Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Hooftman, Alexander; Peace, Christian G.; Ryan, Dylan Gerard; Day, Emily A.; Yang, Ming; McGettrick, Anne F.; Yin, Maureen; Montano, Erica N.; Huo, Lihong; Toller-Kawahisa, Juliana E; Zecchini, Vincent; Ryan, Tristram A. J.; Bolado-Carrancio, Alfonso; Casey, Alva M.; Prag, Hiran A.; Costa, Ana S. H.; Santos, Gabriela De Los; Ishimori, Mariko; Wallace, Daniel J.; Venuturupalli, Swamy; Nikitopoulou, Efterpi; Frizzell, Norma; Johansson, Cecilia; Kriegsheim, Alex von; Murphy, Michael P.; Jefferies, Caroline A.; Frezza, Christian; O’Neill, Luke A. J.

doi:10.1038/s41586-023-05720-6

Cited by 73 publications

(90 citation statements)

References 70 publications

(89 reference statements)

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“…Surprisingly, this was in sharp contrast to fumarate esters, which are successfully used in the management of inflammatory diseases such as psoriasis and multiple sclerosis [36] . In addition, the inhibition of fumarate hydratase suppresses the expression of Il-10 that leads to increased TNFα release [35] . Accumulated citrate, which is exported from the mitochondria to the cytoplasm, is converted to acetyl-coA that is directed towards the production of inflammatory lipid-mediators such as prostaglandins (PGs) [37] (Figure 2, left panel).…”

Section: Immunometabolismmentioning

confidence: 99%

“…Thus, the concept that metabolic activities dictate the function of immune cells was coined as "immunometabolism" in the early 2010s [41] . Since then, several seminal studies have demonstrated how diverse metabolites function as signaling intermediates that dictate the immune response [10,35,[42][43][44] . Interestingly, it is increasingly being recognized that bacterial pathogens can subvert immunometabolism to promote infection [12,45,46] .…”

Section: Immunometabolismmentioning

confidence: 99%

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Immunometabolic control by Klebsiella pneumoniae

Prince

Lung

2023

Immunometabolism

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Klebsiella pneumoniae is a common Gram-negative pathogen associated with community-acquired and healthcare-associated infections. Its ability to acquire genetic elements resulted in its rapid development of resistance to virtually all antimicrobial agents. Once infection is established, K. pneumoniae is able to evade the host immune response and perhaps more importantly, undergo metabolic rewiring to optimize its ability to maintain infection. K. pneumoniae lipopolysaccharide and capsular polysaccharide are central factors in the induction and evasion of immune clearance. Less well understood is the importance of immunometabolism, the intersection between cellular metabolism and immune function, in the host response to K. pneumoniae infection. Bacterial metabolism itself is perceived as a metabolic stress to the host, altering the microenvironment at the site of infection. In this review, we will discuss the metabolic responses induced by K. pneumoniae, particularly in response to stimulation with the metabolically active bacteria versus pathogen-associated molecular patterns alone, and their implications in shaping the nature of the immune response and the infection outcome. A better understanding of the immunometabolic response to K. pneumoniae may help identify new targets for therapeutic intervention in the treatment of multidrug-resistant bacterial infections.

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Section: Immunometabolismmentioning

confidence: 99%

Section: Immunometabolismmentioning

confidence: 99%

Immunometabolic control by Klebsiella pneumoniae

Prince

Lung

2023

Immunometabolism

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“…Released mtDNA and mtRNA have been reported to activate cytosolic nucleic acid sensors to induce type-I interferon production and inflammatory response. 3,4 Zecchini et al 1 and Hooftman et al 2 illustrated that FH deficiency induced an IFN response via the release of mtDNA or mtRNA in different physiological models, which is a novel crosstalk between mitochondrial metabolism and innate immunity. The accumulation of fumarate, a key metabolite of the TCA cycle, is likely to play a crucial role.…”

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confidence: 99%

“…mtDNA was previously reported to be transmitted between tumor cells via extracellular vesicles, 5 but the transport of mtDNA in MDVs was identified for the first time. Hooftman et al 2 found that FH inhibition resulted in the release of mtRNA by increasing the MMP. There are few reports on the mechanism of mtRNA release, mainly the observation of mtRNA release due to the Bcell lymphoma-2 associated X, apoptosis regulator/B-cell lymphoma-2 antagonist/killer 1-mediated permeabilization of the outer membrane during programmed cell death.…”

mentioning

confidence: 99%

“…The analysis of the crosstalk between mitochondrial metabolism and innate immunity is also a highlight of both researches. Zecchini et al 2 comprehensively analyzed the inflammatory response triggered by FH inhibition, while Hooftman et al 2 evaluated the changes of aspartate-argininosuccinate shunt by LPS stimulation and the metabolic rewiring caused by FH inhibition. FH inhibition using pharmacological inhibitor FHIN1 induced alteration of TCA cycle metabolites, modulation of cytosolic processes, and substantial redox stress responses.…”

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confidence: 99%

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Fumarate hydratase inhibition activates innate immunity via mitochondrial nucleic acid release

Zhou

Zeng³

2023

MedComm

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Recently, two back-to-back studies (Zecchini et al. 1 and Hooftman et al. 2 ) were published in Nature, illustrating the vital protective role of fumarate hydratase (FH) in innate immune responses. Their findings showed that FH inhibition induced the accumulation of fumarate, leading to the release of mitochondrial DNA (mtDNA) and mitochondrial RNA (mtRNA) respectively, which further increased the production of type-I interferon (IFN) through activation of the DNA sensor cyclic guanosine monophosphate-adenosine monophosphate adenosine synthetase (cGAS) and RNA sensors tolllike receptor 7 (TLR7), retinoic acid-inducible gene I (RIG-I), and melanoma differentiation-associated gene 5 (MDA5). Their work revealed the relationship between FH inhibition and mitochondrial nucleic acid release as well as innate immune activation, which was a crucial breakthrough in the crosstalk between metabolism and immunity.FH is a key metabolic enzyme in the tricarboxylic acid (TCA) cycle and catalyzes the reversible hydrationThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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α‐Ketoglutarate–Dependent KDM6 Histone Demethylases and Interferon‐Stimulated Gene Expression in Lupus

Montano,

Bose,

Huo

et al. 2024

Arthritis & Rheumatology

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ObjectiveInvestigate the hypothesis that interferon (IFN) stimulated gene (ISG) expression in systemic lupus erythematosus (SLE) monocytes is linked to changes in metabolic reprogramming and epigenetic regulation of ISG expression.MethodsMonocytes from healthy volunteers and SLE patients at baseline or following IFNα treatment were analyzed by extracellular flux analysis, proteomics, metabolomics, chromatin immunoprecipitation and gene expression. The histone demethylases KDM6A/B were inhibited using GSK‐J4. GSK‐J4 was tested in pristane and resiquimod (R848) models of IFN‐driven SLE.ResultsSLE monocytes had enhanced rates of glycolysis and oxidative phosphorylation compared to healthy control (HC) monocytes, as well as increased levels of isocitrate dehydrogenase (IDH2) and its product, α‐ketoglutarate (α‐KG). As α‐KG is a required cofactor for histone demethylases KDM6A and KDM6B, we hypothesized that IFNα may be driving ‘trained immune’ responses through altering histone methylation. IFNα priming (day 1) resulted in a sustained increase in the expression of ISGs in primed cells (day 5) and enhanced expression on restimulation with IFNα. Importantly decreased H3K27 trimethylation was observed at the promoters of ISGs following IFNα priming. Finally, GSK‐J4 (KDM6A/B inhibitor) resulted in decreased ISG expression in SLE patient monocytes, as well as reduced autoantibody production, ISG expression and kidney pathology in R848‐treated Balb/c mice.ConclusionOur study suggests chronic IFNα exposure alters epigenetic regulation of ISG expression in SLE monocytes via changes in immunometabolism, a mechanism reflecting trained immunity to type I IFN. Importantly, it opens the possibility that targeting histone modifying enzymes such as KDM6A/B may reduce IFN responses in SLE.image

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Macrophage fumarate hydratase restrains mtRNA-mediated interferon production

Cited by 73 publications

References 70 publications

Immunometabolic control by Klebsiella pneumoniae

Immunometabolic control by Klebsiella pneumoniae

Fumarate hydratase inhibition activates innate immunity via mitochondrial nucleic acid release

α‐Ketoglutarate–Dependent KDM6 Histone Demethylases and Interferon‐Stimulated Gene Expression in Lupus

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