► The purpose of this review is to discuss the role of mast cells in food allergy and allergic asthma. ► Classically in allergy mast cells are regarded as pro-inflammatory effector cells. ► Mast cells have also emerged as modulators of allergic sensitization and down-regulators of allergic inflammation. ► Mast cells fulfill a Yin Yang role in allergy.
Keywords: Mast cell; Inflammation; Allergic asthma; Food allergy;