Bekhbat Mandakh, Treadway Michael T, Goldsmith David R, Woolwine Bobbi J, Haroon Ebrahim, Miller Andrew H, Felger Jennifer C
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
Department of Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA 30322, USA; The Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA; Department of Psychology, Emory University, Atlanta, GA, USA.
Brain Behav Immun. 2020 Aug;88:161-165. doi: 10.1016/j.bbi.2020.03.015. Epub 2020 Mar 18.
Inflammation and altered glucose metabolism are two pathways implicated in the pathophysiology of major depressive disorder (MDD). We have previously shown that high inflammation as measured by C-reactive protein (CRP) in MDD patients is associated with symptoms of anhedonia, a core symptom of MDD, along with deficits in dopaminergic reward circuitry. Increased inflammation can shift metabolic demand and reprogram cellular energy sources, which may collectively impact the brain and reward processing to contribute to symptoms of anhedonia. To determine whether immunometabolic gene signatures were enriched in immune cells of depressed patients with increased inflammation and anhedonia, we examined whole-blood gene expression microarray (Illumina HumanHT-12) data from unmedicated, medically-stable patients with MDD (n = 93). Patients were considered to have increased inflammation based on High (>3mg/L) versus Low (≤3mg/L) plasma CRP, and further classified as having a self-reported phenotype of High (n = 30, 33rd percentile) versus Low (n = 32, 67th percentile) Anhedonia. Functional enrichment of gene pathways was assessed by Gene Set Enrichment Analysis (GSEA) using the KEGG pathway database. Pathways related to glucose metabolism (insulin signaling, insulin resistance, HIF-1, PI3K/AKT signaling), cancer (e.g., genes related to insulin and PI3K/AKT signaling), and inflammation (B cell, T cell and Fc receptor signaling) were specifically enriched in patients with both High CRP and High Anhedonia (all FDR q < 0.25). Within patients with High CRP in GSEA, the insulin signaling pathway was the top enriched pathway in patients with High versus Low Anhedonia (n = 10 and 9 respectively), which was driven by genes expressed predominantly in monocytes (z = 2.95, p < 0.01). Conversely, within patients with High Anhedonia, in addition to enrichment of immunometabolic pathways, the tyrosine metabolism pathway was also reduced in patients with High versus Low CRP (n = 20 and 10 respectively). Of note, enrichment of immunometabolic pathways was confirmed in complementary linear regression analyses examining pathways associated with a CRP-by-Anhedonia interaction term while controlling for clinical covariates in all patients (n = 93). These results indicate that increased glucose and low tyrosine metabolism define a subset of depressed patients with high inflammation and anhedonia. Enrichment of cancer-related pathways driven by metabolic genes also suggests a shift in immune cell metabolism from oxidative phosphorylation to glycolysis. Together these data suggest that anhedonia in MDD with high CRP involves both immunometabolic shifts and reduced dopamine precursor availability.
炎症和葡萄糖代谢改变是重度抑郁症（MDD）病理生理学中涉及的两条途径。我们之前已经表明，MDD患者中通过C反应蛋白（CRP）测量的高炎症与快感缺失症状相关，快感缺失是MDD的核心症状之一，同时还与多巴胺能奖赏回路缺陷有关。炎症增加会改变代谢需求并重新编程细胞能量来源，这可能共同影响大脑和奖赏处理，导致快感缺失症状。为了确定免疫代谢基因特征是否在炎症增加和快感缺失的抑郁症患者的免疫细胞中富集，我们检查了来自未用药、医学状况稳定的MDD患者（n = 93）的全血基因表达微阵列（Illumina HumanHT - 12）数据。根据血浆CRP高（>3mg/L）与低（≤3mg/L），患者被认为炎症增加，并进一步分为自我报告的高快感缺失（n = 30，第33百分位数）与低快感缺失（n = 32，第67百分位数）表型。使用KEGG通路数据库通过基因集富集分析（GSEA）评估基因通路的功能富集。与葡萄糖代谢（胰岛素信号传导、胰岛素抵抗、HIF - 1、PI3K/AKT信号传导）、癌症（例如与胰岛素和PI3K/AKT信号传导相关的基因）和炎症（B细胞、T细胞和Fc受体信号传导）相关的通路在高CRP和高快感缺失的患者中特别富集（所有FDR q < 0.25）。在GSEA中CRP高的患者中，胰岛素信号通路是高快感缺失与低快感缺失患者（分别为n = 10和9）中富集程度最高的通路，这是由主要在单核细胞中表达的基因驱动的（z = 2.95，p < 0.01）。相反，在高快感缺失的患者中，除了免疫代谢通路的富集外，高CRP与低CRP患者（分别为n = 20和10）中酪氨酸代谢通路也减少。值得注意的是，在所有患者（n = 93）中控制临床协变量的同时，通过检查与CRP - 快感缺失相互作用项相关的通路的互补线性回归分析证实了免疫代谢通路的富集。这些结果表明，葡萄糖代谢增加和酪氨酸代谢降低定义了一组炎症增加和快感缺失的抑郁症患者。由代谢基因驱动的癌症相关通路的富集也表明免疫细胞代谢从氧化磷酸化向糖酵解的转变。这些数据共同表明，高CRP的MDD患者的快感缺失涉及免疫代谢转变和多巴胺前体可用性降低。
