Itaconate suppresses atherosclerosis by activating a Nrf2-dependent antiinflammatory response in macrophages in mice DOI Creative Commons
Jianrui Song, Yanling Zhang, Ryan A. Frieler

et al.

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 134(3)

Published: Dec. 12, 2023

Itaconate has emerged as a critical immunoregulatory metabolite. Here, we examined the therapeutic potential of itaconate in atherosclerosis. We found that both and enzyme synthesizes it, aconitate decarboxylase 1 (Acod1, also known "immune-responsive gene 1"/IRG1) are upregulated during atherogenesis mice. Deletion Acod1 myeloid cells exacerbated inflammation atherosclerosis vivo resulted an elevated frequency specific subset M1-polarized proinflammatory macrophages atherosclerotic aorta. Importantly, levels were inversely correlated with clinical occlusion human aorta specimens. Treating mice derivative 4-ocytyl attenuated induced by high cholesterol. Mechanistically, antioxidant transcription factor, Nuclear factor erythroid-2 Related Factor 2 (Nrf2) was required for to suppress macrophage activation oxidized lipids vitro decrease lesion areas vivo. Overall, our work shows suppresses inducing Nrf2-dependent inhibition responses macrophages. Activation pathway may represent important approach treat

Language: Английский

Systemic Lupus Erythematosus Pathogenesis: Interferon and Beyond DOI Creative Commons
Simone Caielli,

Zurong Wan,

Virginia Pascual

et al.

Annual Review of Immunology, Journal Year: 2023, Volume and Issue: 41(1), P. 533 - 560

Published: Feb. 28, 2023

Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity upstream mechanisms contributing to disease In this review, we focus on recent insights from genetic immune monitoring studies patients that refining our understanding basic mechanisms. Among them, novel mutations genes affecting intrinsic cell activation or clearance interferogenic nucleic acids have been described. Mitochondria emerged as relevant inducers and/or amplifiers SLE pathogenesis through a variety include disruption organelle integrity compartmentalization, defective metabolism, failure quality control measures. These result extra- intracellular release well innate adaptive activation. A classic autoantibody specificities found recapitulate alterations associated with monogenic trigger amplification loops. Finally, atypical extrafollicular T helper subsets proposed contribute the generation autoantibodies. Overall, provide opportunities deepen immunophenotypic surveillance open door patient stratification personalized, rational approaches therapy.

Language: Английский

Citations

108
Neutrophils resist ferroptosis and promote breast cancer metastasis through aconitate decarboxylase 1 DOI Creative Commons
Yun Zhao, Zhongshun Liu, Guoqiang Liu

et al.

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(10), P. 1688 - 1703.e10

Published: Oct. 1, 2023

Language: Английский

Citations

101
Mitochondrial complex I activity in microglia sustains neuroinflammation DOI Creative Commons
Luca Peruzzotti‐Jametti,

Carolyn M. Willis,

Grzegorz Krzak

et al.

Nature, Journal Year: 2024, Volume and Issue: 628(8006), P. 195 - 203

Published: March 13, 2024

Abstract Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark several chronic neurological diseases, including multiple sclerosis 1 . Distinct metabolic and mitochondrial features guide the activation diverse functional states 2 However, how these act to perpetuate inflammation central nervous system unclear. Here, using multiomics approach, we identify molecular signature that sustains microglia through complex I activity driving reverse electron transport production reactive oxygen species. Mechanistically, blocking in pro-inflammatory protects against neurotoxic damage improves outcomes an animal disease model vivo. Complex potential therapeutic target foster neuroprotection inflammatory disorders 3

Language: Английский

Citations

76
Mitochondrial signalling and homeostasis: from cell biology to neurological disease DOI Creative Commons
Jack J. Collier, Monika Oláhová, Thomas G. McWilliams

et al.

Trends in Neurosciences, Journal Year: 2023, Volume and Issue: 46(2), P. 137 - 152

Published: Jan. 10, 2023

Efforts to understand how mitochondrial dysfunction contributes neurodegeneration have primarily focussed on the role of mitochondria in neuronal energy metabolism. However, progress understanding etiological nature emerging functions has yielded new ideas about basis neurological disease. Studies aimed at deciphering signal through interorganellar contacts, vesicular trafficking, and metabolic transmission revealed that regulation immunometabolism, cell death, organelle dynamics, neuroimmune interplay are critical determinants neural health. Moreover, homeostatic mechanisms exist protect health turnover via nanoscale proteostasis lysosomal degradation become integrated within signalling pathways support plasticity stress responses nervous system. This review highlights these distinct converge influence contribute disease pathology.

Language: Английский

Citations

72
The NLRP3 inflammasome: regulation by metabolic signals DOI Creative Commons

Antoni Olona,

Stuart Leishman, Paras Anand

et al.

Trends in Immunology, Journal Year: 2022, Volume and Issue: 43(12), P. 978 - 989

Published: Nov. 9, 2022

Language: Английский

Citations

70
Regulatory Mechanism of M1/M2 Macrophage Polarization in the Development of Autoimmune Diseases DOI Creative Commons
Yuan Peng,

Mengxian Zhou,

Yang Hong

et al.

Mediators of Inflammation, Journal Year: 2023, Volume and Issue: 2023, P. 1 - 20

Published: June 8, 2023

Macrophages are innate immune cells in the organism and can be found almost tissues organs. They highly plastic heterogeneous participate response, thereby playing a crucial role maintaining homeostasis of body. It is well known that undifferentiated macrophages polarize into classically activated (M1 macrophages) alternatively (M2 under different microenvironmental conditions. The directions macrophage polarization regulated by series factors, including interferon, lipopolysaccharide, interleukin, noncoding RNAs. To elucidate various autoimmune diseases, we searched literature on with PubMed database. Search terms as follows: macrophages, polarization, signaling pathways, RNA, inflammation, systemic lupus erythematosus, rheumatoid arthritis, nephritis, Sjogren’s syndrome, Guillain-Barré multiple sclerosis. In present study, summarize common diseases. addition, also features recent advances particular focus immunotherapeutic potential diseases potentially effective therapeutic targets.

Language: Английский

Citations

70
Metabolic Reprogramming via ACOD1 depletion enhances function of human induced pluripotent stem cell-derived CAR-macrophages in solid tumors DOI Creative Commons
Xudong Wang, Siyu Su,

Yuqing Zhu

et al.

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

Published: Sept. 18, 2023

The pro-inflammatory state of macrophages, underpinned by their metabolic condition, is essentially affecting capacity combating tumor cells. Here we find, via a pooled gene knockout CRISPR screen that KEAP1 and ACOD1 are strong regulators the in macrophages. We show generated our induced pluripotent stem cell-derived CAR-macrophage (CAR-iMAC) platform, strongly persistently polarized toward state, which manifests increased reactive oxygen species (ROS) production, more potent phagocytosis enhanced cytotoxic functions against cancer cells vitro. In ovarian or pancreatic mouse models, ACOD1-depleted CAR-iMACs exhibit repressing tumors, leading to survival. addition, combining with immune checkpoint inhibitors (ICI), such as anti-CD47 anti-PD1 antibodies, result even stronger suppressing effect. Mechanistically, depletion reduces levels immuno-metabolite itaconate, allowing prevent NRF2 from entering nucleus activate an anti-inflammatory program. This study thus lays down proof principle for targeting myeloid immunotherapy introduces metabolically engineered human iPSC-derived polarization anti-tumor adoptive cell transfer therapies.

Language: Английский

Citations

64
Metabolic rewiring promotes anti-inflammatory effects of glucocorticoids DOI

Jean-Philippe Auger,

Max Zimmermann,

Maria M. Faas

et al.

Nature, Journal Year: 2024, Volume and Issue: 629(8010), P. 184 - 192

Published: April 10, 2024

Language: Английский

Citations

64
Dysregulation of metabolic pathways in pulmonary fibrosis DOI Creative Commons

Rishi Rajesh,

Reham Atallah, Thomas Bärnthaler

et al.

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 246, P. 108436 - 108436

Published: May 5, 2023

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder of unknown origin and the most common interstitial lung disease. It progresses with recruitment fibroblasts myofibroblasts that contribute to accumulation extracellular matrix (ECM) proteins, leading loss compliance alveolar integrity, compromising gas exchange capacity lung. Moreover, while there are therapeutics available, they do not offer cure. Thus, pressing need identify better therapeutic targets. With advent transcriptomics, proteomics, metabolomics, cellular mechanisms underlying disease progression understood. Metabolic homeostasis one such factor its dysregulation has been shown impact outcome IPF. Several metabolic pathways involved in metabolism lipids, protein carbohydrates have implicated While metabolites crucial for generation energy, it now appreciated several non-metabolic roles regulating processes as proliferation, signaling, death among other functions. Through this review, we succinctly elucidate role also discuss potential which target or pathways.

Language: Английский

Citations

52
Mitochondrial-derived vesicles in metabolism, disease, and aging DOI Creative Commons
Tim König, Heidi M. McBride

Cell Metabolism, Journal Year: 2024, Volume and Issue: 36(1), P. 21 - 35

Published: Jan. 1, 2024

Mitochondria are central hubs of cellular metabolism and tightly connected to signaling pathways. The dynamic plasticity mitochondria fuse, divide, contact other organelles flux metabolites is their function. To ensure bona fide functionality interconnectivity, diverse molecular mechanisms evolved. An ancient long-overlooked mechanism the generation mitochondrial-derived vesicles (MDVs) that shuttle selected mitochondrial cargoes target organelles. Just recently, we gained significant insight into functions MDV transport, ranging from role in quality control immune signaling, thus demonstrating unexpected physiological aspects transport. This review highlights origin MDVs, biogenesis, cargo selection, with a specific focus on contribution transport across cell organ barriers. Additionally, implications MDVs peroxisome neurodegeneration, metabolism, aging, cancer discussed.

Language: Английский

Citations

48