Biochemistry of proinflammatory macrophage activation

Nonnenmacher, Yannic; Hiller, Karsten

doi:10.1007/s00018-018-2784-1

Cited by 88 publications

(93 citation statements)

References 135 publications

(201 reference statements)

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“…Innate immunity constitutes the first line of defense against pathogen infection and contributes to the activation of adaptive immune response for a more potent protection. Macrophages with a critical role in innate immunity respond rapidly to the pathogens, after, they undergo a transition from their classical highly inflammatory phenotype to a less inflammatory state to limit the damage and promote tissue repair . Although the mechanisms responsible for these changes are still not completely understood, it is believed that metabolic reprogramming is a major cause .…”

Section: Introductionmentioning

confidence: 99%

“…Macrophages with a critical role in innate immunity respond rapidly to the pathogens, after, they undergo a transition from their classical highly inflammatory phenotype to a less inflammatory state to limit the damage and promote tissue repair. 1 Although the mechanisms responsible for these changes are still not completely understood, it is believed that metabolic reprogramming is a major cause. 2 Activated macrophages are known to undergo extensive metabolic reprogramming with substantial accumulation of cellular metabolites such as itaconate.…”

Section: Introductionmentioning

confidence: 99%

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Itaconate: an emerging determinant of inflammation in activated macrophages

Zhang

Zheng

et al. 2018

Immunol Cell Biol

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Macrophages play a central role in innate immunity as the first line of defense against pathogen infection. Upon exposure to inflammatory stimuli, macrophages rapidly respond and subsequently undergo metabolic reprogramming to substantially produce cellular metabolites such as itaconate. As a derivate of the tricarboxylic acid cycle, itaconate is derived from the decarboxylation of cis‐aconitate mediated by immunoresponsive gene 1 in the mitochondrial matrix. It is well known that itaconate has a direct antimicrobial effect by inhibiting isocitrate lyase. Strikingly, two recent studies published in Nature showed that itaconate markedly decreases the production of proinflammatory mediators in lipopolysaccharide‐treated macrophages and ameliorates sepsis and psoriasis in animal models, revealing a novel biological action of itaconate beyond its regular roles in antimicrobial defense. The mechanism for this anti‐inflammatory effect has been proposed to involve the inhibition of succinate dehydrogenase, blockade of IκBζ translation and activation of Nrf2. These intriguing discoveries provide a new explanation for how macrophages are switched from a pro‐ to an anti‐inflammatory state to limit the damage and facilitate tissue repair under proinflammatory conditions. Thus, the emerging effect of itaconate as a crucial determinant of macrophage inflammation has important implications in further understanding cellular immunometabolism and developing future therapeutics for the treatment of inflammatory diseases. In this review, we focus on the roles of itaconate in controlling the inflammatory response during macrophage activation, providing a rationale for future investigation and therapeutic intervention.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Itaconate: an emerging determinant of inflammation in activated macrophages

Zhang

Zheng

et al. 2018

Immunol Cell Biol

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“…228 Permeable itaconate and 4-octyl itaconate (OI) restricted the type 1 IFN response and the production of inflammatory cytokines by macrophages. 47,48 OI was tested in PBMCs from lupus patients in which it decreased the production of pro-inflammatory cytokines, such as TNFα and IL-6, through the activation of NRF2 signaling. 229 These important recent developments in immunometabolism research should lead the implementation of studies to test whether Krebs cycle metabolite intermediates that have secondary immune signaling functions could be targeted in lupus.…”

Section: Multiple Parameters Of Mt Dysfunction Have Been Reported Inmentioning

confidence: 99%

Metabolic determinants of lupus pathogenesis

Teng

Brown

Choi

et al. 2020

Immunological Reviews

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The metabolism of healthy murine and more recently human immune cells has been investigated with an increasing amount of details. These studies have revealed the challenges presented by immune cells to respond rapidly to a wide variety of triggers by adjusting the amount, type, and utilization of the nutrients they import. A concept has emerged that cellular metabolic programs regulate the size of the immune response and the plasticity of its effector functions. This has generated a lot of enthusiasm with the prediction that cellular metabolism could be manipulated to either enhance or limit an immune response. In support of this hypothesis, studies in animal models as well as human subjects have shown that the dysregulation of the immune system in autoimmune diseases is associated with a skewing of the immunometabolic programs. These studies have been mostly conducted on autoimmune CD4 + T cells, with the metabolism of other immune cells in autoimmune settings still being understudied. Here we discuss systemic metabolism as well as cellular immunometabolism as novel tools to decipher fundamental mechanisms of autoimmunity. We review the contribution of each major metabolic pathway to autoimmune diseases, with a focus on systemic lupus erythematosus (SLE), with the relevant translational opportunities, existing or predicted from results obtained with healthy immune cells. Finally, we review how targeting metabolic programs may present novel therapeutic venues. K E Y W O R D Sglucose, glutamine, lupus, metabolic inhibitors, metabolism

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“…Mechanistically, itaconate derivatives can regulate nuclear factor kappa B inhibitor zeta (IκBζ) via activating transcription factor 3 (ATF3), ameliorating IL-17 IκBζ-driven inflammation [76]. Further, cell-permeable itaconate derivatives decreased cytokine production in macrophages and limited the type I IFN response, indicating a possible therapeutic use for itaconate and its derivatives in IFN-driven diseases such as SLE [77,78]. Further, cell-permeable itaconate derivatives decreased cytokine production in macrophages and limited the type I IFN response, indicating a possible therapeutic use for itaconate and its derivatives in IFN-driven diseases such as SLE [77,78].…”

Section: Review Series: Translating Immunometabolismmentioning

confidence: 99%

“…Another study identified that activation of nuclear factor-like 2 (Nrf2) via Kelch-like ECH-associated protein 1 (KEAP1) alkylation could explain the anti-inflammatory effects exhibited by itaconate [77]. Further, cell-permeable itaconate derivatives decreased cytokine production in macrophages and limited the type I IFN response, indicating a possible therapeutic use for itaconate and its derivatives in IFN-driven diseases such as SLE [77,78].…”

Section: Review Series: Translating Immunometabolismmentioning

confidence: 99%

Immune cell metabolism in autoimmunity

Teng

Cornaby

et al. 2019

Clinical and Experimental Immunology

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Immune metabolism is a rapidly moving field. While most of the research has been conducted to define the metabolism of healthy immune cells in the mouse, it is recognized that the overactive immune system that drives autoimmune diseases presents metabolic abnormalities that provide therapeutic opportunities, as well as a means to understand the fundamental mechanisms of autoimmune activation more clearly. Here, we review recent publications that have reported how the major metabolic pathways are affected in autoimmune diseases, with a focus on rheumatic diseases. mental Immunology 2019, 197: 141-142. T cell metabolism in chronic viral infection. Clinical and Experimental Immunology 2019, 197: 143-152. Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting. Clinical and Experimental Immunology 2019, 197: 153-160. Sensing between reactions -how the metabolic microenvironment shapes immunity. Clinical and Experimental Immunology 2019, 197: 161-169. Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis. OTHER ARTICLES PUBLISHED IN THIS REVIEW SERIES Translating immunometabolism: towards curing human diseases by targeting metabolic processes underpinning the immune response. Clinical and Experi

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Biochemistry of proinflammatory macrophage activation

Cited by 88 publications

References 135 publications

Itaconate: an emerging determinant of inflammation in activated macrophages

Itaconate: an emerging determinant of inflammation in activated macrophages

Metabolic determinants of lupus pathogenesis

Immune cell metabolism in autoimmunity

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