The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain DOI Creative Commons

Melanie Ohm,

Shirin Hosseini, Niklas Lonnemann

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: June 19, 2024

Abstract Despite advances in antimicrobial and anti-inflammatory treatment, inflammation its consequences remain a major challenge the field of medicine. Inflammatory reactions can lead to life-threatening conditions such as septic shock, while chronic has potential worsen condition body tissues ultimately significant impairment their functionality. Although central nervous system long been considered immune privileged peripheral responses, recent research shown that strong responses periphery also affect brain, leading reactive microglia, which belong innate reside neuroinflammation. The inflammatory response is primarily protective mechanism defend against pathogens tissue damage. However, excessive have negative effects on neuronal structure function. Neuroinflammation underlies pathogenesis many neurological neurodegenerative diseases accelerate progression. Consequently, targeting signaling pathways offers therapeutic strategies for various neuropathological conditions, particularly Parkinson’s Alzheimer’s disease, by curbing inflammation. Here blood-brain barrier strategies, therefore it would be highly advantageous foster utilize brain mechanisms. tricarboxylic acid cycle-derived metabolite itaconate upregulated activated macrophages act an immunomodulator with functions. Mesaconate, isomer itaconate, similarly reduces macrophages. Nevertheless, most studies focused esterified forms effects, influence CNS remained largely unexplored. Therefore, this study investigated immunomodulatory endogenously synthesized mesaconate lipopolysaccharide (LPS)-induced neuroinflammatory processes. Our results show both reduce LPS-induced neuroinflammation, evidenced lower levels mediators, reduced microglial reactivity rescue synaptic plasticity, cellular correlate learning memory processes brain. Overall, emphasizes are remarkable importance due endogenous origin production, usually leads high tolerance.

Language: Английский

The gasdermin family: emerging therapeutic targets in diseases DOI Creative Commons
Cheng‐long Zhu, Sheng Xu, Ruoyu Jiang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 7, 2024

Abstract The gasdermin (GSDM) family has garnered significant attention for its pivotal role in immunity and disease as a key player pyroptosis. This recently characterized class of pore-forming effector proteins is orchestrating processes such membrane permeabilization, pyroptosis, the follow-up inflammatory response, which are crucial self-defense mechanisms against irritants infections. GSDMs have been implicated range diseases including, but not limited to, sepsis, viral infections, cancer, either through involvement pyroptosis or independently this process. regulation GSDM-mediated gaining recognition promising therapeutic strategy treatment various diseases. Current strategies inhibiting GSDMD primarily involve binding to GSDMD, blocking cleavage GSDMD-N-terminal (NT) oligomerization, albeit with some off-target effects. In review, we delve into cutting-edge understanding interplay between elucidate activation GSDMs, explore their associations diseases, discuss recent advancements potential developing inhibitors.

Language: Английский

Citations

24
Control of immune cell signaling by the immuno-metabolite itaconate DOI Creative Commons
Roland Lang, Md Nur A Alam Siddique

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Feb. 28, 2024

Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell’s metabolic activity provide energy and biomolecules for inflammatory proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns cytokines upregulate expression of enzyme ACOD1 that generates immune-metabolite itaconate decarboxylation TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well immunomodulatory activities, which makes it attractive endogenous effector fighting infection restraining inflammation. Here, we first summarize pathways stimuli inducing in macrophages. The focus review then lies mechanisms itaconate, its synthetic derivatives isomers, modulate immune pathways. Multiple targets have been revealed, from inhibition enzymes post-translational modification many proteins at cysteine or lysine residues. modulation like STING, SYK, JAK1, RIPK3 KEAP1, transcription regulators (e.g. Tet2, TFEB) inflammasome components (NLRP3, GSDMD) provides a biochemical basis immune-regulatory effects ACOD1-itaconate pathway. While field intensely studied control macrophages inflammation models, neutrophils now entered scene producers cellular itaconate. Furthermore, regulation adaptive responses exogenously added derivatives, can be mediated direct indirect T cells antigen-presenting cells, respectively. Taken together, research date revealed relevance diverse pathways, opportunities potential therapeutic preventive manipulation host defense

Language: Английский

Citations

11
LL-37 improves sepsis-induced acute lung injury by suppressing pyroptosis in alveolar epithelial cells DOI
Quanzhen Wang, Wei Wen,

Lei Zhou

et al.

International Immunopharmacology, Journal Year: 2024, Volume and Issue: 129, P. 111580 - 111580

Published: Feb. 3, 2024

Language: Английский

Citations

9
The absence of IRG1 exacerbates bone loss in a mouse model of ovariectomy‐induced osteoporosis by increasing osteoclastogenesis through the potentiation of NLRP3 inflammasome activation DOI
Fang Wang,

Yanqiao Liu,

Yanqin Zhao

et al.

International Immunopharmacology, Journal Year: 2025, Volume and Issue: 148, P. 114099 - 114099

Published: Jan. 26, 2025

Language: Английский

Citations

1
Bhlhe40 deficiency attenuates LPS-induced acute lung injury through preventing macrophage pyroptosis DOI Creative Commons
Xingxing Hu, Menglin Zou, Weishuai Zheng

et al.

Respiratory Research, Journal Year: 2024, Volume and Issue: 25(1)

Published: Feb. 24, 2024

Abstract Background Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) as common life-threatening diseases with high mortality rates are mostly associated inflammation in lungs. Recently, increasing evidence supports activated gasdermin D (GSDMD)-mediated pyroptosis macrophage closely ALI. Basic helix-loop-helix family member e40 (Bhlhe40) is a transcription factor that comprehensively involved inflammation. However, there little experimental connecting Bhlhe40 GSDMD-driven pyroptosis. The study sought to verify the hypothesis required for GSDMD-mediated lipopolysaccharide (LPS)-induced inflammatory injury. Method We performed studies using -knockout ( −/− ) mice, small interfering RNA (siRNA) targeting inhibitor disulfiram investigate potential roles of on LPS-induced ALI underlying mechanisms. Results was highly expressed total tissues macrophages mice. mice showed alleviative pathological response upon LPS stimulation. Meanwhile, we found deficiency significantly suppressed vivo vitro. By further mechanistic analysis, demonstrated inhibited subsequent by repressing canonical (caspase-1-mediated) non-canonical (caspase-11-mediated) signaling pathways Conclusion These results indicate can inhibit therefore alleviate Targeting may be therapeutic strategy

Language: Английский

Citations

7
Role and mechanisms of autophagy, ferroptosis, and pyroptosis in sepsis-induced acute lung injury DOI Creative Commons

Yao Shen,

Yingying He, Ying Pan

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: Aug. 5, 2024

Sepsis-induced acute lung injury (ALI) is a major cause of death among patients with sepsis in intensive care units. By analyzing model sepsis-induced ALI using lipopolysaccharide (LPS) and cecal ligation puncture (CLP), treatment methods strategies to protect against were discussed, which could provide an experimental basis for the clinical ALI. Recent studies have found that imbalance autophagy, ferroptosis, pyroptosis key mechanism triggers ALI, regulating these mechanisms can improve injuries caused by LPS or CLP. This article summarized reviewed regulatory networks their important roles process LPS/CLP-induced sepsis, discusses possible targeted drugs above effects, describes dilemma prospects, provides new perspectives future

Language: Английский

Citations

6
The potential therapeutic role of itaconate and mesaconate on the detrimental effects of LPS-induced neuroinflammation in the brain DOI Creative Commons

Melanie Ohm,

Shirin Hosseini, Niklas Lonnemann

et al.

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Aug. 20, 2024

Despite advances in antimicrobial and anti-inflammatory treatment, inflammation its consequences remain a major challenge the field of medicine. Inflammatory reactions can lead to life-threatening conditions such as septic shock, while chronic has potential worsen condition body tissues ultimately significant impairment their functionality. Although central nervous system long been considered immune privileged peripheral responses, recent research shown that strong responses periphery also affect brain, leading reactive microglia, which belong innate reside neuroinflammation. The inflammatory response is primarily protective mechanism defend against pathogens tissue damage. However, excessive have negative effects on neuronal structure function. Neuroinflammation underlies pathogenesis many neurological neurodegenerative diseases accelerate progression. Consequently, targeting signaling pathways offers therapeutic strategies for various neuropathological conditions, particularly Parkinson's Alzheimer's disease, by curbing inflammation. Here blood-brain barrier hurdle strategies, therefore it would be highly advantageous foster utilize brain mechanisms. tricarboxylic acid cycle-derived metabolite itaconate upregulated activated macrophages act an immunomodulator with functions. Mesaconate, isomer itaconate, similarly reduces macrophages. Nevertheless, most studies focused esterified forms effects, influence CNS remained largely unexplored. Therefore, this study investigated immunomodulatory endogenously synthesized mesaconate lipopolysaccharide (LPS)-induced neuroinflammatory processes. Our results show both reduce LPS-induced neuroinflammation, evidenced lower levels mediators, reduced microglial reactivity rescue synaptic plasticity, cellular correlate learning memory processes brain. Overall, emphasizes are remarkable importance due endogenous origin production, usually leads high tolerance.

Language: Английский

Citations

5
Preclinical insights into the potential of itaconate and its derivatives for liver disease therapy DOI
Xiaodong Wu, Yanhong Song, Zhengwei Yuan

et al.

Metabolism, Journal Year: 2025, Volume and Issue: unknown, P. 156152 - 156152

Published: Feb. 1, 2025

Language: Английский

Citations

0
Elevated GFI1 in Alveolar Macrophages Suppresses ACOD1 Expression and Exacerbates Lipopolysaccharide‐Induced Lung Injury in Obesity DOI Creative Commons
Jingyue Ma,

Yichan Ao,

Zhen Yue

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

To investigate the mechanisms behind worsening of acute lung injury (ALI) in obesity, transcriptomic sequencing is performed, and significantly reduced mRNA levels Aconitate Decarboxylase 1 (ACOD1) tissue high-fat diet (HFD) mice are found. Clinical samples collected, an ALI model established HFD mice, both human mouse analyzed, revealing a significant decrease ACOD1 expression alveolar macrophages obesity. Further vivo vitro experiments show that knockdown worsens injury, inflammation, oxidative stress, while overexpression alleviates these effects. Moreover, nuclear factor erythroid 2-related 2 (Nrf2) inhibition diminishes protective effects exacerbated by Additionally, context growth independent (GFI1) protein elevated macrophages, its leads to upregulated expression. Therefore, this study suggests downregulation key likely driven GFI1 upregulation.

Language: Английский

Citations

0
Integrated multi-omics analyses reveal the pro-inflammatory and pro-fibrotic pulmonary macrophage subcluster in silicosis DOI Creative Commons

Hanyujie Kang,

Xueqing Gu,

Siyu Cao

et al.

Ecotoxicology and Environmental Safety, Journal Year: 2024, Volume and Issue: 284, P. 116899 - 116899

Published: Aug. 23, 2024

Silicosis is a lethal occupational disease caused by long-term exposure to respirable silica dust. Pulmonary macrophages play crucial role in mediating the initiation of silicosis. However, phenotypic and functional heterogeneities pulmonary silicosis have not been well-studied.

Language: Английский

Citations

2