The cell-free DNA (cfDNA) is always present in plasma, and it is biomarker of growing interest in prenatal diagnostics as well as in oncology and transplantology for therapy efficiency monitoring. But does this cfDNA have a physiological role? Here we show that cfDNA presence and clearance in plasma of healthy individuals plays an indispensable role in immune system regulation. We exposed THP1 cells to healthy individuals' plasma with (NP) and without (TP) cfDNA. In cells treated with NP, we found elevated expression of genes whose products maintain immune system homeostasis. Exposure of cells to TP triggered an innate immune response (IIR), documented particularly by elevated expression of pro-inflammatory interleukin 8. The results of mass spectrometry showed a higher abundance of proteins associated with IIR activation due to the regulation of complement cascade in cells cultivated with TP. These expression profiles provide evidence that the presence of cfDNA and its clearance in plasma of healthy individuals regulate fundamental mechanisms of the inflammation process and tissue homeostasis. The detailed understanding how neutrophil extracellular traps and their naturally occurring degradation products affect the performance of immune system is of crucial interest for future medical applications.
- MeSH
- biologické markery krev MeSH
- chromatografie kapalinová MeSH
- dospělí MeSH
- extracelulární pasti imunologie MeSH
- hmotnostní spektrometrie MeSH
- krevní plazma MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- monocyty imunologie MeSH
- přirozená imunita * MeSH
- sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
- tandemová hmotnostní spektrometrie MeSH
- THP-1 buňky MeSH
- volné cirkulující nukleové kyseliny krev MeSH
- zánět MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Deficiency of fatty acid translocase Cd36 has been shown to have a major role in the pathogenesis of metabolic syndrome in the spontaneously hypertensive rat (SHR). We have tested the hypothesis that the effects of Cd36 mutation on the features of metabolic syndrome are contextually dependent on genomic background. We have derived two new congenic strains by introgression of limited chromosome 4 regions of SHR origin, both including the defective Cd36 gene, into the genetic background of a highly inbred model of insulin resistance and dyslipidemia, polydactylous (PD) rat strain. We subjected standard diet-fed adult males of PD and the congenic PD.SHR4 strains to metabolic, morphometric and transcriptomic profiling. We observed significantly improved glucose tolerance and lower fasting insulin levels in PD.SHR4 congenics than in PD. One of the PD.SHR4 strains showed lower triglyceride concentrations across major lipoprotein fractions combined with higher levels of low-density lipoprotein cholesterol compared with the PD progenitor. The hepatic transcriptome assessment revealed a network of genes differentially expressed between PD and PD.SHR4 with significant enrichment by members of the circadian rhythmicity pathway (Arntl (Bmal1), Clock, Nfil3, Per2 and Per3). In summary, the introduction of the chromosome 4 region of SHR origin including defective Cd36 into the PD genetic background resulted in disconnected shifts of metabolic profile along with distinct changes in hepatic transcriptome. The synthesis of the current results with those obtained in other Cd36-deficient strains indicates that the eventual metabolic effect of a deleterious mutation such as that of SHR-derived Cd36 is not absolute, but rather a function of complex interactions between environmental and genomic background, upon which it operates.
- MeSH
- antigeny CD36 genetika metabolismus MeSH
- genom MeSH
- glukosa genetika metabolismus MeSH
- glukózový toleranční test MeSH
- játra metabolismus MeSH
- krysa rodu rattus MeSH
- modely u zvířat MeSH
- potkani inbrední SHR genetika MeSH
- transkriptom MeSH
- zvířata kongenní genetika MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- antigeny CD36 genetika MeSH
- hypertriglyceridemie farmakoterapie MeSH
- porucha glukózové tolerance terapie MeSH
- thiazoly terapeutické užití MeSH
- tuková tkáň metabolismus účinky léků MeSH
- tukové buňky metabolismus účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- aglutinační testy MeSH
- bércové vředy etiologie MeSH
- fibrinogen krev MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- MeSH
- imunoterapie MeSH
- kožní nemoci farmakoterapie imunologie MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- lichen planus MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- autoimunitní nemoci MeSH
- teoretické modely MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- recenze MeSH
- MeSH
- lidé MeSH
- RNA-viry enzymologie ultrastruktura MeSH
- syndromy imunologické nedostatečnosti etiologie patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
