Elsevier

International Immunopharmacology

Volume 40, November 2016, Pages 362-384
International Immunopharmacology

Review
Targeting mast cells: Uncovering prolific therapeutic role in myriad diseases

https://doi.org/10.1016/j.intimp.2016.09.019Get rights and content

Highlights

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    Therapeutic role of mast cells in myriad diseases.

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    Inflammatory mediators have role in various diseases like asthma, cancer.

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    CRTH2 antagonists showed anti-asthma and anti-allergic rhinitis activity.

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    H4 antagonists have been used in pruritis and rhinitis treatment.

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    Considerable difference exist between human and murine mast cells.

Abstract

The mast cells are integral part of immune system and they have pleiotropic physiological functions in our body. Any type of abnormal stimuli causes the mast cells receptors to spur the otherwise innocuous mast cells to degranulate and release inflammatory mediators like histamine, cytokines, chemokines and prostaglandins. These mediators are involved in various diseases like allergy, asthma, mastocytosis, cardiovascular disorders, etc. Herein, we describe the receptors involved in degranulation of mast cells and are broadly divided into four categories: G-protein coupled receptors, ligand gated ion channels, immunoreceptors and pattern recognition receptors. Although, activation of pattern recognition receptors do not cause mast cell degranulation, but result in cytokines production. Degranulation itself is a complex process involving cascade of events like membrane fusion events and various proteins like VAMP, Syntaxins, DOCK5, SNAP-23, MARCKS. Furthermore, we described these mast cell receptors antagonists or agonists useful in treatment of myriad diseases. Like, omalizumab anti-IgE antibody is highly effective in asthma, allergic disorders treatment and recently mechanistic insight of IgE uncovered; matrix mettaloprotease inhibitor marimistat is under phase III trial for inflammation, muscular dystrophy diseases; ZPL-389 (H4 receptor antagonist) is in Phase 2a Clinical Trial for atopic dermatitis and psoriasis; JNJ3851868 an oral H4 receptor antagonist is in phase II clinical development for asthma, rheumatoid arthritis. Therefore, research is still in inchoate stage to uncover mast cell biology, mast cell receptors, their therapeutic role in myriad diseases.

Introduction

The Mast Cells (MCs) origin could be traced to a leukocyte ancestor operating as primitive local innate immunity, which primarily functioned as phagocytic action and pathogens killing activity. Since, from the beginning this type of defensive cell, the MC phylogenetic progenitor progressively evolved into a tissue regulatory cell, which later on might have been incorporated into the networks of recombinase activating genes (RAG)-mediated adaptive immunity in the Cambrian era, about 550 million years ago. Perhaps the early MCs appeared about 450–500 million years ago, albeit we shared them with lamprey, hagfish, and sharks (our last common ancestor) [1]. Furthermore, developmental biological data, alluded that the PGD2 pathway of arachidonic acid metabolism developed before the LTC4 pathway during evolution, that heparin evolved to store histamine and varied enzymatically active serine proteases in the MC's secretory granules, and that heparin expressing MCs appeared > 500 million years ago, before the inception or development of adaptive immunity [2]. Hence, mast cell originates, diversify after millions year of evolution.

Mast cells are integral part of immune system and they have pleiotropic physiological functions in our body including protective ones. Because of mast cells close vicinity with blood vessels, allows them to have a crucial sentinel role in host defence [3]. Mast cells have been reported in the regulation of innate and adaptive immune responses: including tolerance to skin graft rejection [4], [5], in settings of T cell and antibody mediated autoimmunity [6], in protective immunity against viral [7], and microbial pathogens [8]. Furthermore, they play crucial role in tissue remodelling, wound healing [9], angiogenesis [10], protection from cancer by participation in tumor stroma [11]. Mast cells also limit UV-B induced inflammation, and injury [12]. Indeed, mast cells inactivate, neutralize honeybee, and viper venom. [13]. Thus, mast cells are not responsible for incendiary effects, but also plays pivotal role in protective body functions.

In this review we try uncover human and rodent mast cells development, differentiation, and receptors differences. Furthermore, we also uncover mast cell disorders, mast cells receptors mechanism, targeting mast cells with receptor antagonists and mast cell enzyme inhibitors.

Section snippets

Mast cell development and differentiation

The considerable differences exist between murine and human mast cells development and differentiation. In human two major types of MCs have been reported: MCs containing only tryptase (MCT), mostly found in mucosal tissues (lamina propria, in the airways), and MCs containing tryptase, chymase and carboxypeptidase A (MCTC) chiefly abundant in the serosal microenvironment (skin, small bowel submucosa, and peritoneal cavity). Although, MCs are absent in avascular tissues, such as mineralized

Mast cell receptors

There are four types of receptors expressed on mast cells and are succinctly described (with their ligands, messengers and cellular effects) in Table 2.

Mast cell degranulation and its effects

The mast cell degranulation can occur in response to myriad stimuli, by involvement of GPCRs, LGICs, IgE receptor ligation, and either from endogenous peptides (such as endothelin 1) or exogenous peptides (such as venom-derived and bacteria-derived peptides) [54]. The degranulation is intricate process which involves multiple membrane fusion events: granule–granule fusion and the fusion of granules with the plasma membrane [55]. These fusion events are essentially dependent on the interaction

Mast cells disorders

Mast cells diseases include primary mast cell disorders, secondary mast cell disorders and miscellaneous mast cell diseases (Fig. 5).

Mast cell receptors antagonists or agonists

Flavonols (kaempferol, quercetin, myrcetin, morin) inhibit inflammatory mediators release from human mast cells by inhibition of Ca2 + and PKC-θ signaling [118]. Flavone methlut (3′,4′,5,7-tetramethoxyluteolin) is a potent inhibitor of human MC inflammatory mediator release. It acts by decreasing intracellular calcium levels and decreasing NF-kB activation at both the transcriptional and translational levels [119]. Ca2 +, NF-kB signaling is involved in mast cell receptors final process of

G-protein coupled receptors antagonists

Table 4 describe compounds/drugs G-protein mechanism of action. Following types of G-protein coupled receptors are involved in various mast cells associated diseases (Fig. 8).

Conclusion

The mast cell mediators role is well established in pathophysiology of various diseases like asthma, cancer, dermatitis, mastocytosis, and psoriasis. Therefore, targeting of mast cells receptors have potential therapeutic value: P2X7 antagonists AZD9056 is in phase 2 study and CE-224,535 is in phase 2a study for rheumatoid arthritis; matrix mettaloprotease inhibitor marimistat is under phase III trial for inflammation, cancer, muscular dystrophy diseases. The MRGPRX2, N-formyl-peptide receptor

Acknowledgement

We would like to thank University Grant Commission, New Delhi for providing research grant (F. NO. 41-1378/2012) for Mast Cell research. We would like to thank Chris Lele (GRE instructor, Magoosh) for his erudition towards English language. We would like to thank Dr. Ram Sarup Singh and Rupinder Pal Singh (Department of Biotechnology, Punjabi University, Patiala), Dr. Amandeep Gargi (Microbiologist, USA), Dr. Amteshwar Singh Jaggi and Dr. Nirmal Singh, Rishabh Mohan (PhD medicinal chemistry,

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