Neutrophil serine protease 4 is required for mast cell-dependent vascular leakage

Andrew P Ahyoung,Robert J Newman,Sterling Eckard ,Stefan Gerhardy,Daniel Kirchhofer,Anand Kumar Katakam,Juan Zhang,Robby M Weimer,Aditya Murthy,Jason A Hackney,Jennie R Lill,Qui Phung ,Patrick Caplazi,Mike Reichelt,Paolo Manzanillo,Merone Roose‐Girma ,Michele A Grimbaldeston ,Shuei Liong Lin ,Hongkang Xi,Christian L Cox ,Wyne P Lee,Lucinda Tam ,Alvin Gogineni,Menno Van Lookeren Campagne

doi:10.1038/s42003-020-01407-0

Andrew P Ahyoung, Robert J Newman + Show 22 more

Open Access

https://doi.org/10.1038/s42003-020-01407-0

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Abstract

Vascular leakage, or edema, is a serious complication of acute allergic reactions. Vascular leakage is triggered by the release of histamine and serotonin from granules within tissue-resident mast cells. Here, we show that expression of Neutrophil Serine Protease 4 (NSP4) during the early stages of mast cell development regulates mast cell-mediated vascular leakage. In myeloid precursors, the granulocyte–macrophage progenitors (GMPs), loss of NSP4 results in the decrease of cellular levels of histamine, serotonin and heparin/heparan sulfate. Mast cells that are derived from NSP4-deficient GMPs have abnormal secretory granule morphology and a sustained reduction in histamine and serotonin levels. Consequently, in passive cutaneous anaphylaxis and acute arthritis models, mast cell-mediated vascular leakage in the skin and joints is substantially reduced in NSP4-deficient mice. Our findings reveal that NSP4 is required for the proper storage of vasoactive amines in mast cell granules, which impacts mast cell-dependent vascular leakage in mouse models of immune complex-mediated diseases.

Highlights

Vascular leakage, or edema, is a serious complication of acute allergic reactions
Neutrophil Serine Protease 4 (NSP4) deficiency did not cause any gross abnormalities in neutrophil effector function ex vivo, nor did neutrophils appreciably contribute to the vascular leakage in our K/BxN model, suggesting that the observed NSP4 function is associated with the mast cell lineage
Our results indicate that NSP4 neither regulates the differentiation of granulocyte–macrophage progenitors (GMPs) to mast cells nor affects mast cell trafficking to tissues

Summary

Introduction

Edema, is a serious complication of acute allergic reactions. Vascular leakage is triggered by the release of histamine and serotonin from granules within tissueresident mast cells. Mast cells are tissue-resident immune cells that play a pivotal role in microbial defense, toxin neutralization, and tissue remodeling[1,2,3,4] They contain electron-dense secretory granules that store inflammatory mediators[5]. Stored mediators released upon antigen stimulation include the vasoactive amines histamine and serotonin, and mast cell proteases, such as tryptase, chymase, and carboxypeptidase A35. Other secreted products, such as leukotrienes, and various chemokines and cytokines are de novo synthesized following mast cell activation and do not rely on sorting and packaging into granules[5]. The NSP family is a group of four homologous proteases that include neutrophil elastase (NE), cathepsin

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