Metabolic Reprogramming of Innate Immune Cells as a Possible Source of New Therapeutic Approaches in Autoimmunity

Mohammadnezhad, Leila; Azgomi, Mojtaba Shekarkar; Manna, Marco Pio La; Sireci, Guido; Rizzo, Carla; Badami, Giusto Davide; Tamburini, Bartolo; Dieli, Francesco; Guggino, Giuliana; Caccamo, Nadia

doi:10.3390/cells11101663

Cited by 15 publications

(9 citation statements)

References 216 publications

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“…For example, glucose uptake through the GLUT3 transporter plays a crucial role in Th17 cell function in autoimmune diseases (Shi et al 2011 ; Gerriets et al 2016 ), and it regulates the metabolic pathways that control the expression of genes involved in the inflammatory response of Th17 cells (Hochrein et al 2022 ). Therefore, although metabolic reprogramming occurring in immune cells is necessary for cell differentiation, proliferation, and effector function, it may mediate the imbalance of immune homeostasis, contributing to the onset and progression of autoimmune diseases (Mohammadnezhad et al 2022 ).…”

Section: Glucose Metabolism In Autoimmunitymentioning

confidence: 99%

Glucose metabolic reprogramming in autoimmune diseases

Jeong

Lee

Han

2023

Animal Cells and Systems

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Autoimmune diseases are conditions in which the immune system mistakenly targets and damages healthy tissue in the body. In recent decades, the incidence of autoimmune diseases has increased, resulting in a significant disease burden. The current autoimmune therapies focus on targeting inflammation or inducing immunosuppression rather than addressing the underlying cause of the diseases. The activity of metabolic pathways is elevated in autoimmune diseases, and metabolic changes are increasingly recognized as important pathogenic processes underlying these. Therefore, metabolically targeted therapies may represent an important strategy for treating autoimmune diseases. This review provides a comprehensive overview of the evidence surrounding glucose metabolic reprogramming and its potential applications in drug discovery and development for autoimmune diseases, such as type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis.

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Section: Glucose Metabolism In Autoimmunitymentioning

confidence: 99%

Glucose metabolic reprogramming in autoimmune diseases

Jeong

Lee

Han

2023

Animal Cells and Systems

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“…Innate immune cell reprogramming of metabolic pathways is another basis for forming a trained immunity ( 51 ). When innate immune cells are exposed to the first pathogen stimulus, metabolic pathways and epigenetic modifications occur, providing rapid and enhanced immune response upon subsequent pathogen challenge ( 5 , 52 ). Thus, the trained immunity of arthropods and mollusks could also be affected by epigenetic modifications and metabolic reprogramming, which provides a broader pattern of specificity and immune memory.…”

Section: Trained Immunity In Arthropods and Mollusksmentioning

confidence: 99%

“…The cellular immunity of invertebrates mediated by hemocytes consists of inflammatory responses, includes phagocytosis, encapsulation, cytotoxicity, and synthesis or release of microbicidal agents ( 117 ). Different immune signals induce different cellular metabolic reorganizations, which are critical for the epigenetic modifications in trained immunity ( 33 , 52 , 118 ). Given that immune responses are high-energy processes, metabolism provides energy to maintain cellular hemostasis and enhances immune cells’ functions ( 51 ).…”

Section: The Effect Of Metabolic and Epigenetic Modification On Train...mentioning

confidence: 99%

The mechanisms and factors that induce trained immunity in arthropods and mollusks

Zhao,

Lin,

Zheng

et al. 2023

Front. Immunol.

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Besides dividing the organism’s immune system into adaptive and innate immunity, it has long been thought that only adaptive immunity can establish immune memory. However, many studies have shown that innate immunity can also build immunological memory through epigenetic reprogramming and modifications to resist pathogens’ reinfection, known as trained immunity. This paper reviews the role of mitochondrial metabolism and epigenetic modifications and describes the molecular foundation in the trained immunity of arthropods and mollusks. Mitochondrial metabolism and epigenetic modifications complement each other and play a key role in trained immunity.

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“…Our understanding of sepsis has shifted to incorporate metabolic dysfunction as a central component of its pathogenesis. Inflammation-driven metabolic reprogramming and its consequences in the immune compartment have been investigated extensively ( Hu et al, 2022 ; Arner and Rathmell, 2023 ; Mohammadnezhad et al, 2022 ). However, our understanding of metabolic derangements in central organs like the liver is limited.…”

Section: Introductionmentioning

confidence: 99%

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

Mainali,

Buechler,

Otero

et al. 2024

eLife

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One primary metabolic manifestation of inflammation is the diversion of cis-aconitate within the tricarboxylic acid (TCA) cycle to synthesize the immunometabolite itaconate. Itaconate is well established to possess immunomodulatory and metabolic effects within myeloid cells and lymphocytes, however, its effects in other organ systems during sepsis remain less clear. Utilizing Irg1 knockout mice that are deficient in synthesizing itaconate, we aimed at understanding the metabolic role of itaconate in the liver and systemically during sepsis. We find itaconate aids in lipid metabolism during sepsis. Specifically, Irg1 KO mice develop a heightened level of hepatic steatosis when induced with polymicrobial sepsis. Proteomics analysis reveal enhanced expression of enzymes involved in fatty acid oxidation in following 4-ocytl itaconate (4-OI) treatment in vitro. Downstream analysis reveals itaconate stabilizes the expression of the mitochondrial fatty acid uptake enzyme CPT1a, mediated by its hypoubiquitination. Chemoproteomic analysis revealed itaconate interacts with proteins involved in protein ubiquitination as a potential mechanism underlying its stabilizing effect on CPT1a. From a systemic perspective, we find itaconate deficiency triggers a hypothermic response following endotoxin stimulation, potentially mediated by brown adipose tissue (BAT) dysfunction. Finally, by use of metabolic cage studies, we demonstrate Irg1 KO mice rely more heavily on carbohydrates versus fatty acid sources for systemic fuel utilization in response to endotoxin treatment. Our data reveal a novel metabolic role of itaconate in modulating fatty acid oxidation during polymicrobial sepsis.

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Metabolic Reprogramming of Innate Immune Cells as a Possible Source of New Therapeutic Approaches in Autoimmunity

Cited by 15 publications

References 216 publications

Glucose metabolic reprogramming in autoimmune diseases

Glucose metabolic reprogramming in autoimmune diseases

The mechanisms and factors that induce trained immunity in arthropods and mollusks

Itaconate stabilizes CPT1a to enhance lipid utilization during inflammation

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