Project description:Supranormal levels of aldosterone are associated with increased cardiovascular risk in humans, and with accelerated atherosclerosis in animal models. Atherosclerosis is a low-grade inflammatory disorder, with monocyte-derived macrophages as major drivers of plaque formation. Monocytes can adopt a long-term pro-inflammatory phenotype after brief stimulation with microbial pathogens or endogenous atherogenic lipoproteins via a process termed trained immunity. Using a primary human in vitro model, we demonstrate that aldosterone induces trained immunity via the mineralocorticoid receptor. We identify fatty acid synthesis as a crucial pathway necessary for the induction of trained immunity in monocyte-derived macrophages and demonstrate that pharmacological inhibition of this pathway blunts aldosterone-induced trained immunity. At the level of gene regulation, aldosterone promotes enrichment of the transcriptionally-permissive H3K4me3 modification at promoters of genes central to the fatty acid synthesis pathway. These data provide mechanistic insight into the contribution of aldosterone to inflammation, atherosclerosis and cardiovascular disease.
Project description:We demonstrate that hydroxychloroquine inhibits trained immunity at the functional and epigenetic level and is accompanied by reduced expression of interferon-stimulated genes. Trained immunity comprises a functional adaptation induced by epigenetic reprogramming which facilitates the anti-viral innate immune response.
Project description:scRNAseq of monocytes from in vitro Trained immunity experiments stimulated by β-glucan (BG), uric acid (UA), muramyl dipeptide (MDP), oxidized low-density lipoprotein (oxLDL), or RPMI-Control, and respective samples restimulated with Lipopolysaccharide (LPS).
Project description:Cells harbor two systems for the synthesis of fatty acids, one in the cytoplasm (FASN or fatty acid synthase) and one in the mitochondria (mtFAS). In contrast to FASN, mtFAS is poorly characterized, with the major product(s), metabolic roles, and cellular function(s) essentially unknown. Here we show that hypomorphic mtFAS mutants display a profound loss of electron transport chain (ETC) complexes and exhibit compensatory reductive carboxylation. This effect on ETC complexes is independent of the synthesis of lipoic acid, the best characterized function of mtFAS, as mutants lacking lipoic acid synthesis have an intact ETC. Finally, mtFAS impairment blocks the differentiation of skeletal myoblasts in vitro. These data suggest that ETC activity in mammals is profoundly controlled by mtFAS function, thereby connecting anabolic fatty acid synthesis with the oxidation of carbon fuels.
Project description:Antibiotic resistance and the pandemic of infectious diseases pose major hazards to human health. As a novel anti-infection strategy, trained immunity has a promising future. Recombinant Streptococcus pneumoniae Endopeptidase O (rPepO) is a novel trained immunity inducer that is a highly effective broad-spectrum anti-infective molecule. Here, we demonstrate that rPepO training induces a protective effect by improving the function of several immune cells. rPepO trains macrophages in the periphery to improve their immunological response. In addition, macrophage-derived complement C3 stimulates B lymphocytes to bolster the host's initial line of defense. While trained-macrophage-derived G-CSF changes the host's hematopoiesis and promotes central trained immunity. The "trained" label is found on freshly differentiated mononuclear macrophages, which also possess significantly enhanced anti-infective properties. Consequently, our research reveals that rPepO can induce peripheral and central trained immunity and possesses broad-spectrum and durable antimicrobial characteristics.
Project description:Besides centrally induced innate immune memory/trained immunity in the bone marrow/peripheral blood by parenteral vaccination or infection, recently emerging evidence suggests that the barrier mucosal tissue-resident innate immune memory may develop via a local inflammatory pathway following mucosal immunologic exposure. However, it remains unclear whether the mucosal-resident innate immune memory may result from integrating distally generated immunological signals following parenteral vaccination/infection. We show here that subcutaneous Bacillus Calmette-Guérin (BCG) vaccination is able to induce memory alveolar macrophages (AM) and trained immunity at the respiratory barrier mucosa. Although parenteral BCG vaccine can centrally train bone marrow progenitors and circulating monocytes, induction of memory AM is entirely independent of circulating monocytes. Rather, parenteral BCG vaccination, via distal mycobacterial dissemination, causes a time-dependent alteration in gut microbiome, barrier function and microbial metabolites including short-chain fatty acids, and subsequently the changes in circulating and lung tissue metabolites, leading to induction of tissue-resident memory macrophages and trained innate immunity in the lung. Our study thus reveals a novel gut microbiota-mediated pathway for innate immune memory development at distal barrier mucosal tissues. Our findings have far-reaching implications in developing next-generation parenteral vaccine strategies against respiratory pathogens such as M.tb.
Project description:Besides centrally induced innate immune memory/trained immunity in the bone marrow/peripheral blood by parenteral vaccination or infection, recently emerging evidence suggests that the barrier mucosal tissue-resident innate immune memory may develop via a local inflammatory pathway following mucosal immunologic exposure. However, it remains unclear whether the mucosal-resident innate immune memory may result from integrating distally generated immunological signals following parenteral vaccination/infection. We show here that subcutaneous Bacillus Calmette-Guérin (BCG) vaccination is able to induce memory alveolar macrophages (AM) and trained immunity at the respiratory barrier mucosa. Although parenteral BCG vaccine can centrally train bone marrow progenitors and circulating monocytes, induction of memory AM is entirely independent of circulating monocytes. Rather, parenteral BCG vaccination, via distal mycobacterial dissemination, causes a time-dependent alteration in gut microbiome, barrier function and microbial metabolites including short-chain fatty acids, and subsequently the changes in circulating and lung tissue metabolites, leading to induction of tissue-resident memory macrophages and trained innate immunity in the lung. Our study thus reveals a novel gut microbiota-mediated pathway for innate immune memory development at distal barrier mucosal tissues. Our findings have far-reaching implications in developing next-generation parenteral vaccine strategies against respiratory pathogens such as M.tb.
Project description:Adipocytes are the primary sites for fatty acid storage, but the synthesis rate of fatty acids is very low. The physiological significance of this phenomenon remains unclear. Here, we show that surplus fatty acid synthesis in adipocytes induces necroptosis and lipodystrophy. Transcriptional activation of FASN elevates fatty acid synthesis, but decreases NADPH level and increases ROS production, which ultimately leads to adipocyte necroptosis. We identify MED20, a subunit of the Mediator complex, as a negative regulator of FASN transcription. Adipocyte-specific male Med20 knockout mice progressively develop lipodystrophy, which is reversed by scavenging ROS. Further, in a murine model of HIV-associated lipodystrophy and a human patient with acquired lipodystrophy, ROS neutralization significantly improves metabolic disorders, indicating a causal role of ROS in disease onset. Our study well explains the low fatty acid synthesis rate in adipocytes, and sheds light on the management of acquired lipodystrophy.