Extracellular Inflammasome Particles Are Released After Marathon Running and Induce Proinflammatory Effects in Endothelial Cells

Kögel, Alexander; Fikenzer, Sven; Uhlmann, Luisa; Opitz, Lena; Kneuer, Jasmin M; Hæusler, Karl Georg; Endres, Matthias; Kratzsch, Jürgen; Schwarz, Viktoria; Werner, Christian; Gaul, Susanne; Laufs, Ulrich

doi:10.3389/fphys.2022.866938

Cited by 5 publications

(2 citation statements)

References 59 publications

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“…Interestingly, several studies have shown a correlation between high-intensity/-volume exercise and arterial calcification [ 25 ]. Additionally, (i) marathon runners experience NLRP3 inflammasome-related vascular inflammation [ 26 ], in which UCP1 expression may play a role [ 27 ], and (ii) a strong correlation between the upregulation of acute phase proteins and performing world-class/Olympic sports has been found [ 28 ]. These findings may contribute to a potential explanation for a higher prevalence of arterial calcification in elite athletes.…”

Section: Discussionmentioning

confidence: 99%

A Proteomic Screen to Unravel the Molecular Pathways Associated with Warfarin-Induced or TNAP-Inhibited Arterial Calcification in Rats

Opdebeeck

Neven

Maudsley

et al. 2023

IJMS

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Arterial media calcification refers to the pathological deposition of calcium phosphate crystals in the arterial wall. This pathology is a common and life-threatening complication in chronic kidney disease, diabetes and osteoporosis patients. Recently, we reported that the use of a TNAP inhibitor, SBI-425, attenuated arterial media calcification in a warfarin rat model. Employing a high-dimensionality unbiased proteomic approach, we also investigated the molecular signaling events associated with blocking arterial calcification through SBI-425 dosing. The remedial actions of SBI-425 were strongly associated with (i) a significant downregulation of inflammatory (acute phase response signaling) and steroid/glucose nuclear receptor signaling (LXR/RXR signaling) pathways and (ii) an upregulation of mitochondrial metabolic pathways (TCA cycle II and Fatty Acid β-oxidation I). Interestingly, we previously demonstrated that uremic toxin-induced arterial calcification contributes to the activation of the acute phase response signaling pathway. Therefore, both studies suggest a strong link between acute phase response signaling and arterial calcification across different conditions. The identification of therapeutic targets in these molecular signaling pathways may pave the way to novel therapies against the development of arterial media calcification.

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Section: Discussionmentioning

confidence: 99%

A Proteomic Screen to Unravel the Molecular Pathways Associated with Warfarin-Induced or TNAP-Inhibited Arterial Calcification in Rats

Opdebeeck

Neven

Maudsley

et al. 2023

IJMS

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“…Additionally, ASC specks are detected in the extracellular environment ( 229 , 265 ) in pathological conditions such as brain injury ( 266 , 267 ), recurrent ischemic stroke ( 268 ), and Alzheimer’s disease ( 269 , 270 ). These extracellular ASC specks may activate extracellular caspase-1 that has been released from provoked cells or intracellular caspase-1 in other recipient cells ( 71 , 271 , 272 ) following the internalization and release of specks from endosomes, facilitating IL-1β maturation and/or GSDMD processing ( 228 , 273 ), or nucleate other proteins such as Amyloid-β ( 274 – 276 ) for disease progression. A recent study also provides evidence of the role of post-pyroptotic extracellular ASC specks in MSU induced-gouty arthritis and antigen-induced arthritis, in which nanobodies against mouse ASC could ameliorates inflammation ( 71 ).…”

Section: Events Upstream Of Pyroptosis and Cytokine Secretion In Infl...mentioning

confidence: 99%

Uncoupled pyroptosis and IL-1β secretion downstream of inflammasome signaling

Jiang

2023

Front. Immunol.

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Inflammasomes are supramolecular platforms that organize in response to various damage-associated molecular patterns and pathogen-associated molecular patterns. Upon activation, inflammasome sensors (with or without the help of ASC) activate caspase-1 and other inflammatory caspases that cleave gasdermin D and pro-IL-1β/pro-IL-18, leading to pyroptosis and mature cytokine secretion. Pyroptosis enables intracellular pathogen niche disruption and intracellular content release at the cost of cell death, inducing pro-inflammatory responses in the neighboring cells. IL-1β is a potent pro-inflammatory regulator for neutrophil recruitment, macrophage activation, and T-cell expansion. Thus, pyroptosis and cytokine secretion are the two main mechanisms that occur downstream of inflammasome signaling; they maintain homeostasis, drive the innate immune response, and shape adaptive immunity. This review aims to discuss the possible mechanisms, timing, consequences, and significance of the two uncoupling preferences downstream of inflammasome signaling. While pyroptosis and cytokine secretion may be usually coupled, pyroptosis-predominant and cytokine-predominant uncoupling are also observed in a stimulus-, cell type-, or context-dependent manner, contributing to the pathogenesis and development of numerous pathological conditions such as cryopyrin-associated periodic syndromes, LPS-induced sepsis, and Salmonella enterica serovar Typhimurium infection. Hyperactive cells consistently release IL-1β without LDH leakage and pyroptotic death, thereby leading to prolonged inflammation, expanding the lifespans of pyroptosis-resistant neutrophils, and hyperactivating stimuli-challenged macrophages, dendritic cells, monocytes, and specific nonimmune cells. Death inflammasome activation also induces GSDMD-mediated pyroptosis with no IL-1β secretion, which may increase lethality in vivo. The sublytic GSDMD pore formation associated with lower expressions of pyroptotic components, GSDMD-mediated extracellular vesicles, or other GSDMD-independent pathways that involve unconventional secretion could contribute to the cytokine-predominant uncoupling; the regulation of caspase-1 dynamics, which may generate various active species with different activities in terms of GSDMD or pro-IL-1β, could lead to pyroptosis-predominant uncoupling. These uncoupling preferences enable precise reactions to different stimuli of different intensities under specific conditions at the single-cell level, promoting cooperative cell and host fate decisions and participating in the pathogen “game”. Appropriate decisions in terms of coupling and uncoupling are required to heal tissues and eliminate threats, and further studies exploring the inflammasome tilt toward pyroptosis or cytokine secretion may be helpful.

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Exerkines mitigating Alzheimer's disease progression by regulating inflammation: Focusing on macrophage/microglial NLRP3 inflammasome pathway

Cheon,

Kwon,

Kim

2024

Alzheimer's & Dementia

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Recent research highlights the critical role of inflammation in accelerating amyloid beta and phosphorylated tubulin‐associated protein tau cascade and Alzheimer's disease (AD) progression. Emerging evidence suggests that exercise influences AD by modulating inflammatory responses. We conducted a comprehensive search across multiple online databases. Our approach focused on previous and recent studies exploring the links among inflammation, AD, and the effects of exercise, specifically targeting research articles and books published in English. We pointed out that inflammation extends from the periphery to the central nervous system, facilitated by macrophage/microglial NLRP3 (nucleotide‐binding domain, leucine rich–containing family, pyrin domain–containing protein 3) inflammasome signaling, which exacerbates classical AD mechanisms. Moreover, we provided further insights into the modulation of inflammasome signaling through exercise and exerkines, which may contribute to mitigating AD development. These insights deepen our understanding of AD mechanisms and offer the potential for identifying key therapeutic targets and biomarkers crucial for effective disease management and treatment.Highlights Inflammation is potentially linked to the acceleration of classical Alzheimer's disease (AD) pathogenesis, including the pathways involving amyloid beta and phosphorylated tau, mediated by pro‐inflammatory cytokines. Inflammation, initiated by the nucleotide‐binding domain, leucine rich–containing family, pyrin domain–containing protein 3 (NLRP3) inflammasome signaling pathway within M1‐type macrophages/microglia, may contribute to neuroinflammation and AD progression. Exercise has the potential to reduce inflammation and the development of AD by influencing NLRP3 inflammasome signaling via exerkines.

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Extracellular Inflammasome Particles Are Released After Marathon Running and Induce Proinflammatory Effects in Endothelial Cells

Cited by 5 publications

References 59 publications

A Proteomic Screen to Unravel the Molecular Pathways Associated with Warfarin-Induced or TNAP-Inhibited Arterial Calcification in Rats

A Proteomic Screen to Unravel the Molecular Pathways Associated with Warfarin-Induced or TNAP-Inhibited Arterial Calcification in Rats

Uncoupled pyroptosis and IL-1β secretion downstream of inflammasome signaling

Exerkines mitigating Alzheimer's disease progression by regulating inflammation: Focusing on macrophage/microglial NLRP3 inflammasome pathway

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