Bone Marrow Transplantation Rescues Monocyte Recruitment Defect and Improves Cystic Fibrosis in Mice.
Bone Marrow Transplantation Rescues Monocyte Recruitment Defect and Improves Cystic Fibrosis in Mice.
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DOI：
10.4049/jimmunol.1901171
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发表时间：
2022-02-01
期刊：
影响因子：
--
通讯作者：
Ley K
中科院分区：
文献类型：
--
作者：
Fan Z;Pitmon E;Wen L;Miller J;Ehinger E;Herro R;Liu W;Chen J;Mikulski Z;Conrad DJ;Marki A;Orecchioni M;Kumari P;Zhu YP;Marcovecchio PM;Hedrick CC;Hodges CA;Rathinam VA;Wang K;Ley K
囊性纤维化（CF）是一种遗传性危及生命的疾病，伴有反复肺部感染和多器官炎症，影响着全世界数以万计的人。CF患者的致病基因，囊性纤维化跨膜传导调节因子（CFTR）发生突变。传统上认为，CFTR在上皮细胞中的功能是引起疾病症状的原因。最近的研究显示了另一个缺陷：来自CF患者的单核细胞在整合素激活和粘附方面存在缺陷。由于单核细胞在控制感染中起关键作用，单核细胞功能缺陷可能导致CF的进展。在这项研究中，我们证明了CFTRΔF508小鼠（CF小鼠）的单核细胞在流动下表现出粘附缺陷。在亚致死照射后，用野生型（WT）骨髓移植CF小鼠，用WT单核细胞取代了大部分（60-80%）CF单核细胞，显著提高了生存率，并减轻了炎症。WT/CF混合骨髓嵌合体在体内直接表现出CF单核细胞对支气管肺泡灌洗和肠固有层的募集缺陷。CF骨髓重构的WT小鼠也表现出致命性，提示单核细胞CF缺陷不仅是致病的必要条件，而且是致病的充分条件。我们还发现，单核细胞特异性敲除CFTR会延缓体重增加，并加剧dss诱导的结肠炎。我们的研究结果表明，通过骨髓移植提供WT单核细胞可以挽救CF小鼠的死亡率，这表明类似的方法可能减轻CF患者的疾病。
Cystic fibrosis (CF) is an inherited life-threatening disease accompanied by repeated lung infections and multi-organ inflammation that affects tens of thousands of people worldwide. The causative gene, cystic fibrosis transmembrane conductance regulator (CFTR), is mutated in CF patients. CFTR functions in epithelial cells have traditionally been thought to cause the disease symptoms. Recent work has shown an additional defect: monocytes from CF patients show a deficiency in integrin activation and adhesion. Since monocytes play critical roles in controlling infections, defective monocyte function may contribute to CF progression. In this study, we demonstrate that monocytes from CFTRΔF508 mice (CF mice) show defective adhesion under flow. Transplanting CF mice with wild-type (WT) bone marrow after sublethal irradiation replaced most (60–80%) CF monocytes with WT monocytes, significantly improved survival, and reduced inflammation. WT/CF mixed bone marrow chimeras directly demonstrated defective CF monocyte recruitment to the bronchoalveolar lavage and the intestinal lamina propria in vivo. WT mice reconstituted with CF bone marrow also show lethality, suggesting that the CF defect in monocytes is not only necessary but also sufficient to cause disease. We also showed that monocyte-specific knockout of CFTR retards weight gains and exacerbates DSS-induced colitis. Our findings show that providing WT monocytes by bone marrow transfer rescues mortality in CF mice, suggesting that similar approaches may mitigate disease in CF patients.
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影响因子：
5.2
作者：
Kassmer, Susannah H.;Bruscia, Emanuela M.;Zhang, Ping-Xia;Krause, Diane S.
通讯作者：
Krause, Diane S.
影响因子：
16.6
作者：
Gresnigt MS;Cunha C;Jaeger M;Gonçalves SM;Malireddi RKS;Ammerdorffer A;Lubbers R;Oosting M;Rasid O;Jouvion G;Fitting C;Jong DJ;Lacerda JF;Campos A Jr;Melchers WJG;Lagrou K;Maertens J;Kanneganti TD;Carvalho A;Ibrahim-Granet O;van de Veerdonk FL
通讯作者：
van de Veerdonk FL
影响因子：
5.2
作者：
Jennings, Mark T.;Dasenbrook, Elliot C.;Merlo, Christian A.
通讯作者：
Merlo, Christian A.
DOI：
10.1038/nrg3849
发表时间：
2015-01
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.6
作者：
Di Pietro C;Zhang PX;O'Rourke TK;Murray TS;Wang L;Britto CJ;Koff JL;Krause DS;Egan ME;Bruscia EM
通讯作者：
Bruscia EM