ABSTRACT
Misdirected immunity gives rise to the autoimmune tissue inflammation of rheumatoid arthritis, in which excess production of the cytokine tumor necrosis factor (TNF) is a central pathogenic event. Mechanisms underlying the breakdown of self-tolerance are unclear, but T cells in the arthritic joint have a distinctive metabolic signature of ATPlo acetyl-CoAhi proinflammatory effector cells. Here we show that a deficiency in the production of mitochondrial aspartate is an important abnormality in these autoimmune T cells. Shortage of mitochondrial aspartate disrupted the regeneration of the metabolic cofactor nicotinamide adenine dinucleotide, causing ADP deribosylation of the endoplasmic reticulum (ER) sensor GRP78/BiP. As a result, ribosome-rich ER membranes expanded, promoting co-translational translocation and enhanced biogenesis of transmembrane TNF. ERrich T cells were the predominant TNF producers in the arthritic joint. Transfer of intact mitochondria into T cells, as well as supplementation of exogenous aspartate, rescued the mitochondria-instructed expansion of ER membranes and suppressed TNF release and rheumatoid tissue inflammation.
Subject(s)
Arthritis, Rheumatoid/metabolism , Aspartic Acid/metabolism , CD4-Positive T-Lymphocytes/metabolism , Mitochondria/metabolism , Synovial Membrane/metabolism , Tumor Necrosis Factor-alpha/biosynthesis , ADP-Ribosylation , Adoptive Transfer , Animals , Arthritis, Rheumatoid/genetics , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Autoimmunity , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/transplantation , CD4-Positive T-Lymphocytes/ultrastructure , Case-Control Studies , Cells, Cultured , Endoplasmic Reticulum/immunology , Endoplasmic Reticulum/metabolism , Endoplasmic Reticulum/ultrastructure , Endoplasmic Reticulum Chaperone BiP/metabolism , Female , Humans , Male , Mice , Mitochondria/immunology , Mitochondria/transplantation , Mitochondria/ultrastructure , Synovial Membrane/immunology , Synovial Membrane/ultrastructure , Tumor Necrosis Factor-alpha/geneticsABSTRACT
RATIONALE: Environmental enrichment (EE) could influence brain plasticity and behavior in rodents. Whether the early EE may predispose individuals to a particular social hierarchy in the social dominance tube test (SDTT) at adulthood is still unknown. OBJECTIVE: The present study directly investigated the influence of EE on competitive success in the SDTT among adult rats. METHODS: Male rats were maintained in EE from postnatal days 21 to 35. Social dominance behavior was determined by SDTT, competitive food foraging test, and mate preference test at adulthood. IBA-1 expression in the hypothalamus was examined using immunohistochemistry and western blot. RESULTS: EE rats were prone to become submissive during a social encounter with standard environment (SE) rats in the SDTT. No difference was found in food foraging in the competitive food foraging test between SE and EE rats. Male EE rats were more attractive than the SE to the female rats in the mate preference test. IBA-1 expression was found to be decreased in the hypothalamus of EE rats compared to SE group. Infusion of a microglia inhibitor reduced percentage of forward in SE rats in the SDTT. Infusion of DNA methyltransferase inhibitor prevented the development of subordinate status in EE rats and restored the expression of IBA-1 in the hypothalamus. CONCLUSIONS: The results suggest that early EE did not lead to reduced social hierarchy in the male rat. However, EE caused a reduction in the percentage of forward in the SDTT, which might be associated with reduced number of microglia in the hypothalamus.