Elevated Pro-Inflammatory Cell-Free MicroRNA Levels in Cerebrospinal Fluid of Premature Infants after Intraventricular Hemorrhage

Fejes, Zsolt; Erdei, J.; Pócsi, Marianna; Takai, Jun; Jeney, Viktória; Nagy, Andrea; Varga, Alíz; Bácsi, Attila; Bognár, László; Novák, László; Kappelmayer, János; Nagy, Béla

doi:10.3390/ijms21186870

Cited by 14 publications

(21 citation statements)

References 51 publications

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“…Since miR-155 plays a wide range of regulatory roles in immune cells, it is not surprising that miR-155 is closely involved in the regulation of inflammatory disorders. Recently, it is reported that the hemorrhage-induced cerebrospinal fluid miR-155 is expected to be a biomarker of intraventricular hemorrhage in premature infants as miR-155 effectively reflected inflammatory conditions [ 56 ]. miR-155 is also closely related to the regulation of autoimmune diseases, such as rheumatoid arthritis (RA) [ 57 ], systemic lupus erythematosus (SLE) [ 58 ], and experimental autoimmune encephalomyelitis (EAE) [ 59 ].…”

Section: The Role Of Mir-155 In Sepsismentioning

confidence: 99%

MicroRNA-155: Regulation of Immune Cells in Sepsis

Chen

Wang

Xia

et al. 2021

Mediators of Inflammation

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MicroRNAs are small noncoding RNAs which regulate gene expression at the posttranscriptional level. miR-155 is encoded by the miR-155 host gene (miR155HG), also known as the noncoding B cell integration cluster (BIC). MicroRNAs are widely expressed in various hematopoietic cells and are involved in regulating the immune system. In this review, we summarized how miR-155 modulates specific immune cells and the regulatory role of miR-155 in sepsis. miR-155 is expressed by different populations of innate and adaptive immune cells and is involved in the regulation of development, proliferation, and function in these cells. Sepsis is associated with uncontrollable inflammatory responses, accompanied by unacceptably high mortality. Due to the inadequacy of diagnostic markers as well as treatment strategies, treating sepsis can be a huge challenge. So far, a large number of experiments have shown that the expression of miR-155 is increased at an early stage of sepsis and that this increase is positively correlated with disease progression and severity. In addition, by blocking the proinflammatory effects of miR-155, it can effectively improve sepsis-related organ injury, providing novel insights to identify potential biomarkers and therapeutic targets for sepsis. However, since most of the current research is limited to animal experiments, further clinical research is required to determine the function of miR-155 and its mechanism related to sepsis.

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Section: The Role Of Mir-155 In Sepsismentioning

confidence: 99%

MicroRNA-155: Regulation of Immune Cells in Sepsis

Chen

Wang

Xia

et al. 2021

Mediators of Inflammation

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“…Subsequently, changes in specific miRs within exosomes in cerebrospinal fluid (CSF) following post-hemorrhagic hydrocephalus have been shown (Spaull et al, 2019). Proinflammatory miRs have also been found to correlate with oxidized hemoglobin metabolites and heme in CSF after intraventricular hemorrhage (Fejes et al, 2020). Additionally, miRs have been widely studied in hypoxic-ischemic encephalopathy in term neonates, in serum, dried blood spots and whole blood, as potential biomarkers of injury severity (Ponnusamy et al, 2016;Wang et al, 2018;Zhang et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Intrauterine Growth Restriction Followed by Oxygen Support Uniquely Interferes with Genetic Regulators of Myelination

Chang

Lurie

Sharma

et al. 2021

eNeuro

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Intrauterine growth restriction (IUGR) and oxygen exposure in isolation and combination adversely affect the developing brain, putting infants at risk for neurodevelopmental disability including cerebral palsy. Rodent models of IUGR and postnatal hyperoxia have demonstrated oligodendroglial injury with subsequent white matter injury (WMI) and motor dysfunction. Here we investigate transcriptomic dysregulation in IUGR with and without hyperoxia exposure to account for the abnormal brain structure and function previously documented. We performed RNA sequencing and analysis using a mouse model of IUGR and found that IUGR, hyperoxia, and the combination of IUGR with hyperoxia (IUGR/hyperoxia) produced distinct changes in gene expression. IUGR in isolation demonstrated the fewest differentially expressed genes compared to control. In contrast, we detected several gene alterations in IUGR/hyperoxia; genes involved in myelination were strikingly downregulated. We also identified changes to specific regulators including TCF7L2, BDNF, SOX2, and DGCR8, through Ingenuity Pathway Analysis, that may contribute to impaired myelination in IUGR/hyperoxia. Our findings show that IUGR with hyperoxia induces unique transcriptional changes in the developing brain. These indicate mechanisms for increased risk for WMI in IUGR infants exposed to oxygen and suggest potential therapeutic targets to improve motor outcomes. Significance StatementThis study demonstrates that perinatal exposures of IUGR and/or postnatal hyperoxia result in distinct transcriptomic changes in the developing brain. In particular, we found that genes involved in normal developmental myelination, myelin maintenance, and remyelination were most dysregulated when IUGR was combined with hyperoxia. Understanding how multiple risk factors lead to WMI is the first step in developing future therapeutic interventions. Additionally, because oxygen exposure is often unavoidable after birth, an understanding of gene perturbations in this setting will increase our awareness of the need for tight control of oxygen use to minimize future motor disability.

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“…Mean ± SEM are depicted. Dotted lines depict the mean value of the particular parameter measured in preterm non-IVH control samples [23]. Mean total heme was as low as 0.8 µmol/L and free heme was practically undetectable in the control samples, and this is why the dotted lines cannot be recognized in parts C and D. To compare the data of the two groups, the Mann-Whitney U test or unpaired t-test was applied.…”

Section: Sustained Elevation In Soluble Pro-inflammatory Protein Markers In the Csf After Ivh-ivmentioning

confidence: 99%

“…Increased CSF miR-21 and miR-221 levels have been linked to delayed cerebral ischemia (DCI) in adults with a subarachnoid hemorrhage (SAH) [21], while reduced miR-152 showed anti-inflammatory properties after intracerebral hemorrhage [22]. Our group has recently investigated the expression of some pro-inflammatory miRNAs in CSF specimens of preterm infants after IVH as potential prognostic biomarkers [23].…”

Section: Introductionmentioning

confidence: 99%

Preterm Intraventricular Hemorrhage-Induced Inflammatory Response in Human Choroid Plexus Epithelial Cells

Fejes

Pócsi

Takai

et al. 2021

IJMS

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Following an intraventricular hemorrhage (IVH), red blood cell lysis and hemoglobin (Hb) oxidation with the release of heme can cause sterile neuroinflammation. In this study, we measured Hb derivates and cellular adhesion molecules ICAM-1 and VCAM-1 with cell-free miRNAs in cerebrospinal fluid (CSF) samples obtained from Grade-III and Grade-IV preterm IVH infants (IVH-III and IVH-IV, respectively) at multiple time points between days 0–60 after the onset of IVH. Furthermore, human choroid plexus epithelial cells (HCPEpiCs) were incubated with IVH and non-IVH CSF (10 v/v %) for 24 h in vitro to investigate the IVH-induced inflammatory response that was investigated via: (i) HMOX1, IL8, VCAM1, and ICAM1 mRNAs as well as miR-155, miR-223, and miR-181b levels by RT-qPCR; (ii) nuclear translocation of the NF-κB p65 subunit by fluorescence microscopy; and (iii) reactive oxygen species (ROS) measurement. We found a time-dependent alteration of heme, IL-8, and adhesion molecules which revealed a prolonged elevation in IVH-IV vs. IVH-III with higher miR-155 and miR-181b expression at days 41–60. Exposure of HCPEpiCs to IVH CSF samples induced HMOX1, IL8, and ICAM1 mRNA levels along with increased ROS production via the NF-κB pathway activation but without cell death, as confirmed by the cell viability assay. Additionally, the enhanced intracellular miR-155 level was accompanied by lower miR-223 and miR-181b expression in HCPEpiCs after CSF treatment. Overall, choroid plexus epithelial cells exhibit an abnormal cell phenotype after interaction with pro-inflammatory CSF of IVH origin which may contribute to the development of later clinical complications in preterm IVH.

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Elevated Pro-Inflammatory Cell-Free MicroRNA Levels in Cerebrospinal Fluid of Premature Infants after Intraventricular Hemorrhage

Cited by 14 publications

References 51 publications

MicroRNA-155: Regulation of Immune Cells in Sepsis

MicroRNA-155: Regulation of Immune Cells in Sepsis

Intrauterine Growth Restriction Followed by Oxygen Support Uniquely Interferes with Genetic Regulators of Myelination

Preterm Intraventricular Hemorrhage-Induced Inflammatory Response in Human Choroid Plexus Epithelial Cells

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