Sphingosine-1-Phosphate/Sphingosine-1-Phosphate Receptor 2 Axis Can Promote Mouse and Human Primary Mast Cell Angiogenic Potential through Upregulation of Vascular Endothelial Growth Factor-A and Matrix Metalloproteinase-2

Abstract

Mast cells (MC) are present in most vascularized tissues around the vasculature likely exerting immunomodulatory functions. Endowed with diverse mediators, resident MC represent first-line fine-tuners of local microenvironment. Sphingosine-1-phosphate (S1P) functions as a pluripotent signaling sphingolipid metabolite in health and disease. S1P formation occurs at low levels in resting MC and is upregulated upon activation. Its export can result in type 2 S1P receptor- (S1PR2-) mediated stimulation of MC, further fueling inflammation. However, the role of S1PR2 ligation in proangiogenic vascular endothelial growth factor- (VEGF-) A and matrix metalloproteinase- (MMP-) 2 release from MC is unknown. Using a preclinical MC-dependent model of acute allergic responses and in vitro stimulated primary mouse bone marrow-derived MC (BMMC) or human primary skin MC, we report that S1P signaling resulted in substantial amount of VEGF-A release. Similar experiments using S1pr2-deficient mice or BMMC or selective S1P receptor agonists or antagonists demonstrated that S1P/S1PR2 ligation on MC is important for VEGF-A secretion. Further, we show that S1P stimulation triggered transcriptional upregulation of VEGF-A and MMP-2 mRNA in human but not in mouse MC. S1P exposure also triggered MMP-2 secretion from human MC. These studies identify a novel proangiogenic axis encompassing MC/S1P/S1PR2 likely relevant to inflammation.

Mast cells and sphingosine‐1‐phosphate underlie prelesional remodeling in a mouse model of eczema

“…MC can be activated by S1P, an influential sphingolipid metabolite resulting from the phosphorylation of its precursor sphingosine by SphK . Quantitative lipid analysis using lipidomics mass spectrometry revealed that S1P was significantly increased in mouse skin after 1 exposure to OVA, compared to controls (Figure F and Figure B).…”

“…We previously reported that MC‐derived S1P, produced by sphingosine kinase (SphK), can be exported out to amplify MC cytokine/chemokine production and regulate cell trafficking . S1P can also activate MC independently of the canonical IgE/FcεRI pathway …”

Sphingosine-1 Phosphate: A New Modulator of Immune Plasticity in the Tumor Microenvironment

“…Mast cells may differentiate into two subsets depending upon the tissue they populate and the microenvironmental conditions, as defined by the protease repertoire harbored within cytoplasmic granules: connective tissue or serosal MC express tryptase and chymase, whereas mucosal MC are single positive for tryptase ( 120 ). Importantly, MC-derived proteases can activate matrix metalloproteinases (MMP) that are critical to tumor growth and metastasis, and we recently reported that S1P-mediated MC activation triggered substantial release of MMP and pro-angiogenic VEGF ( 131 ). We and others have shown that MC can produce S1P ( 3 , 132 ).…”

Human eosinophils and mast cells: Birds of a feather flock together

“…The MC/S1P/S1PR2 axis was recently shown to be crucial for propagating early inflammatory responses in murine models of pulmonary and cutaneous allergic responses . Additionally, S1PR2 ligation leads to production of tissue remodeling matrix metalloproteinase‐2 (MMP2) and vascular endothelial growth factor (VEGF)‐α from human MCs . Eosinophils express S1PR1, 3, 4, and 5 and can therefore be recruited to inflamed tissues by MCs and other S1P‐producing cells.…”

“…154,155 Additionally, S1PR2 ligation leads to production of tissue remodeling matrix metalloproteinase-2 (MMP2) and vascular endothelial growth factor (VEGF)α from human MCs. 161 Eosinophils express S1PR1, 3, 4, and 5 and can therefore be recruited to inflamed tissues by MCs and other S1P-producing cells. Eosinophil chemotaxis toward S1P can be abrogated in the presence of the pharmacological S1P receptor antagonist FTY-720, which has significant affinity for all S1PR except S1PR2.…”