Repeated social defeat stress leads to immunometabolic shifts in innate immune cells of the spleen

• Authors: Mandy Bekhbat, Emory University; John Drake, Texas A&M University; Emily C Reed, Texas A&M University; Tatlock H Lauten, Texas A&M University; Tamara Natour, Texas A&M University; Vladimir I Vladimirov, Texas A&M University; Adam J Case, Texas A&M University
• Journal Title: Brain, Behavior, & Immunity - Health
• Volume: Volume 34
• Publisher: Elsevier | 2023-09-25, Pages 100690-None
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1016/j.bbih.2023.100690
• Subjects: Biology, Cell; Health Sciences, Immunology; Health Sciences, General
• Keywords: Metabolic shifts; immune cell activation; RSDS; scRNA-Seq; Glycolytic pathways; Metabolic pathways

Abstract

Psychosocial stress has been shown to prime peripheral innate immune cells, which take on hyper-inflammatory phenotypes and are implicated in depressive-like behavior in mouse models. However, the impact of stress on cellular metabolic states that are thought to fuel inflammatory phenotypes in immune cells are unknown. Using single cell RNA-sequencing, we investigated mRNA enrichment of immunometabolic pathways in innate immune cells of the spleen in mice subjected to repeated social defeat stress (RSDS) or no stress (NS). RSDS mice displayed a significant increase in the number of splenic macrophages and granulocytes (p < 0.05) compared to NS littermates. RSDS-upregulated genes in macrophages, monocytes, and granulocytes significantly enriched immunometabolic pathways thought to play a role in myeloid-driven inflammation (glycolysis, HIF-1 signaling, MTORC1 signaling) as well as pathways related to oxidative phosphorylation (OXPHOS) and oxidative stress (p < 0.05 and FDR<0.1). These results suggest that the metabolic enhancement reflected by upregulation of glycolytic and OXPHOS pathways may be important for cellular proliferation of splenic macrophages and granulocytes following repeated stress exposure. A better understanding of these intracellular metabolic mechanisms may ultimately help develop novel strategies to reverse the impact of stress and associated peripheral immune changes on the brain and behavior.