Immunobiology
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YKL-40, derived from the CHI3L1 gene, has been associated with outcome of infectious and inflammatory diseases. We hypothesized that plasma YKL-40 concentrations and CHI3L1 genotype could be used as prognostic biomarkers in the assessment of systemic inflammatory response syndrome (SIRS) and sepsis. The objective of the study was to assess the prognostic value of plasma YKL-40 and CHI3L1 genotype in patients with SIRS and sepsis. ⋯ CHI3L1 minor allele homozygosity was associated with low plasma YKL-40 at time of admission (p=0.002) and no variation (p=0.462) in concentrations throughout the first 14 days in the ICU, but this was not associated with better survival. In conclusion patients with SIRS and sepsis, plasma YKL-40 ≤505ng/ml at time of ICU admission was associated with better survival. However, this association was not observed for patients homozygous for the low expressing YKL-40 CHI3L1 allele.
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To examine the effect of downregulation of high mobility group box 1 (HMGB1) on severe acute pancreatitis (SAP) associated with acute lung injury (ALI), and its subsequent effect on disease severity. ⋯ These results demonstrate that HMGB1 could augment Inflammation by inducing nuclear translocation of NF-κB, thus aggratating the severity of SAP associated with ALI.
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Dark Agouti (DA) rats are highly susceptible to induction of experimental autoimmune encephalomyelitis (EAE), still they completely recover from the disease. Here, we were interested to determine contribution of major anti-inflammatory cytokines transforming growth factor (TGF)-β and interleukin (IL)-10 to the recovery of DA rats from EAE. To that extent we determined CNS expression of these cytokines in DA rats at different phases of EAE and compared data to those obtained in EAE-resistant Albino Oxford (AO) rats. ⋯ Thus, we next explored effects of IL-10 on astrocytes, glial cells that largely contribute to control of CNS inflammation. IL-10 stimulated astrocytic expression of an important regulator of neuroinflammation, CXCL12. Thus, IL-10 might contribute to recovery of DA rats from EAE through induction of CXCL12 expression in astrocytes.
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Sepsis is still a major burden for our society with high incidence of morbidity and mortality each year. Molecular mechanisms underlying the systemic inflammatory response syndrome (SIRS) associated with sepsis are still ill defined and most therapies developed to target the acute inflammatory component of the disease are insufficient. Recently the role of nuclear receptors (NRs) became a major topic of interest in transcriptional regulation of inflammatory processes. ⋯ In contrast, mice deficient for the nuclear receptor NR4A1 exhibited an exacerbated innate immune response, and showed a significantly higher mortality after lethal endotoxemic challenge. This dramatic phenotype could be restored in ISG12/NR4A1 double deficient mice. We conclude from our data in vitro and in vivo that ISG12 is a novel modulator of innate immune responses regulating anti-inflammatory nuclear receptors such as NR4A1.
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The methylmalonic acidemia is an inborn error of metabolism (IEM) characterized by methylmalonic acid (MMA) accumulation in body fluids and tissues, causing neurological dysfunction, mitochondrial failure and oxidative stress. Although neurological evidence demonstrate that infection and/or inflammation mediators facilitate metabolic crises in patients, the involvement of neuroinflammatory processes in the neuropathology of this organic acidemia is not yet established. In this experimental study, we used newborn Wistar rats to induce a model of chronic acidemia via subcutaneous injections of methylmalonate (MMA, from 5th to 28th day of life, twice a day, ranged from 0.72 to 1.67 μmol/g as a function of animal age). ⋯ Concomitantly, MMA increased levels of IL-1β, TNF-α, and expression of iNOS and 3-NT in the cerebral cortex of rats. The overall results indicate that chronic administration of MMA increased pro-inflammatory markers in the cerebral cortex, reduced immune system defenses in blood, and coincide with the behavioral changes found in young rats. This leads to speculate that, through mechanisms not yet elucidated, the neuroinflammatory processes during critical periods of development may contribute to the progression of cognitive impairment in patients with methylmalonic acidemia.