Protective Role of Mast Cells in Primary Systemic Vasculitis: A Perspective

Jason M Springer,Mehrdad Maz,Kottarappat N Dileepan,Selina A Gierer,Vineesh V Raveendran

doi:10.3389/fimmu.2017.00990

Jason M Springer, Mehrdad Maz + Show 3 more

Open Access

https://doi.org/10.3389/fimmu.2017.00990

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Abstract

Mast cells are important cells of the immune system. Although traditionally considered as key players in allergic and hypersensitivity reactions, emerging evidence suggests that mast cells have many complex roles in vascular disease. These include regulation of vasodilation, angiogenesis, activation of matrix metalloproteinases, apoptosis of smooth muscle cells, and activation of the renin angiotensin system. Mast cells are also known to play an immunomodulatory role via modulation of regulatory T-cell (Treg), macrophage and endothelial cell functions. This dual role of the mast cells is evident in myeloperoxidase anti-neutrophil cytoplasmic antibodies-mouse model of glomerulonephritis in which mast cell deficiency worsens glomerulonephritis, whereas inhibition of mast cell degranulation is effective in abrogating the development of glomerulonephritis. Our previous work demonstrated that mast cell degranulation inhibits lipopolysaccharide-induced interleukin 6 (IL-6) production in mice. This effect was not seen in histamine-1-receptor knockout (H1R−/−) mice suggesting a role for histamine in IL-6 homeostasis. In addition, mast cell degranulation-mediated decrease in IL-6 production was associated with an upregulation of suppressor of cytokine signaling-1 protein in the aorta. We propose that mast cells regulate large artery inflammation through T-cells, shifting a primarily Th1 and Th17 toward a Th2 response and leading to enhanced IL-10 production, activation Treg cells, and the inhibition of macrophage functions.

Highlights

Vasculitis refers to inflammation of blood vessels, typically of the arterial circulation
The pathogenesis of vasculitis varies by type, but typically involves recruitment and activation of T-cells and macrophages with resultant generation of a variety of inflammatory cytokines including interleukin 6 (IL-6)
We present our perspective on the mast cell involvement in systemic vasculitis and propose a novel inhibitory mechanism through which mast cells control large artery inflammation (Figure 2)

Summary

INTRODUCTION

Vasculitis refers to inflammation of blood vessels, typically of the arterial circulation. Mast cells play a complex role in vascular homeostasis since they synthesize, store, and secrete both pro- and anti-inflammatory molecules This phenomenon is best demonstrated in human and animal studies of ANCA-associated vasculitis. Our published work has demonstrated a novel phenomenon that mast cell-derived histamine and lipopolysaccharide (LPS) (a TLR4 ligand) synergistically enhance IL-6 gene expression and cytokine production in human umbilical vein endothelial cells and in coronary artery endothelial cells in vitro [39,40,41,42] These findings highlight an important role for mast cells in IL-6 homeostasis in the vasculature. Our preliminary results demonstrating inhibition of LPS-induced aortic IL-6 gene expression and systemic IL-6 production in mice by acute mast cell degranulation support the notion that the mast cell may act as a potent negative modulator of vasculitis. Mast cells accumulated around neointimal neovessels in the GCA lesions [53]

CONCLUSION AND PERSPECTIVE

Findings

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