Itaconate-producing neutrophils regulate local and systemic inflammation following trauma DOI Creative Commons

Janna L. Crossley,

Sonya Ostashevskaya-Gohstand,

Stefano Comazzetto

et al.

JCI Insight, Journal Year: 2023, Volume and Issue: 8(20)

Published: Sept. 14, 2023

Modulation of the immune response to initiate and halt inflammatory process occurs both at site injury as well systemically. Due evolving role cellular metabolism in regulating cell fate function, tendon injuries which undergo normal aberrant repair were evaluated by metabolic profiling determine its impact on healing outcomes. Metabolomics revealed an increasing abundance immunomodulatory metabolite itaconate with site. Subsequent single-cell RNA sequencing, molecular metabolomic validation identified a highly mature neutrophil subtype, not macrophages, primary producers following trauma. These itaconate-producing neutrophils inflammatory, producing cytokines that promote local fibrosis before cycling back bone marrow. In marrow, was shown alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby systemic inflammation. Therapeutically, exogenous found reduce inflammation, promoting tenogenic differentiation impairing vascularization disease ameliorating effects. results present intriguing for sensor inflammation induced injury, potentially production through delivery endogenously produced demonstrate therapeutic potential injury.

Language: Английский

NRF2 signalling in cytoprotection and metabolism DOI Creative Commons
Shohei Murakami,

Yusuke Kusano,

Keito Okazaki

et al.

British Journal of Pharmacology, Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 16, 2023

The KEAP1 ‐ NRF2 system plays a central role in cytoprotection defence mechanisms against oxidative stress. KEAP1‐NRF2 has been regarded as sulfur‐utilizing cytoprotective mechanism, because serves biosensor for electrophiles by using its reactive thiols and is transcriptional factor regulating genes involved sulfur‐mediated redox reactions. key regulator of genes, such antioxidant detoxification also possesses potent anti‐inflammatory activity. Recently the focus attention cellular metabolism mitochondrial function. NRF2‐mediated regulatory metabolites mitochondria have considered diverse, but not yet fully clarified. This review article provides an overview molecular that regulate signalling roles, highlights contribution to metabolism, particularly context function newly‐found sulfur metabolism.

Language: Английский

Citations

43
Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls DOI Creative Commons
Ana Karina Aranda‐Rivera, Alfredo Cruz‐Gregorio, José Pedraza-Chaverrı́

et al.

Antioxidants, Journal Year: 2022, Volume and Issue: 11(6), P. 1112 - 1112

Published: June 3, 2022

The nuclear factor erythroid 2-related 2 (Nrf2) protects the cell against oxidative damage. Nrf2 system comprises a complex network that functions to ensure adequate responses redox perturbations, but also metabolic demands and cellular stresses. It must be kept within physiologic activity range. Oxidative stress alterations in Nrf2-system are central for chronic-kidney-disease (CKD) progression CKD-related morbidity. Activation of CKD is multiple ways related inflammation, kidney fibrosis, mitochondrial effects. In human CKD, both endogenous activation repression exist. state varies with cause disease, comorbidities, stage severity uremic toxin accumulation inflammation. An earlier stage, rapid inflammatory processes associated more robust activation. Advanced stronger repression. moderate kappa B (NF-κB) elevations. relates high NF-κB concentrations, may Kelch-like ECH-associated protein 1 (Keap1)-independent degradation. Furthermore, we review effects pharmacological by bardoxolone methyl, curcumin, resveratrol outline strategies how adapt future Nrf2-targeted therapies requirements patients CKD.

Language: Английский

Citations

42
Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon DOI Creative Commons
Tristram A.J. Ryan, Alexander Hooftman, Aisling M. Rehill

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 14, 2023

Excessive inflammation-associated coagulation is a feature of infectious diseases, occurring in such conditions as bacterial sepsis and COVID-19. It can lead to disseminated intravascular coagulation, one the leading causes mortality worldwide. Recently, type I interferon (IFN) signaling has been shown be required for tissue factor (TF; gene name F3) release from macrophages, critical initiator providing an important mechanistic link between innate immunity coagulation. The mechanism involves IFN-induced caspase-11 which promotes macrophage pyroptosis. Here we find that F3 IFN-stimulated gene. Furthermore, induction by lipopolysaccharide (LPS) inhibited anti-inflammatory agents dimethyl fumarate (DMF) 4-octyl itaconate (4-OI). Mechanistically, inhibition DMF 4-OI suppression Ifnb1 expression. Additionally, they block IFN- caspase-11-mediated pyroptosis, subsequent TF release. Thereby, inhibit TF-dependent thrombin generation. In vivo, suppress generation, pulmonary thromboinflammation, lethality induced LPS, E. coli, S. aureus, with additionally attenuating model SARS-CoV-2 infection. Our results identify clinically approved drug pre-clinical tool compound anticoagulants TF-mediated coagulopathy via IFN-TF axis.

Language: Английский

Citations

42
Nrf2 regulates glucose uptake and metabolism in neurons and astrocytes DOI Creative Commons
Noemí Esteras, Thomas S. Blacker, Evgeny Zherebtsov

et al.

Redox Biology, Journal Year: 2023, Volume and Issue: 62, P. 102672 - 102672

Published: March 14, 2023

The transcription factor Nrf2 and its repressor Keap1 mediate cell stress adaptation by inducing expression of genes regulating cellular detoxification, antioxidant defence energy metabolism. Energy production employ NADH NADPH respectively as essential metabolic cofactors; both are generated in distinct pathways glucose metabolism, enhanced activation. Here, we examined the role on distribution interrelation between metabolism homeostasis using glio-neuronal cultures isolated from wild-type, Nrf2-knockout Keap1-knockdown mice. Employing advanced microscopy imaging single live cells, including multiphoton fluorescence lifetime (FLIM) to discriminate NADPH, found that activation increases uptake into neurons astrocytes. Glucose consumption is prioritized brain cells for mitochondrial production, with a smaller contribution synthesis pentose phosphate pathway redox reactions. As suppressed during neuronal development, this strategy leaves reliant astrocytic maintain balance homeostasis.

Language: Английский

Citations

34
Itaconate: A Potent Macrophage Immunomodulator DOI Open Access
Zeyu Li, Wenbin Zheng, Wen Kong

et al.

Inflammation, Journal Year: 2023, Volume and Issue: 46(4), P. 1177 - 1191

Published: May 4, 2023

Language: Английский

Citations

32
Antiviral, anti-inflammatory and antioxidant effects of curcumin and curcuminoids in SH-SY5Y cells infected by SARS-CoV-2 DOI Creative Commons

Tiago Nicoliche,

Cynthia Silva Bartolomeo, Robertha Mariana Rodrigues Lemes

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: May 10, 2024

COVID-19, caused by SARS-CoV-2, affects neuronal cells, causing several symptoms such as memory loss, anosmia and brain inflammation. Curcuminoids (Me08 e Me23) curcumin (CUR) are derived from Curcuma Longa extract (EXT). Many therapeutic actions have been linked to these compounds, including antiviral action. Given the severe implications of especially within central nervous system, our study aims shed light on potential curcuminoids against SARS-CoV-2 infection, particularly in cells. Here, we investigated effects CUR, EXT, Me08 Me23 human neuroblastoma SH-SY5Y. We observed that significantly decreased expression plasma membrane-associated transmembrane protease serine 2 (TMPRSS2) TMPRSS11D, consequently mitigating elevated ROS levels induced SARS-CoV-2. Furthermore, exhibited antioxidative properties increasing NRF2 gene restoring NQO1 activity following infection. Both effectively reduced replication SH-SY5Y cells overexpressing ACE2 (SH-ACE2). Additionally, all compounds demonstrated ability decrease proinflammatory cytokines IL-6, TNF-α, IL-17, while specifically INF-γ levels. Our findings suggest curcuminoid could serve a agent for impact context system involvement.

Language: Английский

Citations

16
Cocoa flavanols, Nrf2 activation, and oxidative stress in peripheral artery disease: mechanistic findings in muscle based on outcomes from a randomized trial DOI
Ahmed Ismaeel, Mary Mcdermott, Jai K. Joshi

et al.

AJP Cell Physiology, Journal Year: 2024, Volume and Issue: 326(2), P. C589 - C605

Published: Jan. 8, 2024

The current study supports the hypothesis that in people with PAD, cocoa flavanols activate Nrf2, thereby increasing antioxidant protein levels, protecting against skeletal muscle damage, and mitochondrial abundance. These results suggest Nrf2 activation may be an important therapeutic target for improving walking performance PAD.

Language: Английский

Citations

13
Metabolic regulation of type I interferon production DOI Creative Commons

Shane M. O’Carroll,

Fiona Henkel,

Luke O'neill

et al.

Immunological Reviews, Journal Year: 2024, Volume and Issue: 323(1), P. 276 - 287

Published: March 11, 2024

Summary Over the past decade, there has been a surge in discoveries of how metabolic pathways regulate immune cell function health and disease, establishing field immunometabolism. Specifically, such as glycolysis, tricarboxylic acid (TCA) cycle, those involving lipid metabolism have implicated regulating function. Viral infections cause immunometabolic changes which lead to antiviral immunity, but little is known about interferon responses. Interferons are critical cytokines host defense, rapidly induced upon pathogen recognition, also involved autoimmune diseases. This review summarizes change impacts production. We describe (specifically eicosanoids cholesterol), TCA cycle‐linked intermediates itaconate fumarate impact type I interferons. Targeting these presents new therapeutic possibilities modulate interferons during defense or disorders.

Language: Английский

Citations

13
Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing DOI Creative Commons
Kangkang Zha,

Meijun Tan,

Yiqiang Hu

et al.

Bioactive Materials, Journal Year: 2024, Volume and Issue: 37, P. 424 - 438

Published: April 24, 2024

Bone nonunion poses an urgent clinical challenge that needs to be addressed. Recent studies have revealed the metabolic microenvironment plays a vital role in fracture healing. Macrophages and bone marrow-derived mesenchymal stromal cells (BMSCs) are important targets for therapeutic interventions fractures. Itaconate is TCA cycle metabolite has emerged as potent macrophage immunomodulator limits inflammatory response. During osteogenic differentiation, BMSCs tend undergo aerobic glycolysis metabolize glucose lactate. Copper ion (Cu2+) essential trace element participates metabolism may stimulate promote osteogenesis. In this study, we develop 4-octyl itaconate (4-OI)@Cu@Gel nanocomposite hydrogel can effectively deliver release 4-OI Cu2+ modulate improve functions of involved healing process. The findings reveal burst reduces response, promotes M2 polarization, alleviates oxidative stress, while sustained stimulates BMSC differentiation enhances endothelial cell angiogenesis. Consequently, 4-OI@Cu@Gel system achieves rapid mice. Thus, study proposes promising regenerative strategy expedite through reprogramming macrophages BMSCs.

Language: Английский

Citations

9
Optimizing Spectronaut Search Parameters to Improve Data Quality with Minimal Proteome Coverage Reductions in DIA Analyses of Heterogeneous Samples DOI Creative Commons
Christa P. Baker, Roland Bruderer, James Abbott

et al.

Journal of Proteome Research, Journal Year: 2024, Volume and Issue: 23(6), P. 1926 - 1936

Published: May 1, 2024

Data-independent acquisition has seen breakthroughs that enable comprehensive proteome profiling using short gradients. As the coverage continues to increase, quality of data generated becomes much more relevant. Using Spectronaut, we show default search parameters can be easily optimized minimize occurrence false positives across different samples. an immunological infection model system demonstrate impact adjusting settings, analyzed Mus musculus macrophages and compared their spiked withCandida albicans. This experimental enabled identification "false positives" as Candida albicans peptides proteins should not present in musculus-only We reduced positive" identifications by 89% at peptide protein level, thereby considerably increasing data. also these incurred a moderate cost, only reducing overall number "true each biological replicate <6.7% both level. believe value our updated extends beyond two-organism analysis would great any DIA experiment analyzing heterogeneous populations cell types or tissues.

Language: Английский

Citations

9