Mast-Cell Tryptase Release Contributes to Disease Progression in Lymphangioleiomyomatosis
Mast-Cell Tryptase Release Contributes to Disease Progression in Lymphangioleiomyomatosis
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DOI：
10.1164/rccm.202007-2854oc
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发表时间：
2021-08-15
影响因子：
24.7
通讯作者：
Johnson, Simon R.
中科院分区：
文献类型：
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作者：
Babaei-Jadidi, Roya;Dongre, Arundhati;Johnson, Simon R.
原理：淋巴管平滑肌瘤病（LAM）是一种多系统疾病，可引起肺囊肿和呼吸衰竭。TSC（结节性硬化症）基因功能的缺失导致具有失调的mTOR（雷帕霉素的机械靶点）活性的“LAM细胞”的克隆。LAM细胞和成纤维细胞形成的肺结节中也含有肥大细胞，尽管它们的意义尚不清楚。目的：了解肥大细胞积聚的机制以及肥大细胞在LAM发病机制中的作用。使用转录谱分析和qRT-PCR检测基因表达，使用球状体TSC 2-null细胞在体外检测肥大细胞/LAM结节相互作用。测量和主要结果：LAM衍生的细胞/成纤维细胞共培养物在成纤维细胞中诱导多种CXC趋化因子。LAM肺中类胰蛋白酶阳性肥大细胞表达CXCRs（CXC趋化因子受体）增加（P < 0.05）。LAM结节周围的肥大细胞与肺功能丧失率呈正相关（P = 0.016）。LAM球状体吸引肥大细胞，并且该过程通过CXCR 1和CXCR 2的药理学和CRISPR/cas9抑制来抑制。LAM球体引起肥大细胞类胰蛋白酶释放，这诱导成纤维细胞增殖并增加LAM球体大小（1.36 +/- 0.24倍; P = 0.0019）。类胰蛋白酶抑制剂APC 366和色甘酸钠（SCG）抑制肥大细胞诱导的球体生长。在体内，SCG降低肥大细胞活化和Tsc 2缺失的肺肿瘤负荷（媒介物：32.5.3% +/- 23.6%; SCG：5.5% +/- 4.3%; P = 0.0035）。应将SCG重新用于LAM，作为mTOR抑制剂治疗的替代或辅助治疗。
Rationale: Lymphangioleiomyomatosis (LAM) is a multisystem disease that causes lung cysts and respiratory failure. Loss of TSC (tuberous sclerosis complex) gene ftmction results in a clone of "LAM cells" with dysregulated mTOR (mechanistic target of rapamycin) activity. LAM cells and fibroblasts form lung nodules that also contain mast cells, although their significance is unknown.Objectives: To understand the mechanism of mast-cell accumulation and the role of mast cells in the pathogenesis of LAM.Methods: Gene expression was examined using transcriptional profiling and qRT-PCR Mast cell/LAM nodule interactions were examined in vitro using spheroid TSC2-null cell/fibroblast cocultures and in vivo using an immunocompetent Tsc2-null murine homograft model.Measurements and Main Results: LAM-derived cell/fibroblast cocultures induced multiple CXC chemokines in fibroblasts. LAM lungs had increased tryptase-positive mast cells expressing CXCRs (CXC chemokine receptors) (P < 0.05). Mast cells located around the periphery of LAM nodules were positively associated with the rate of lung function loss (P = 0.016). LAM spheroids attracted mast cells, and this process was inhibited by pharmacologic and CRISPR/cas9 inhibition of CXCR1 and CXCR2. LAM spheroids caused mast-cell tryptase release, which induced fibroblast proliferation and increased LAM-spheroid size (1.36 +/- 0.24-fold; P = 0.0019). The tryptase inhibitor APC366 and sodium cromoglycate (SCG) inhibited mast cell-induced spheroid growth. In vivo, SCG reduced mast-cell activation and Tsc2-null lung tumor burden (vehicle: 32.5.3% +/- 23.6%; SCG: 5.5% +/- 4.3%; P = 0.0035).Conclusions: LAM-cell/fibroblast interactions attract mast cells where tryptase release contributes to disease progression. Repurposing SCG for use in LAM should be studied as an alternative or adjunct to mTOR inhibitor therapy.