Cellular and immunometabolic mechanisms of inflammation in depression: Preliminary findings from single cell RNA sequencing and a tribute to Bruce McEwen.
Cellular and immunometabolic mechanisms of inflammation in depression: Preliminary findings from single cell RNA sequencing and a tribute to Bruce McEwen.
复制标题
DOI：
10.1016/j.ynstr.2022.100462
复制
发表时间：
2022-07
影响因子：
5
通讯作者：
Miller, Andrew H.
中科院分区：
文献类型：
--
作者：
Bekhbat, Mandakh;Ulukaya, G. Bengu;Bhasin, Manoj K.;Felger, Jennifer C.;Miller, Andrew H.
炎症与快感缺失的症状有关，快感缺失是重性抑郁症（MD）的核心特征。我们已经表明，通过血浆C-反应蛋白（CRP）和快感缺乏测量的具有高度炎症的MD患者显示代谢重编程的基因特征（例如，转变为糖酵解），维持细胞免疫激活所必需的。为了在单细胞（sc）水平上获得对作为炎症增加的基础的免疫细胞亚群和转录组特征及其与MD行为的关系的初步了解，本文中，我们对来自医学上稳定的未用药的MD门诊患者亚群的外周血单核细胞进行scRNA-Seq。研究了3例在肿瘤坏死因子拮抗剂英夫利昔单抗抗炎激发前和2周后CRP升高（>3 mg/L）的MD患者和3例CRP降低（≤3 mg/L）的患者。使用单细胞向导管道鉴定细胞簇，然后进行途径分析。高CRP的MD患者中CD 14+和CD 16+单核细胞更丰富，英夫利西单抗治疗后分别减少29%和55%。在CD 14+和CD 16+单核细胞内，高CRP患者中上调的基因富集了炎症（吞噬作用、补体、白细胞迁移）和免疫代谢（缺氧诱导因子[HIF]-1、有氧糖酵解）途径。高CRP患者与低CRP患者相比，CD 4 + T细胞亚群的变化包括CD 4+中央记忆（TCM）和幼稚细胞丰度降低约30%和约10%，效应记忆样（TEM样）细胞增加约50%。高C反应蛋白患者的中药细胞显示出氧化磷酸化（OXPHOS）途径的下调，该途径是该细胞类型的主要能量来源。英夫利西单抗治疗后，CD 14+单核细胞和CD 4 + TEM样细胞数量的变化预测快感缺失评分的改善（r = 1.0，p < 0.001）。总之，来自炎症增加的MD患者的单核细胞和CD 4 + T细胞表现出与快感缺乏症状相关的免疫代谢重编程。这些发现是确定与MD炎症表型相关的细胞和分子免疫途径的第一步，这可能导致炎症增加的精神疾病的新型免疫调节治疗。
Inflammation is associated with symptoms of anhedonia, a core feature of major depression (MD). We have shown that MD patients with high inflammation as measured by plasma C-reactive protein (CRP) and anhedonia display gene signatures of metabolic reprograming (e.g., shift to glycolysis) necessary to sustain cellular immune activation. To gain preliminary insight into the immune cell subsets and transcriptomic signatures that underlie increased inflammation and its relationship with behavior in MD at the single-cell (sc) level, herein we conducted scRNA-Seq on peripheral blood mononuclear cells from a subset of medically-stable, unmedicated MD outpatients. Three MD patients with high CRP (>3 mg/L) before and two weeks after anti-inflammatory challenge with the tumor necrosis factor antagonist infliximab and three patients with low CRP (≤3 mg/L) were studied. Cell clusters were identified using a Single Cell Wizard pipeline, followed by pathway analysis. CD14+ and CD16+ monocytes were more abundant in MD patients with high CRP and were reduced by 29% and 55% respectively after infliximab treatment. Within CD14+ and CD16+ monocytes, genes upregulated in high CRP patients were enriched for inflammatory (phagocytosis, complement, leukocyte migration) and immunometabolic (hypoxia-inducible factor [HIF]-1, aerobic glycolysis) pathways. Shifts in CD4+ T cell subsets included ∼30% and ∼10% lower abundance of CD4+ central memory (TCM) and naïve cells and ∼50% increase in effector memory-like (TEM-like) cells in high versus low CRP patients. TCM cells of high CRP patients displayed downregulation of the oxidative phosphorylation (OXPHOS) pathway, a main energy source in this cell type. Following infliximab, changes in the number of CD14+ monocytes and CD4+ TEM-like cells predicted improvements in anhedonia scores (r = 1.0, p < 0.001). In sum, monocytes and CD4+ T cells from MD patients with increased inflammation exhibited immunometabolic reprograming in association with symptoms of anhedonia. These findings are the first step toward determining the cellular and molecular immune pathways associated with inflammatory phenotypes in MD, which may lead to novel immunomodulatory treatments of psychiatric illnesses with increased inflammation.
登录
查看更多内容
影响因子：
11
作者：
Bekhbat M;Goldsmith DR;Woolwine BJ;Haroon E;Miller AH;Felger JC
通讯作者：
Felger JC
影响因子：
6.8
作者：
Costi S;Morris LS;Collins A;Fernandez NF;Patel M;Xie H;Kim-Schulze S;Stern ER;Collins KA;Cathomas F;Parides MK;Whitton AE;Pizzagalli DA;Russo SJ;Murrough JW
通讯作者：
Murrough JW
影响因子：
10.6
作者：
Dowlati, Yekta;Herrmann, Nathan;Lanctot, Krista L.
通讯作者：
Lanctot, Krista L.
影响因子：
15.1
作者：
Bekhbat, Mandakh;Treadway, Michael T.;Felger, Jennifer C.
通讯作者：
Felger, Jennifer C.
影响因子：
15.1
作者：
Alcocer-Gomez, Elisabet;de Miguel, Manuel;Cordero, Mario D.
通讯作者：
Cordero, Mario D.