Deficiency of Circulating Monocytes Ameliorates the Progression of Myxomatous Valve Degeneration in Marfan Syndrome
Deficiency of Circulating Monocytes Ameliorates the Progression of Myxomatous Valve Degeneration in Marfan Syndrome
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DOI：
10.1161/circulationaha.119.042391
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发表时间：
2020-01-14
期刊：
影响因子：
37.8
通讯作者：
Yutzey, Katherine E.
中科院分区：
文献类型：
--
作者：
Kim, Andrew J.;Xu, Na;Yutzey, Katherine E.
背景：粘液瘤性瓣膜变性（MVD）涉及心脏瓣膜进行性增厚和变性，导致瓣膜脱垂、血流回流和心脏功能受损。最近在粘液瘤瓣膜中检测到主要由巨噬细胞组成的白细胞，但这些细胞存在的时间以及它们在 MVD 进展中的贡献尚不清楚。方法：我们使用来自 MFS 小鼠 (Fbn1(C1039G/+))、基因编辑 MFS 猪 (FBN1(Glu433AsnfsX98/+)) 和 MFS 患者的二尖瓣检查了马凡综合征 (MFS) 背景下的 MVD 进展、巨噬细胞和瓣膜微环境。分别使用非综合征人类和犬粘液瘤瓣膜进行额外的组织学和转录组学评估。使用移植 mTomato+ 骨髓的 MFS 小鼠或携带 RFP（红色荧光蛋白）标记的 C-C 趋化因子受体 2 型 (CCR2) 单核细胞的 MFS 小鼠测定巨噬细胞个体发育。生成缺乏募集巨噬细胞的小鼠 (Fbn1(C1039G/+);Ccr2(RFP/RFP))，以确定募集巨噬细胞对 MVD 进展的要求。结果：MFS 小鼠在 2 个月大时重现了粘液瘤性瓣膜疾病的组织病理学特征，包括二尖瓣增厚、小叶细胞结构增加以及以蛋白聚糖积累和胶原断裂为特征的细胞外基质异常。 MFS 小鼠患病二尖瓣同时表现出浸润（MHCII+、CCR2+）和驻留巨噬细胞（CD206+、CCR2-）显着增加，以及趋化因子活性和炎症细胞外基质修饰增加。同样，通过免疫荧光检测，从基因编辑的 MFS 猪和人类 MFS 患者获得的二尖瓣标本显示单核细胞和巨噬细胞（CD14+、CD64+、CD68+、CD163+）增加。此外，对遗传性（MFS 小鼠）和获得性 MVD（人类和狗）的比较转录组评估揭示了患病瓣膜中共同的炎症反应上调。值得注意的是，单核细胞的缺乏可以防止 MVD 进展，从而导致 MHCII 巨噬细胞显着减少、小叶增厚最小化并保留二尖瓣完整性。结论：总而言之，我们的结果表明无菌炎症是疾病进展的一种新范例，并且我们首次确定单核细胞作为 MVD 靶向治疗的可行候选者。
Background: Myxomatous valve degeneration (MVD) involves the progressive thickening and degeneration of the heart valves, leading to valve prolapse, regurgitant blood flow, and impaired cardiac function. Leukocytes composed primarily of macrophages have recently been detected in myxomatous valves, but the timing of the presence and the contributions of these cells in MVD progression are not known. Methods: We examined MVD progression, macrophages, and the valve microenvironment in the context of Marfan syndrome (MFS) using mitral valves from MFS mice (Fbn1(C1039G/+)), gene-edited MFS pigs (FBN1(Glu433AsnfsX98/+)), and patients with MFS. Additional histological and transcriptomic evaluation was performed by using nonsyndromic human and canine myxomatous valves, respectively. Macrophage ontogeny was determined using MFS mice transplanted with mTomato+ bone marrow or MFS mice harboring RFP (red fluorescent protein)-tagged C-C chemokine receptor type 2 (CCR2) monocytes. Mice deficient in recruited macrophages (Fbn1(C1039G/+);Ccr2(RFP/RFP)) were generated to determine the requirements of recruited macrophages to MVD progression. Results: MFS mice recapitulated histopathological features of myxomatous valve disease by 2 months of age, including mitral valve thickening, increased leaflet cellularity, and extracellular matrix abnormalities characterized by proteoglycan accumulation and collagen fragmentation. Diseased mitral valves of MFS mice concurrently exhibited a marked increase of infiltrating (MHCII+, CCR2+) and resident macrophages (CD206+, CCR2-), along with increased chemokine activity and inflammatory extracellular matrix modification. Likewise, mitral valve specimens obtained from gene-edited MFS pigs and human patients with MFS exhibited increased monocytes and macrophages (CD14+, CD64+, CD68+, CD163+) detected by immunofluorescence. In addition, comparative transcriptomic evaluation of both genetic (MFS mice) and acquired forms of MVD (humans and dogs) unveiled a shared upregulated inflammatory response in diseased valves. Remarkably, the deficiency of monocytes was protective against MVD progression, resulting in a significant reduction of MHCII macrophages, minimal leaflet thickening, and preserved mitral valve integrity. Conclusions: All together, our results suggest sterile inflammation as a novel paradigm to disease progression, and we identify, for the first time, monocytes as a viable candidate for targeted therapy in MVD.