Heterogeneity in intrahepatic macrophage populations and druggable target expression in patients with steatotic liver disease-related fibrosis.
Heterogeneity in intrahepatic macrophage populations and druggable target expression in patients with steatotic liver disease-related fibrosis.
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DOI：
10.1016/j.jhepr.2023.100958
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发表时间：
2024-01
期刊：
影响因子：
8.3
通讯作者：
Stevenson, Heather L.
中科院分区：
文献类型：
--
作者：
Saldarriaga, Omar A.;Wanninger, Timothy G.;Arroyave, Esteban;Gosnell, Joseph;Krishnan, Santhoshi;Oneka, Morgan;Bao, Daniel;Millian, Daniel E.;Kueht, Michael L.;Moghe, Akshata;Jiao, Jingjing;Sanchez, Jessica I.;Spratt, Heidi;Beretta, Laura;Rao, Arvind;Burks, Jared K.;Stevenson, Heather L.
关键词：
减少脂肪性肝病（SLD）纤维化的临床试验针对巨噬细胞，结果各不相同。我们评估了SLD患者的肝内巨噬细胞，以确定活动评分或纤维化分期是否影响表型和可药物靶点（如CCR 2和半乳糖凝集素-3）的表达。使用nCounter对来自对照或患有轻微或晚期纤维化的患者的肝活检进行基因表达分析，以确定巨噬细胞相关基因的差异（n = 30）。为了研究个体患者之间的变异性，我们通过用多重抗体组（CD 68/CD 14/CD 16/CD 163/Mac 387或CD 163/CCR 2/galectin-3/Mac 387）染色，然后进行光谱成像和空间分析来比较额外的活检。应用利用深度学习/人工智能的算法来创建细胞簇图、表型谱图，并确定蛋白质表达水平（n = 34）。已知促纤维化的几种基因（例如CD 206、TREM 2、CD 163和ARG 1）在晚期纤维化中显示无显著差异或显著降低。尽管在肝硬化个体患者中观察到基因表达的显著变异性，但与轻微纤维化患者相比，几种可药用靶标及其配体（例如CCR 2、CCR 5、CCL 2、CCL 5和LGALS 3）显著增加。抗体组鉴定了在具有疾病进展或晚期纤维化的患者中显著增加（例如Mac 387+）、减少（例如CD 14+）或富集（例如Mac 387的相互作用）的群体。尽管SLD患者存在异质性，但几种巨噬细胞表型和可药物靶点与NAFLD活动评分和纤维化分期呈正相关。SLD患者肝脏中巨噬细胞和药物靶点相关基因和蛋白表达显著不同。一些患者具有相对高的表达，而另一些患者则与对照组相似。总的来说，更晚期疾病的患者在基因和蛋白水平上都有显着更高的CCR 2和半乳糖凝集素-3表达。了解SLD患者肝脏微环境的个体差异可能对开发有效的治疗方法至关重要。这些结果可以解释为什么这么小比例的患者对巨噬细胞靶向治疗有反应，并为慢性肝病的精确医学指导治疗提供额外的支持。分子分析和光谱成像评估了SLD患者的巨噬细胞。肝硬化患者的可药用靶点（如CCR 2）显著增加。募集的巨噬细胞（Mac 387+）增加，并在SLD中有富集的浸润。某些表型和靶标的变化与活动评分和纤维化分期相关。巨噬细胞表型/靶点在个体中不同，可能影响SLD的治疗。
Clinical trials for reducing fibrosis in steatotic liver disease (SLD) have targeted macrophages with variable results. We evaluated intrahepatic macrophages in patients with SLD to determine if activity scores or fibrosis stages influenced phenotypes and expression of druggable targets, such as CCR2 and galectin-3. Liver biopsies from controls or patients with minimal or advanced fibrosis were subject to gene expression analysis using nCounter to determine differences in macrophage-related genes (n = 30). To investigate variability among individual patients, we compared additional biopsies by staining them with multiplex antibody panels (CD68/CD14/CD16/CD163/Mac387 or CD163/CCR2/galectin-3/Mac387) followed by spectral imaging and spatial analysis. Algorithms that utilize deep learning/artificial intelligence were applied to create cell cluster plots, phenotype profile maps, and to determine levels of protein expression (n = 34). Several genes known to be pro-fibrotic (e.g. CD206, TREM2, CD163, and ARG1) showed either no significant differences or significantly decreased with advanced fibrosis. Although marked variability in gene expression was observed in individual patients with cirrhosis, several druggable targets and their ligands (e.g. CCR2, CCR5, CCL2, CCL5, and LGALS3) were significantly increased when compared to patients with minimal fibrosis. Antibody panels identified populations that were significantly increased (e.g. Mac387+), decreased (e.g. CD14+), or enriched (e.g. interactions of Mac387) in patients that had progression of disease or advanced fibrosis. Despite heterogeneity in patients with SLD, several macrophage phenotypes and druggable targets showed a positive correlation with increasing NAFLD activity scores and fibrosis stages. Patients with SLD have markedly varied macrophage- and druggable target-related gene and protein expression in their livers. Several patients had relatively high expression, while others were like controls. Overall, patients with more advanced disease had significantly higher expression of CCR2 and galectin-3 at both the gene and protein levels. Appreciating individual differences within the hepatic microenvironment of patients with SLD may be paramount to developing effective treatments. These results may explain why such a small percentage of patients have responded to macrophage-targeting therapies and provide additional support for precision medicine-guided treatment of chronic liver diseases. Molecular analysis and spectral imaging evaluated macrophages in patients with SLD. Druggable targets (e.g. CCR2) were significantly increased in patients with cirrhosis. Recruited macrophages (Mac387+) were increased and had enriched infiltration in SLD. Variation of certain phenotypes and targets correlated with activity scores and fibrosis stages. Macrophage phenotypes/targets vary in individuals and may affect the treatment of SLD.
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影响因子：
16.6
作者：
MacParland SA;Liu JC;Ma XZ;Innes BT;Bartczak AM;Gage BK;Manuel J;Khuu N;Echeverri J;Linares I;Gupta R;Cheng ML;Liu LY;Camat D;Chung SW;Seliga RK;Shao Z;Lee E;Ogawa S;Ogawa M;Wilson MD;Fish JE;Selzner M;Ghanekar A;Grant D;Greig P;Sapisochin G;Selzner N;Winegarden N;Adeyi O;Keller G;Bader GD;McGilvray ID
通讯作者：
McGilvray ID
DOI：
10.1002/hep.29477
发表时间：
2018-05
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Friedman SL;Ratziu V;Harrison SA;Abdelmalek MF;Aithal GP;Caballeria J;Francque S;Farrell G;Kowdley KV;Craxi A;Simon K;Fischer L;Melchor-Khan L;Vest J;Wiens BL;Vig P;Seyedkazemi S;Goodman Z;Wong VW;Loomba R;Tacke F;Sanyal A;Lefebvre E
通讯作者：
Lefebvre E
影响因子：
7.3
作者：
通讯作者：
--
影响因子：
2.2
作者：
Friedman, Scott;Sanyal, Arun;Ratziu, Vlad
通讯作者：
Ratziu, Vlad
影响因子：
13.5
作者：
Antoniades, Charalambos Gustav;Quaglia, Alberto;Wendon, Julia
通讯作者：
Wendon, Julia