Trained immunity is a long-lasting change in the responsiveness of innate immune cells, leading to a stronger response upon an unrelated secondary challenge. Epigenetic, transcriptional, and metabolic reprogramming contribute to the development of trained immunity. By investigating the impact of gene variants on trained immunity responses after Bacillus Calmette-Guérin (BCG) vaccination, we identified a strong association between polymorphisms in the RORA gene and BCG-induced trained immunity in PBMCs isolated from healthy human donors. RORα, encoded by the RORA gene in humans, is a nuclear receptor and a transcription factor, regulating genes involved in circadian rhythm, inflammation, cholesterol, and lipid metabolism. We found that natural RORα agonists in the circulation negatively correlate with the strength of trained immunity responses after BCG vaccination. Moreover, pharmacological inhibition of RORα in human PBMCs led to higher cytokine production capacity and boosted trained immunity induction by BCG. Blocking RORα activity also resulted in morphological changes and increased ROS and lactate production of BCG-trained cells. Blocking lactate dehydrogenase A (LDHA) and glycolysis with sodium oxamate reduced the cytokine production capacity of cells trained with a combination of BCG and the RORα agonist. In conclusion, this study highlights the potential role of RORα in trained immunity, and its impact on human vaccination and diseases should be further investigated.

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. Here, a macrophage infection model was used to unravel the role of the histone deacetylase sirtuin 6 (SIRT6) in Mtb-triggered regulation of the innate immune response. Mtb infection downregulated microRNA-26a and upregulated its target SIRT6. SIRT6 suppressed glycolysis and expression of HIF-1α-dependent glycolytic genes during infection. In addition, SIRT6 regulated the levels of intracellular succinate which controls stabilization of HIF-1α, as well as the release of interleukin (IL)-1β. Furthermore, SIRT6 inhibited inducible nitric oxide synthase (iNOS) and proinflammatory IL-6 but augmented anti-inflammatory arginase expression. The miR-26a/SIRT6/HIF-1α axis therefore regulates glycolysis and macrophage immune responses during Mtb infection. Our findings link SIRT6 to rewiring of macrophage signaling pathways facilitating dampening of the antibacterial immune response.

Directing immunometabolism presents new opportunities to modulate key cell types associated with the formation of foreign body response (FBR) capsule. Contrasting approaches directing immunometabolism are investigated to mitigate FBR: a broadly suppressive metabolic inhibitor (MI) cocktail comprised of 2-deoxyglucose (2-DG), metformin, and 6-diazo-5-oxo-l-norleucine (DON) with daily systemic dosing regimen, and local weekly injection of the more narrowly focused tryptophan catabolizing IDO-Gal3 fusion protein. Treatments significantly decrease FBR capsule formed around subcutaneously implanted cellulose disks. MI cocktail results in a substantially thinner FBR capsule (40% of control), while weekly local injection of IDO-Gal3 also results in a thinner FBR capsule (69% of control). RNA-sequencing capsule transcripts reveal MI cocktail promotes quiescence, with decreased antigen processing and presentation, T helper subset differentiation, and cytokine-cytokine receptor pathway. IDO-Gal3 promotes pro-regenerative, alternatively activated M2-like macrophages and T helper 2 cells, with increased expression of type 2 response-associated genes (Il4, Il13, Arg1, Mrc1, Chil3, Gata3). IDO-Gal3 decreases pro-inflammatory innate sensing pathways, and C-type lectin receptor, NOD-like receptor, RIG-I-like receptor, and Toll-like receptor signaling. This work helps define key gene targets and pathways concomitantly regulated in the FBR capsule during immunometabolic modulation compared to control FBR capsule.

The skin is a complex organ that serves as a critical barrier against external pathogens and environmental impact. Recent advances in immunometabolism have highlighted the intricate link between cellular metabolism and immune function, particularly in the context of skin cancers. This review aims to provide a comprehensive overview of the key metabolic pathways and adaptations that occur in immune cells during homeostasis and activation, and explore how metabolic reprogramming contributes to the pathogenesis of specific skin cancers. We discuss the complex interplay between tumor cells and infiltrating immune cells, which shapes the tumor microenvironment and influences disease outcomes. The review delves into the role of various metabolic pathways, such as glycolysis, oxidative phosphorylation, and lipid metabolism, in the regulation of immune cell function and their impact on the development and progression of skin cancers. Furthermore, we examine the potential of targeting metabolic pathways as a therapeutic strategy in skin cancers and discuss the challenges and future perspectives in this rapidly evolving field. By understanding the metabolic basis of skin immune responses, we can develop novel, personalized therapies for the treatment of skin cancers, ultimately improving patient outcomes and quality of life. The insights gained from this review will contribute to the growing body of knowledge in immunometabolism and its application in the management of skin cancers, paving the way for more effective and targeted interventions in the future.

The immune system plays a crucial role in protecting the body from invading pathogens and maintaining tissue homoeostasis. Maintaining homoeostatic lipid metabolism is an important aspect of efficient immune cell function and when disrupted immune cell function is impaired. There are numerous metabolic diseases whereby systemic lipid metabolism and cellular function is impaired. In the context of metabolic disorders, chronic inflammation is suggested to be a major contributor to disease progression. A major contributor to tissue dysfunction in metabolic disease is ectopic lipid deposition, which is generally caused by diet and genetic factors. Thus, we propose the idea, that similar to tissue and organ damage in metabolic disorders, excessive accumulation of lipid in immune cells promotes a dysfunctional immune system (beyond the classical foam cell) and contributes to disease pathology. Herein, we review the evidence that lipid accumulation through diet can modulate the production and function of immune cells by altering cellular lipid content. This can impact immune cell signalling, activation, migration, and death, ultimately affecting key aspects of the immune system such as neutralising pathogens, antigen presentation, effector cell activation and resolving inflammation.

Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating metabolic and inflammatory programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. We find that staggered Toll-like receptor and type I IFN signaling in macrophages permit a transient energetic state of combined oxidative phosphorylation (OXPHOS) and aerobic glycolysis followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. This disruption promotes type I IFN, suppressing other pro-inflammatory cytokines, notably interleukin-1β. Upon infection, iNOS expression peaks at 24 h, followed by lactate-driven Nos2 repression via histone lactylation. Type I IFN pre-conditioning prolongs infection-induced iNOS expression, amplifying type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN results in elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.

The recent birth of the immunometabolism field has comprehensively demonstrated how the rewiring of intracellular metabolism is critical for supporting the effector functions of many immune cell types, such as myeloid cells. Among all, the transcriptional regulation mediated by Hypoxia-Inducible Factors (HIFs) and Nuclear factor erythroid 2-related factor 2 (NRF2) have been consistently shown to play critical roles in regulating the glycolytic metabolism, redox homeostasis and inflammatory responses of macrophages (Mφs). Although both of these transcription factors were first discovered back in the 1990s, new advances in understanding their function and regulations have been continuously made in the context of immunometabolism. Therefore, this review attempts to summarize the traditionally and newly identified functions of these transcription factors, including their roles in orchestrating the key events that take place during glycolytic reprogramming in activated myeloid cells, as well as their roles in mediating Mφ inflammatory responses in various bacterial infection models.

Everyone knows that an infection can make you feel sick. Although we perceive infection-induced changes in metabolism as a pathology, they are a part of a carefully regulated process that depends on tissue-specific interactions between the immune system and organs involved in the regulation of systemic homeostasis. Immune-mediated changes in homeostatic parameters lead to altered production and uptake of nutrients in circulation, which modifies the metabolic rate of key organs. This is what we experience as being sick. The purpose of sickness metabolism is to generate a metabolic environment in which the body is optimally able to fight infection while denying vital nutrients for the replication of pathogens. Sickness metabolism depends on tissue-specific immune cells, which mediate responses tailored to the nature and magnitude of the threat. As an infection increases in severity, so do the number and type of immune cells involved and the level to which organs are affected, which dictates the degree to which we feel sick. Interestingly, many alterations associated with metabolic disease appear to overlap with immune-mediated changes observed following infection. Targeting processes involving tissue-specific interactions between activated immune cells and metabolic organs therefore holds great potential for treating both people with severe infection and those with metabolic disease. In this review, we will discuss how the immune system communicates in situ with organs involved in the regulation of homeostasis and how this communication is impacted by infection.

OBJECTIVE: Ketogenic diets are proposed as a therapeutic approach for type 1 and type 2 diabetes due to their low glucose intake. However, their potential effects on the immune system need investigation. This study aims to explore how glucose concentration and beta-hydroxybutyrate (BHB) impact T cell phenotype, metabolism, and function, with a focus on systemic inflammatory response (T2D) and autoimmunity (T1D).
METHODS: T cells from healthy donors were cultured in vitro under varying glucose concentrations with or without BHB. Flow cytometry was employed to analyze changes in T cell phenotype, while proliferation was evaluated through a CFSE dilution assay. Additionally, we used a novel flow cytometry method allowing a direct assessment of T cell metabolism.
RESULTS: Culturing T cells in low glucose concentrations revealed their dependency on glucose metabolism, leading to reduced proliferation rates, overexpression of exhaustion markers and increased susceptibility to Treg suppression and the influence of immune-modulating drugs such as rapamycin, FK506, and MMF. Notably, T cells cultured in low glucose concentrations increased the expression of BDH1 to utilize BHB as an alternative fuel source. Finally, the addition of BHB to the culture effectively rescued T cell impairments caused by insufficient glucose levels.
CONCLUSIONS: T cells display limited capacity to adapt to low glucose levels, resulting in profound functional impairment. However, T cell functions can be efficiently recovered by the presence of 2mM BHB.

Algal polysaccharide is an important food functional factor with diverse bioactive and low toxicity. Previous studies have confirmed Caulerpa chemnitzia polysaccharides (CRVP) have immunomodulatory activity, but the immunomodulatory mechanism of CRVP in macrophages has not been thoroughly explored yet. In our research, we found that CRVP has outstanding immunomodulatory activity in macrophages, which is reflected in promoting cell proliferation, upregulating cytokines (IL-1β, IL-6, and TNF-α) expression, and increasing NO and ROS levels. Additionally, the result of joint analysis of untargeted metabolomics showed metabolism played a major role in the immunomodulatory of CRVP and suggested succinic acid was a key metabolite. Further verification indicated that the accumulation of succinic acid in macrophages after administered with CRVP, induced the down-regulation of prolyl hydroxylase domain 2 (PHD2) and up-regulation of hypoxia-inducible factor-1α (HIF-1α), thereby enhancing IL-1β expression. Together, the immunomodulatory activity of CRVP in macrophages via succinate/PHD2/HIF-1α/IL-1β pathway.