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.

血管渗漏或水肿是急性过敏反应的严重并发症。血管渗漏是由组织驻留肥大细胞内的颗粒释放组胺和血清素引发的。在这里，我们发现肥大细胞发育早期阶段中性粒细胞丝氨酸蛋白酶 4 (NSP4) 的表达调节肥大细胞介导的血管渗漏。在骨髓前体细胞中，粒细胞-巨噬细胞祖细胞 (GMP) 中，NSP4 的缺失会导致组胺、血清素和肝素/硫酸乙酰肝素的细胞水平降低。源自 NSP4 缺陷 GMP 的肥大细胞具有异常的分泌颗粒形态以及组胺和血清素水平持续降低。因此，在被动皮肤过敏反应和急性关节炎模型中，NSP4缺陷小鼠中肥大细胞介导的皮肤和关节血管渗漏显着减少。我们的研究结果表明，NSP4 是肥大细胞颗粒中血管活性胺的正确储存所必需的，这会影响免疫复合物介导的疾病小鼠模型中肥大细胞依赖性血管渗漏。