bioRxiv Science⌕ Search

Biology subjects

Ford, G.

Publications and source records attributed to Ford, G..

2 recordsLinked to original sources
bioRxiv2023

Transcription Factor NRF2 is Activated by Erythrophagocytosis of Oxidized Red Blood Cell Products and Suppresses the IL-12-IFNg-IL-10 Axis in a Murine Model of Hyperinflammatory Disease

Hyperinflammatory diseases including macrophage activation syndrome (MAS) and hemophagocytic lymphohistocytosis (HLH) are characterized by multi-lineage cytopenias, hypercytokinemia, and tissue hemophagocytosis. However, the mechanisms by which erythrophagocytosis mediates iron metabolism and regulates the hyperactive immune response remain unclear. The transcription factor NRF2 is an important sensor for inflammatory and redox distress. The targets of NRF2 are antioxidant response elements responsible for transcription of genes related to restoration of redox homeostasis within the cell. Here we demonstrate that mice with CpG-induced MAS have evidence of systemic oxidative and nitrosative distress - including increased serum nitric oxide and elevated systemic lipid peroxidation. In this model, NRF2 knockout mice develop significantly worse organomegaly, hypercytokinemia, and reticulocytosis. NRF2 knockout mice have unexpected exacerbation in the cytokines that are central to hyperinflammatory physiology - namely IL-12, IFN gamma (IFNg), and IL-10. In vitro we demonstrate that oxidized red blood cell products and heme itself suppress IL-12 protein production and transcription from bone marrow derived dendritic cells in a NRF2-dependent manner. Together our studies demonstrate that erythrophagocytosis of oxidized red blood cell products suppresses the Il-12-IFNg-IL-10 axis which drives hyperinflammation in murine hyperinflammation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/571271v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1a2330corg.highwire.dtl.DTLVardef@1c59944org.highwire.dtl.DTLVardef@1d151b5org.highwire.dtl.DTLVardef@14b4301_HPS_FORMAT_FIGEXP M_FIG C_FIG Created with BioRender

immunology↗
bioRxiv2018

Levetiracetam and Rufinamide are effective at supressing spike and wave seizure activity in an in vitro model of absence epilepsy.

Spike-and-wave discharges (SpW) are seen in absence-type epilepsies. They are heterogeneous in terms of their clinical burden and their electrographic signature, which is used to classify different types of absence seizures; typical absence, in which SpW frequency is 3-4Hz and atypical absence, which shows a slower 1-2Hz frequency. Treatment of SpW varies dependent upon the syndrome, but both Valproic Acid (VPA) and Ethosuximide (ESM) are shown to be effective in controlling typical absence seizures. Other anti-epileptics (AEDs), Levetiracetam (LEV) and Rufinamide (RUF), have shown promise in treating absence epilepsies and their associated syndromes. Here we examine the efficacy of these AEDs on an in vitro model of SpW.\n\nBoth LEV and RUF show an effective reduction in both the number of SpW events and the spike component amplitude; VPA shows no effect, whilst ESM enhances the spike amplitude. Phenytoin exacerbates the SpW activity, increasing both the number of SpW, amplitude of the SpW and the number of spikes within each event. These data suggest that both LEV and RUF could be effective in the treatment of absence-type epilepsies. They also suggest this model could be an effective tool to test other AEDs aimed at treating atypical absence syndromes.

neuroscience↗