Altered Macrophage Function Associated with Crystalline Lung Inflammation in Acid Sphingomyelinase Deficiency.
Altered Macrophage Function Associated with Crystalline Lung Inflammation in Acid Sphingomyelinase Deficiency.
复制标题
酸性鞘磷脂酶缺乏症中与结晶性肺炎症相关的巨噬细胞功能改变。
DOI：
10.1165/rcmb.2020-0229oc
复制
发表时间：
2021
影响因子：
6.4
通讯作者：
Petra
中科院分区：
文献类型：
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作者：
Poczobutt,JoannaM;Mikosz,AndrewM;Poirier,Christophe;Beatman,EricaL;Serban,KarinaA;Gally,Fabienne;Cao,Danting;McCubbrey,AlexandraL;Cornell,ChristinaF;Schweitzer,KellyS;Berdyshev,EvgenyV;Bronova,IrinaA;Paris,François;Petra
ASM（酸性鞘磷脂酶）的缺乏导致溶酶体储存尼曼-匹克病（NPD）。B型NPD患者可能发生进行性间质性肺病，并伴有频繁的呼吸道感染。虽然使用ASM缺陷（ASMKO）小鼠NPD模型的几项研究显示炎症和泡沫状巨噬细胞，但对NPD相关肺部疾病的发病机制几乎没有了解。使用ASMKO小鼠，我们报告了ASM缺乏症与一种复杂的炎症表型相关，其特征是单核细胞衍生的CD 11b+巨噬细胞的显著积聚和空气/肺泡CD 11 c + CD 11b −巨噬细胞的扩张，两者都具有增加的大小，粒度和泡沫。替代途径和经典途径均被激活，调理（Fc包被）靶点的原位吞噬作用降低，凋亡细胞的清除（胞浆细胞增多）得以保留，Th 2细胞因子分泌增加，CD 11 c +/CD 11b+细胞增加，肺和血浆促炎细胞因子增加两倍以上。ASMKO肺的巨噬细胞、中性粒细胞、嗜酸性粒细胞和非炎性肺细胞也显示出几丁质酶样蛋白Ym 1/2的显著积聚，其形成大的嗜酸性多边形Charcot-Leyden样晶体。除了提供对可能与NPD相关的肺部炎症新特征的深入了解外，我们的报告还提供了ASM与晶体相关肺部炎症发展之间的新联系，以及巨噬细胞生物学的改变。
Deficiency of ASM (acid sphingomyelinase) causes the lysosomal storage Niemann-Pick disease (NPD). Patients with NPD type B may develop progressive interstitial lung disease with frequent respiratory infections. Although several investigations using the ASM-deficient (ASMKO) mouse NPD model revealed inflammation and foamy macrophages, there is little insight into the pathogenesis of NPD-associated lung disease. Using ASMKO mice, we report that ASM deficiency is associated with a complex inflammatory phenotype characterized by marked accumulation of monocyte-derived CD11b+macrophages and expansion of airspace/alveolar CD11c+CD11b−macrophages, both with increased size, granularity, and foaminess. Both the alternative and classical pathways were activated, with decreasedin situphagocytosis of opsonized (Fc-coated) targets, preserved clearance of apoptotic cells (efferocytosis), secretion of Th2 cytokines, increased CD11c+/CD11b+cells, and more than a twofold increase in lung and plasma proinflammatory cytokines. Macrophages, neutrophils, eosinophils, and noninflammatory lung cells of ASMKO lungs also exhibited marked accumulation of chitinase-like protein Ym1/2, which formed large eosinophilic polygonal Charcot-Leyden–like crystals. In addition to providing insight into novel features of lung inflammation that may be associated with NPD, our report provides a novel connection between ASM and the development of crystal-associated lung inflammation with alterations in macrophage biology.