Mast Cells: Fascinating but Still Elusive after 140 Years from Their Discovery

Some of the basic characteristics of tissue mast cells were described over 140 years ago by Paul Ehrlich, the founder of modern immunology [...].


Preface
Some of the basic characteristics of tissue mast cells were described over 140 years ago by Paul Ehrlich, the founder of modern immunology [1]. At that time, the mast cells' distinguishing feature was the affinity of their cytoplasmic granules for certain basic dyes. For several decades, mast cells and their mediators were essentially considered to play mainly a proinflammatory role in allergic disorders, such as bronchial asthma [2][3][4], allergic rhinitis [5], urticaria [6,7], food allergy [8,9], anaphylaxis [10,11], atopic dermatitis [12], and angioedema [13]. With the appreciation of these cells as major potential sources of a myriad of cytokines and chemokines, it became evident in the 1990s that mast cells may express immunoregulatory functions [14,15]. During the last decades, it was demonstrated that mast cells can also produce different proangiogenic [16][17][18] and lymphangiogenic factors [19,20], suggesting that they may actually play a role in tumor initiation and growth [21][22][23][24]. Moreover, these cells can be activated by different viral [25,26] and bacterial proteins [27,28] and thereby represent a potentially important cell during microbial infections. Therefore, the spectrum of diseases in which mast cells and their mediators have been implicated has extended to include bacterial, fungal, viral, and helminth infections [26,[29][30][31]; several diseases of the cardiovascular [14,32,33] and gastrointestinal systems [34][35][36]; and the joints [37,38]. Figure 1 schematically summarizes the wide spectrum of pathophysiological conditions in which mast cells and their mediators have been implicated during the last decades. This volume contains contributions by several established investigators in the field of mast cell biology. The volume starts with a collaborative paper by Stephen J. Galli, Gilda Varricchi, and Gianni Marone, illustrating initial and more recent studies which have attempted to identify distinct "subpopulations" of mast cells based on the analyses of transcriptomes of anatomically distinct mouse mast cell populations [39][40][41][42]. The authors illustrate the important roles played by mast cells to the control of homeostasis in different pathophysiological conditions. Moreover, they discuss the possibility that distinct subpopulations of mast cells could play different roles in cardiovascular disorders and in tumorigenesis. Finally, the authors speculate that at least two major subsets of mast cells, MC1 and MC2, like macrophages (M1 and M2 subtypes) [43], dendritic cells (D1 and D2) [44], and neutrophils (N1 and N2) [45,46], could play distinct or even opposite roles in different pathophysiological conditions. role of subsets of mast cells in different human gastric cancers will demand studies of increasing complexity beyond those assessing merely mast cell density and microlocalization. Antonelli and coworkers, based on their long-lasting experience, comprehensively reviewed the roles of immune and inflammatory cells, cytokines, and chemokines in the thyroid cancer microenvironment [74]. Ribatti and Vacca illustrate the role of bone marrow angiogenesis in the pathogenesis and progression of hematological malignancies [75]. Based on their extensive experience, they discuss the roles played by mast cells in the modulation of angiogenesis in patients with multiple myeloma. Sagi-Eisenberg describes a novel mechanism by which adenosine, released by activated mast cells, can autocrinally activate the A3 adenosine receptor [76].
Mast cells are strategically located at sites that interface with the external environment, such as the skin [77], lung [78], and intestine [34,79]. These locations allow mast cells to act as sentinels for tissue damage and pathogen invasion [4]. Moreover, the association between mast cells and blood vessels [32,52] is optimal to foster the rapid recruitment of immune cells out of the bloodstream and into the inflamed tissues. This process is facilitated by the mast cell production of TNF-α [80][81][82][83][84] and IL-1β [85,86] that activate endothelial cells, the release of vasoactive mediators (i.e., histamine and cysteinyl leukotrienes) [87,88], and chemokines that promote the recruitment of inflammatory and immune cells [24,70,[89][90][91][92]. Marshall and coworkers elegantly reviewed the complex roles of mast cell responses to viruses and pathogen products [26]. This review highlights the complexity of mast cell biology in the context of innate immune responses. Di Nardo and collaborators elegantly demonstrated that mast cells express lipocalin 2 (LPCN2), a known inhibitor of bacterial growth. Using mast cells derived from mice deficient in LPCN2, they show that this antimicrobial peptide is an important component of mast cell activity against Escherichia coli. They also demonstrate that sphingosine-1-phosphate (S1P) activates a specific receptor (S1PR) on mast cells to release LPC2, which exerts antimicrobial activity against several bacteria such as Staphylococcus aureus and E. coli [93]. Piliponsky and collaborators extensively reviewed the role of mast cells and their mediators in viral, bacterial, and fungal infections [29]. They discuss recent studies focused on mast cell interactions with flaviviruses and Candida albicans, and mast cell functions in a model of cecal ligation and puncture. Collectively, the results of these studies illustrate that mast cells can either promote host resistance to infections or contribute to a dysregulated host response that can increase host morbidity and mortality.
Coeliac disease is a human autoimmune-like disorder characterized by chronic inflammation of the small intestine induced by proline-and glutamine-rich wheat gluten [94,95]. Coeliac disease is the result of complex interactions of genetic, environmental, and immunological factors [96]. Although coeliac disease is considered a prototype of T-cell mediated disease [96], the innate immune system can contribute to its pathogenesis. Frossi and collaborators' review has interesting results, indicating that mast cells and their mediators could play a role in the pathogenesis of coeliac disease [94].
Rheumatoid arthritis is a chronic systemic autoimmune disease primarily affecting the joints [97]. Mast cells are present in healthy synovial tissue [98] and their density is increased in rheumatoid arthritis synovitis [99,100]. However, the exact functions and the correlations of mast cell density with disease development and progression are still largely unknown. Moreover, contradictory data have been obtained in animal models and from patients with long-lasting disease [101][102][103]. Rivellese and coworkers present a careful revision of the literature on mast cells in rheumatoid arthritis, including recent observations from patients with early disease indicating that these cells are relevant markers of disease severity [37,38].
In recent years, accumulating evidence has revealed the close anatomical contact and functional interactions between neurons and mast cells [104][105][106]. Theoharides and coworkers present a careful revision of the literature and recent findings on mediators released from activated mast cells that could activate microglia [107,108], causing localized inflammation [109][110][111] and some symptoms of autism spectrum disorder [112].
Boo and collaborators present original results in a mouse model of allergen-provoked localized vulvodynia, supporting the hypothesis that mast cells are involved in this painful disorder [113].

Conclusions and Future Directions
This is a wonderful time in mast cell research. Indeed, the last years have witnessed unprecedented progress in our understanding of the development of mast cells [40][41][42]. Moreover, extraordinary progress has been made in understanding the complex homeostatic and protective roles of these cells in different pathophysiological conditions [31,39,114,115]. Mast cells, known for decades for their detrimental role in allergic diseases, are now recognized to play crucial roles in a diverse array of physiological and pathologic functions [15,30,116]. We would like to speculate that such different, sometime opposite effects of mast cells are made possible by the plurality of mast cell subpopulations.
Recently, comprehensive analysis of the transcriptome of individual anatomically distinct mast cells [117] and fate-mapping system [40,41,118] demonstrate that rodent mast cells form a highly heterogeneous population of immune cells [40][41][42], similar to macrophages [43,119] and T cells [120,121]. These fascinating results indicate that much more remains to be discovered in development, migration to tissues, biochemistry, and functions of different subsets of rodent and human mast cells.
Boo and collaborators present original results in a mouse model of allergen-provoked localized vulvodynia, supporting the hypothesis that mast cells are involved in this painful disorder [113].

Conclusions and Future Directions
This is a wonderful time in mast cell research. Indeed, the last years have witnessed unprecedented progress in our understanding of the development of mast cells [40][41][42]. Moreover, extraordinary progress has been made in understanding the complex homeostatic and protective roles of these cells in different pathophysiological conditions [31,39,114,115]. Mast cells, known for decades for their detrimental role in allergic diseases, are now recognized to play crucial roles in a diverse array of physiological and pathologic functions [15,30,116]. We would like to speculate that such different, sometime opposite effects of mast cells are made possible by the plurality of mast cell subpopulations. Recently, comprehensive analysis of the transcriptome of individual anatomically distinct mast cells [117] and fate-mapping system [40,41,118] demonstrate that rodent mast cells form a highly heterogeneous population of immune cells [40][41][42], similar to macrophages [43,119] and T cells [120,121]. These fascinating results indicate that much more remains to be discovered in development, migration to tissues, biochemistry, and functions of different subsets of rodent and human mast cells.
After 140 years from their discovery, mast cells remain fascinating but still elusive cells of the immune system. The characterization of subpopulations of mast cells by single-cell RNA-seq, together with analysis of encoded proteins, will be of paramount importance to modulate the injury-or repair-inducing abilities of these immune cells.
Author Contributions: The authors contributed equally to the drafting the manuscript and approved the final version of the paper. All authors have read and agreed to the published version of the manuscript Funding: This work was supported in part by grants from the CISI-Lab Project (University of Naples Federico II), CRèME Project, and TIMING Project (Regione Campania) to G.M.

Acknowledgments:
The authors thank all the contributors who have generously submitted their articles to this book. The authors thank Gjada Criscuolo (University of Naples Federico II, Italy) and Meredith Liu for their time, dedication, and competence throughout the preparation of this volume.

Conflicts of Interest:
The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.