IL-33 and Superantigenic Activation of Human Lung Mast Cells Induce the Release of Angiogenic and Lymphangiogenic Factors.

Leonardo Cristinziano,Gilda Varricchi,Amato De Paulis,Giuseppe Spadaro,Luca Modestino,Gianni Marone,Stefania Loffredo,Maria Rosaria Galdiero,Remo Poto,Anne Lise Ferrara,Gjada Criscuolo

doi:10.3390/cells10010145

Abstract

Human lung mast cells (HLMCs) express the high-affinity receptor FcεRI for IgE and are strategically located in different compartments of human lung, where they play a role in several inflammatory disorders and cancer. Immunoglobulin superantigens (e.g., protein A of Staphylococcus aureus and protein L of Peptostreptococcus magnus) bind to the variable regions of either the heavy (VH3) or light chain (κ) of IgE. IL-33 is a cytokine expressed by epithelial cells that exerts pleiotropic functions in the lung. The present study investigated whether immunoglobulin superantigens protein A and protein L and IL-33 caused the release of inflammatory (histamine), angiogenic (VEGF-A) and lymphangiogenic (VEGF-C) factors from HLMCs. The results show that protein A and protein L induced the rapid (30 min) release of preformed histamine from HLMCs. By contrast, IL-33 did not induce the release of histamine from lung mast cells. Prolonged incubation (12 h) of HLMCs with superantigens and IL-33 induced the release of VEGF-A and VEGF-C. Preincubation with IL-33 potentiated the superantigenic release of histamine, angiogenic and lymphangiogenic factors from HLMCs. Our results suggest that IL-33 might enhance the inflammatory, angiogenic and lymphangiogenic activities of lung mast cells in pulmonary disorders.

Highlights

Mast cells, localized in different compartments of human lung [1,2,3,4], are critical sentinels in immunity [5,6]
In a series of preliminary experiments, we found that increasing concentrations (1–300 nM) of protein L caused the release of inflammatory mediators from Human lung mast cells (HLMCs)
Primary mast cells isolated from human lung parenchyma can be activated by a human IgG anti-IgE isolated from a patient with atopic dermatitis to release histamine, VEGF-A, and VEGF-C

Summary

Introduction

Mast cells, localized in different compartments of human lung [1,2,3,4], are critical sentinels in immunity [5,6]. Human lung mast cells express the high-affinity receptor (FcεRI) for immunoglobulin E [1,27,28]. IgE is a heterotetramer consisting of two identical heavy chains and two identical light chains that bind with high affinity (Ka ∼= 1010 M−1) to FcεRI on mast cells [29]. Aggregation of IgE/FcεRI complex by multivalent antigen, divalent anti-IgE or anti-FcεRI initiates human mast cell activation [32,33] and the release of preformed (e.g., histamine), de novo synthesized lipid mediators [e.g., prostaglandin D2 (PGD2) and cysteinyl leukotriene C4 (LTC4)], chemokines [34,35] and cytokines [8]. Human lung mast cells [14], like macrophages [36], basophils [37], and neutrophils [38], release angiogenic (e.g., vascular endothelial growth factor A: VEGF-A) and lymphangiogenic factors (e.g., vascular endothelial growth factor C: VEGF-C) [7,14,36]

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