Single-cell transcriptomics highlights immunological dysregulations of monocytes in the pathobiology of COPD.
Single-cell transcriptomics highlights immunological dysregulations of monocytes in the pathobiology of COPD.
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单细胞转录组学强调了慢性阻塞性肺病病理学中单核细胞的免疫失调
DOI：
10.1186/s12931-022-02293-2
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发表时间：
2022-12-20
影响因子：
5.8
通讯作者：
中科院分区：
文献类型：
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作者：
慢性阻塞性肺疾病(COPD)是一种常见的呼吸系统疾病，其发病机制的复杂性与年龄/吸烟密切相关，且对其认识较少。在这里，我们对66,610个COPD细胞和不同吸烟史的年龄分层对照肺组织进行了单细胞RNA测序(scRNA-seq)分析，以确定COPD肺中最易受衰老/吸烟依赖或独立影响的细胞类型。通过进行一系列先进的生物信息学分析，如基因集丰富分析、轨迹分析、细胞-细胞相互作用分析、调节潜力分析、加权相关网络分析、功能相互作用分析和基因集变异分析，我们将细胞类型水平的变化整合到系统水平的故障中，并提供了一个更清晰的COPD病理模型，其中包含衰老和吸烟促进COPD发展的特定机制。最后，我们整合了公开可用的9个个体的scRNA-seq数据，产生了总共110,931个细胞，并重复分析以增强我们发现的可信度。我们的研究指出，单核细胞中COPD分子变化丰富，进一步诱导了先前未知的对肺泡上皮细胞的促炎作用。此外，老化的单核细胞和俱乐部细胞通过维持自身免疫的呼吸道生态位促进了COPD的发展。令人意想不到的是，巨噬细胞在COPD发病机制中长期被认为具有消炎作用，它主要通过吸烟依赖的方式导致鞘磷脂变阻器的失衡。这些发现在包括其他公共单细胞转录数据的荟萃分析中得到了验证。综上所述，我们的研究为COPD的发病机制提供了一个清晰的观点，并展示了单核细胞靶向在COPD诊断和治疗中的潜力。网上版载有补充材料，可在10.1186/s12931-022-02293-2查阅。
Chronic obstructive pulmonary disease (COPD) is a common respiratory disease, whose pathogenetic complexity was strongly associated with aging/smoking and poorly understood. Here we performed single-cell RNA sequencing (scRNA-seq) analysis of 66,610 cells from COPD and age-stratified control lung tissues of donors with different smoking histories to prioritize cell types most perturbed in COPD lungs in aging/smoking dependent or independent manner. By performing an array of advanced bioinformatic analyses, such as gene set enrichment analysis, trajectory analysis, cell–cell interactions analysis, regulatory potential analysis, weighted correlation network analysis, functional interaction analysis, and gene set variation analysis, we integrated cell-type-level alterations into a system-level malfunction and provided a more clarified COPD pathological model containing specific mechanisms by which aging and smoking facilitate COPD development. Finally, we integrated the publicly available scRNA-seq data of 9 individuals, resulting in a total of 110,931 cells, and replicated the analyses to enhance the credibility of our findings. Our study pointed to enrichment of COPD molecular alteration in monocytes, which further induced a previously unrecognized pro-inflammatory effect on alveolar epithelial cells. In addition, aged monocytes and club cells facilitated COPD development via maintaining an autoimmune airway niche. Unexpectedly, macrophages, whose defect to resolve inflammation was long-recognized in COPD pathogenesis, primarily induced an imbalance of sphingolipids rheostat in a smoking-dependent way. These findings were validated in a meta-analysis including other public single-cell transcriptomic data. In sum, our study provided a clarified view of COPD pathogenesis and demonstrated the potential of targeting monocytes in COPD diagnosis and treatment. The online version contains supplementary material available at 10.1186/s12931-022-02293-2.
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影响因子：
82.9
作者：
Cloonan SM;Glass K;Laucho-Contreras ME;Bhashyam AR;Cervo M;Pabón MA;Konrad C;Polverino F;Siempos II;Perez E;Mizumura K;Ghosh MC;Parameswaran H;Williams NC;Rooney KT;Chen ZH;Goldklang MP;Yuan GC;Moore SC;Demeo DL;Rouault TA;D'Armiento JM;Schon EA;Manfredi G;Quackenbush J;Mahmood A;Silverman EK;Owen CA;Choi AM
通讯作者：
Choi AM
影响因子：
7.5
作者：
Chakinala, Raja Chandra;Khatri, Akshay;Gupta, Kriti;Koike, Kengo;Epelbaum, Oleg
通讯作者：
Epelbaum, Oleg
DOI：
10.1126/science.1252945
发表时间：
2014-10-03
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baruch K;Deczkowska A;David E;Castellano JM;Miller O;Kertser A;Berkutzki T;Barnett-Itzhaki Z;Bezalel D;Wyss-Coray T;Amit I;Schwartz M
通讯作者：
Schwartz M
影响因子：
8.8
作者：
Danahay, Henry;Pessotti, Angelica D.;Jaffe, Aron B.
通讯作者：
Jaffe, Aron B.
DOI：
10.1016/j.bbalip.2016.09.019
发表时间：
2017-01
期刊：
Biochimica et biophysica acta. Molecular and cell biology of lipids
影响因子：
--
作者：
Hernández-Corbacho MJ;Salama MF;Canals D;Senkal CE;Obeid LM
通讯作者：
Obeid LM