Abstract

Sphingolipid metabolites are emerging as important signaling molecules in allergic diseases specifically asthma. One of the sphingolipid metabolite, sphingosine-1-phosphate (S1P), is involved in cell differentiation, proliferation, survival, migration, and angiogenesis. In the allergic diseases, alteration of S1P levels influences the differentiation and responsiveness of mast cells (MCs). S1P is synthesized by two sphingosine kinases (SphKs), sphingosine kinase 1, and sphingosine kinase 2. Engagement of IgE to the FcεRI receptor induces the activation of both the SphKs and generates S1P. Furthermore, SphKs are also essential to FcεRI-mediated MC activation. Activated MCs export S1P into the extracellular space and causes inflammatory response and tissue remodeling. S1P signaling has dual role in allergic responses. Activation of SphKs and secretion of S1P are required for MC activation; however, S1P signaling plays a vital role in the recovery from anaphylaxis. Several non-coding RNAs have been shown to play a crucial role in controlling the MC-associated inflammatory and allergic responses. Thus, S1P signaling pathway and its regulation by non-coding RNA could be explored as an exciting potential therapeutic target for asthma and other MC-associated diseases.

Highlights

  • Mast cells (MCs) are best known to trigger IgE-dependent/independent allergic diseases

  • sphingosine kinase 1 (SphK1)-deficient MCs show normal degranulation in vitro; decreased histamine release upon a systemic challenge has been noted in SphK1-knockout mice

  • It was shown that inhibition of miRNA-221 suppresses the airway inflammation in asthmatic mouse model [53]. These findings suggest that miR-221 might play an important role in the onset and development of asthma

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Summary

INTRODUCTION

Mast cells (MCs) are best known to trigger IgE-dependent/independent allergic diseases They play a significant role in providing immunity to host in response to various infections [1]. MCs can be activated by diverse stimuli including allergens, pollens, and toxins and may release a spectrum of molecules, including preformed mediators (such as histamine, proteases, and other enzymes). They are accountable for numerous symptoms of allergic reactions including edema and enhanced vascular permeability [2]. After coupling to G-proteins, these receptors either activate or inhibit downstream signaling pathways, including c-Jun N-terminal kinase, extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, phospholipase C, phospholipase D, STAT3, Rho, Rac, and cyclic AMP [4]. ABCC1, one of the ABC members, has been implicated in the FcεRI-stimulated export of S1P from RBL-2H3 and human LAD2 MCs [18]

Role of SphKs in MC Activation
AND ASTHMA
CONCLUDING REMARKS

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