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The Microbiome – Role in Personalized Medicine
Published in David Perlmutter, The Microbiome and the Brain, 2019
Furthermore, the enteric immune system is yet another voice participating in the cross-talk. More than half of an individual’s immune system is clustered around their gastrointestinal system in the form of the mucosal-associated lymphoid tissue (MALT) and the gastrointestinal-associated lymphoid tissue (GALT). The contents of the gut, which includes the microbiome, has a significant impact on the functional status of the MALT and GALT. Cross-talk between the microbiome and these immune systems can result in immune activation of both the gut-associated innate and adaptive immune cells.32 In this capacity, the microbiome is an immunomodulator that can have an impact on systemic metabolism. In 2018, Olefsky et al. published a paper in Cell describing an integrated view of immunometabolism and the important role that microbiota-produced metabolites have on influencing host inflammation and metabolism.33 The release of metabolites such as lipopolysaccharides (LPS) from the cell wall of specific enteric bacteria can activate toll-like receptors, like TLR4, that initiate the inflammatory process. Other gastrointestinal receptors such as GPR41 and GPR43, as well as bile acid receptors TGR5 and farnesoid X receptor (FXR), modulate systemic inflammation and metabolism and have been shown to be influenced by the microbiome.
Time to ‘Couple’ Redox Biology with Exercise Immunology
Published in James N. Cobley, Gareth W. Davison, Oxidative Eustress in Exercise Physiology, 2022
Alex J. Wadley, Steven J. Coles
Immunometabolism is a rapidly expanding field in immunological research, with rewiring of cellular metabolism now linked with modulating multiple immune processes (Dimeloe et al., 2017). For example, T cells become highly reliant on glycolysis upon activation to support their effector functions (Fox, Hammerman and Thompson, 2005; van der Windt and Pearce, 2012). Interestingly, emerging data indicate that shifts in cellular redox state also support this metabolic reprogramming (Muri and Kopf, 2020). Indeed, T cell activation, which involves antigen presentation to the T cell receptor (TCR), is enhanced and sustained by mitochondrial and NADPH oxidase-derived ROS (Jackson et al., 2004; Kamiński et al., 2012). Following TCR signalling, CD28 ligation is the costimulatory signal needed to evoke the pronounced glycolytic shift. This is sustained through rapid glucose transport (GLUT1) and reduction of accumulating pyruvate to lactate, which maintains the cellular NAD+: NADH ratio. Despite a lower ATP yield per molecule of glucose, aerobic glycolysis drives more rapid metabolism of glucose than mitochondrial oxidation. The metabolic shift also supports the provision of biosynthetic precursors (nucleotides, amino acids and fatty acids) via the pentose phosphate pathway (PPP) that sustain the formation of effector molecules for T cell functions (Vander Heiden, Cantley and Thompson, 2009; Macintyre and Rathmell, 2013). The PPP enhances nicotinamide adenine dinucleotide phosphate (NADPH) supply (van der Windt and Pearce, 2012), the crucial cofactor needed to provide reducing equivalent for multiple cellular antioxidant enzymes (e.g., peroxiredoxin, thioredoxin, glutaredoxin) and the abundant tripeptide, glutathione. This activation-induced shift in T cell metabolism, therefore, provides reductive capacity for these cells to modulate cellular RONS and thus maintain redox homeostasis and functional capacity (Ma et al., 2018). Interestingly, this evidence indirectly supports our findings of more reductive CD8+ T cells in the circulation after exercise (CD8+Reduced+) (Wadley et al., 2018a,b). Given that we know that exercise evokes a marked and preferential increase in immune cells that are highly primed for their effector functions, we can intuitively suggest that these cells would have a more glycolytic phenotype. Future work should intertwine the fields of immunology, metabolism and redox biochemistry to further understand the mobilisation of specific immune cells after exercise.
Somewhere over the sex differences rainbow of myocardial infarction remodeling: hormones, chromosomes, inflammasome, oh my
Published in Expert Review of Proteomics, 2019
Kristine Y. DeLeon-Pennell, Merry L. Lindsey
Cellular metabolism plays a role in immune cell physiology. For example, pro-inflammatory (M1) macrophage metabolism is characterized by high glycolysis and relatively low oxidative phosphorylation, whereas M2 macrophage metabolism is characterized by oxidative phosphorylation, fatty acid oxidation, and upregulated arginase 1 activity [78]. Estrogen-signaling mainly through ERα is known to regulate metabolic pathways by altering glucose homeostasis [79,80]. In addition, estrogen promotes an anti-inflammatory and pro-resolving macrophage phenotype through activation of ERα [28,81,82]. Glycoproteomic analysis of plasma from patients with MI who developed heart failure mapped to an increase in LXR/RXR pathway activation in men but not women, signifying heart failure in men is dependent on cholesterol and fatty acid homeostasis [10]. While strong evidence indicates hormones play a role in cellular metabolism, the impact of immunometabolism on cellular physiology requires further examination. In addition, dissecting out the hormonal versus chromosomal mechanisms at play during disease development using proteomic approaches is needed to fully understand sex differences in cardiovascular wound healing.
Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy
Published in OncoImmunology, 2019
Sara Verdura, Elisabet Cuyàs, Begoña Martin-Castillo, Javier A. Menendez
One of the greatest obstacles to making cancer immunotherapy more broadly effective could be rooted in a basic concept of cell biology, namely metabolism. Immunometabolism, which is a relatively new field in cancer immunotherapy, is gaining momentum through the realization that faulty metabolic remodeling underlies impaired antitumor immune responses, and also that controlling metabolism can enhance antitumor immunity and synergize with existing checkpoint inhibitors.1–5 There is no doubt that harnessing the highly complex, antagonistic and symbiotic metabolite-mediated communication between tumor cells and the range of immune cell compartments residing in the tumor microenvironment (TME) has such potential. The question now is how to resolve the apparent conundrum of simultaneously orchestrating the precise direction and intensity of multiple metabolic checkpoints not only in T-cells, immune suppressor cells (tumor-associated macrophages [TAM], myeloid-derived suppressor cells [MDSC], regulatory T-[Treg]-cells), and cancer cells within the TME, but also in the gut microbiota, and its consequent systemic effects on host metabolism.
Inhibition of fatty acid metabolism by etomoxir or TOFA suppresses murine dendritic cell activation without affecting viability
Published in Immunopharmacology and Immunotoxicology, 2019
Connie C. Qiu, Atilio E. Atencio, Stefania Gallucci
In conclusion, we show that modulation of FAO by etomoxir may be more effective than modulation of FAS by TOFA for suppressing the activation of both pDCs and cDCs. Our data also show that low doses of etomoxir can significantly inhibit the production of ISGs by both pDCs and cDCs, emphasizing how shifts in metabolism are important for immune cell activation, and highlighting FAO as a specific pathway important for the activation of two main subsets of DCs. A surge in immunometabolism research has led to increased interest in metabolic modulators, and their potential as novel therapeutics. Our studies show how a range of etomoxir and TOFA doses affects pDC and cDC outcomes of activation, related to different immune responses, suggesting the possibility to modulate tolerance versus specific immune responses, rather than blindly inhibit the immune system, like present immunosuppressive therapies do. In summary, our findings suggest that DC metabolism may be an exploitable target in SLE.