2 research outputs found
presentation_1_Type-I Interferons Inhibit Interleukin-10 Signaling and Favor Type 1 Diabetes Development in Nonobese Diabetic Mice.PDF
<p>Destruction of insulin-producing β-cells by autoreactive T lymphocytes leads to the development of type 1 diabetes. Type-I interferons (TI-IFN) and interleukin-10 (IL-10) have been connected with the pathophysiology of this disease; however, their interplay in the modulation of diabetogenic T cells remains unknown. We have discovered that TI-IFN cause a selective inhibition of IL-10 signaling in effector and regulatory T cells, altering their responses. This correlates with diabetes development in nonobese diabetic mice, where the inhibition is also spatially localized to T cells of pancreatic and mesenteric lymph nodes. IL-10 signaling inhibition is reversible and can be restored via blockade of TI-IFN/IFN-R interaction, paralleling with the resulting delay in diabetes onset and reduced severity. Overall, we propose a novel molecular link between TI-IFN and IL-10 signaling that helps better understand the complex dynamics of autoimmune diabetes development and reveals new strategies of intervention.</p
Integrated Omic Analysis of a Guinea Pig Model of Heart Failure and Sudden Cardiac Death
Here, we examine
key regulatory pathways underlying the transition
from compensated hypertrophy (HYP) to decompensated heart failure
(HF) and sudden cardiac death (SCD) in a guinea pig pressure-overload
model by integrated multiome analysis. Relative protein abundances
from sham-operated HYP and HF hearts were assessed by iTRAQ LC–MS/MS.
Metabolites were quantified by LC–MS/MS or GC–MS. Transcriptome
profiles were obtained using mRNA microarrays. The guinea pig HF proteome
exhibited classic biosignatures of cardiac HYP, left ventricular dysfunction,
fibrosis, inflammation, and extravasation. Fatty acid metabolism,
mitochondrial transcription/translation factors, antioxidant enzymes,
and other mitochondrial procsses, were downregulated in HF but not
HYP. Proteins upregulated in HF implicate extracellular matrix remodeling,
cytoskeletal remodeling, and acute phase inflammation markers. Among
metabolites, acylcarnitines were downregulated in HYP and fatty acids
accumulated in HF. The correlation of transcript and protein changes
in HF was weak (<i>R</i><sup>2</sup> = 0.23), suggesting
post-transcriptional gene regulation in HF. Proteome/metabolome integration
indicated metabolic bottlenecks in fatty acyl-CoA processing by carnitine
palmitoyl transferase (<i>CPT1B</i>) as well as TCA cycle
inhibition. On the basis of these findings, we present a model of
cardiac decompensation involving impaired nuclear integration of Ca<sup>2+</sup> and cyclic nucleotide signals that are coupled to mitochondrial
metabolic and antioxidant defects through the CREB/PGC1α transcriptional
axis