The Role of Metaflammation in the Development of Senescence-Associated Secretory Phenotype and Cognitive Dysfunction in Aging Mice

Хилажева, Е. Д.; Belozor, Оlga S.; Panina, Yu. A.; Gorina, Ya. V.; Mosyagina, A. I.; Vasiliev, A. V.; Malinovskaya, N. A.; Kоmleva, Yu. K.

doi:10.1134/s0022093022050222

Cited by 4 publications

(1 citation statement)

References 43 publications

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“…However, while infectious triggers of the immune system -outside the current SARS-CoV-2 pandemic -have diminished 1 , chronic, low-grade in ammation is increasingly present in contemporary Western societies. This subclinical in ammatory process (also called 'meta ammation') is thought to be causally linked to the development of many non-communicable diseases such as atherosclerosis, obesity, type II diabetes and even cancer or neurodegeneration in the ageing modern society [2][3][4][5] .…”

Section: Introductionmentioning

confidence: 99%

Sphingomyelin d18:1/14:0 activates TLR4 in metaflammation

Latz

Gorki

Dohnalová

et al. 2023

Preprint

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Chronic low-grade inflammation, also called metaflammation, is associated with prevalent non-communicable diseases, such as atherosclerosis. Anti-inflammatory therapy provides a clinical benefit in patients, but the triggers that incite metaflammation remain largely unknown. To uncover non-genetic inflammatory factors influencing atherosclerosis severity, we performed an unbiased in vivo screen measuring thousands of host- and microbe-derived molecules in a mouse model of atherosclerosis. Machine learning-supported analyses identified, next to known pro- and anti-atherogenic factors, the medium fatty acid-chain sphingomyelin d18:1/14:0 (S14) as highly positively associated with atherogenesis. S14 activated macrophage innate immune signalling, immune-metabolic reprogramming and pro-inflammatory gene transcription. The inflammatory activity of S14 was TLR4- and MD-2-dependent, consistent with biochemical and molecular dynamics simulation analyses showing that S14 promoted the formation of active TLR4/MD-2 dimers. Human interventional and observational trials demonstrated that dietary changes altered concentrations of S14 and that increased circulating S14 was associated with carotid plaque development in obese individuals. Collectively, these findings identify an inducible endogenous ligand for TLR4 that drives metaflammation, providing the rationale for preventative approaches and pharmacological interventions that may curb detrimental inflammation secondary to Western-type lifestyle habits.

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Section: Introductionmentioning

confidence: 99%

Sphingomyelin d18:1/14:0 activates TLR4 in metaflammation

Latz

Gorki

Dohnalová

et al. 2023

Preprint

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Simvastatin-Loaded Polymeric Nanoparticles: Targeting Inflammatory Macrophages for Local Adipose Tissue Browning in Obesity Treatment

Mohaghegh,

Ahari,

Buttles

et al. 2024

ACS Nano

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Obesity is defined as chronic, low-grade inflammation within specific tissues. Given the escalating prevalence of obesity among individuals of all ages, obesity has reached epidemic proportions, posing an important public health challenge. Despite significant advancements in treating obesity, conventional approaches remain largely ineffective or involve severe side effects, thus underscoring the pressing need to explore and develop treatment approaches. Targeted and local immunomodulation using nanoparticles (NPs) can influence fat production and utilization processes. Statins, known for their anti-inflammatory properties, show the potential for mitigating obesity-related inflammation. A localized delivery option offers several advantages over oral and parenteral delivery methods. Here, we developed simvastatin (Sim) encapsulated within PLGA NPs (Sim-NP) for localized delivery of Sim to adipose tissues (ATs) for immunomodulation to treat obesity. In vitro experiments revealed the strong anti-inflammatory effects of Sim-NPs, which resulted in enhanced modulation of macrophage (MΦ) polarization and induction of AT browning. We then extended our investigation to an in vivo mouse model of high-fat-diet (HFD)-induced obesity. Sim-NP administration led to the controlled release of Sim within AT, directly impacting MΦ activity and inducing AT browning while inducing weight loss. Our findings demonstrated that Sim-NP administration effectively inhibited the progression of obesity-related inflammation, controlled white fat production, and enhanced AT modulation. These results highlight the potential of Sim-NP as a potent nanotherapy for treating obesity by modulating the immune system.

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