Cellular and immunometabolic mechanisms of inflammation in depression: Preliminary findings from single cell RNA sequencing and a tribute to Bruce McEwen

Mandakh Bekhbat; G Bengü Ulukaya; Manoj K Bhasin; Jennifer C Felger; Andrew H Miller

doi:10.1016/j.ynstr.2022.100462

Cellular and immunometabolic mechanisms of inflammation in depression: Preliminary findings from single cell RNA sequencing and a tribute to Bruce McEwen

Neurobiol Stress. 2022 May 24:19:100462. doi: 10.1016/j.ynstr.2022.100462. eCollection 2022 Jul.

Authors

Mandakh Bekhbat¹, G Bengü Ulukaya², Manoj K Bhasin^{2

3}, Jennifer C Felger^{1

4}, Andrew H Miller^{1

4}

Affiliations

¹ Department of Psychiatry and Behavioral Sciences, Emory University, GA, 30322, Atlanta, USA.
² Department of Biomedical Informatics, Emory University, GA, 30322, Atlanta, USA.
³ Department of Pediatrics, Emory University, GA, 30322, Atlanta, USA.
⁴ The Winship Cancer Institute, Emory University, GA, 30322, Atlanta, USA.

Abstract

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 (T_CM) and naïve cells and ∼50% increase in effector memory-like (T_EM-like) cells in high versus low CRP patients. T_CM 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⁺ T_EM-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.

Keywords: Anhedonia; Depression; Immunometabolism; Inflammation; Monocytes; Single cell RNA-Sequencing; T cells.

Abstract

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