Anti-Inflammatory CDGSH Iron-Sulfur Domain 2: A Biomarker of Central Nervous System Insult in Cellular, Animal Models and Patients

Spinal cord injury (SCI) promotes brain inflammation; conversely, brain injury promotes spinal neuron loss. There is a need to identify molecular biomarkers and therapeutic targets for central nervous system (CNS) injury. CDGSH iron-sulfur structural domain 2 (CISD2), an NF-κB antagonist, is downregulated after injury in vivo and in vitro. We aimed to examine the diagnostic value of CISD2 in patients with CNS insult. Plasma and cerebrospinal fluid (CSF) CISD2 levels were decreased in 13 patients with CNS insult and were negatively correlated with plasma IL6 levels (associated with disease severity; r = −0.7062; p < 0.01). SCI-induced inflammatory mediators delivered through CSF promoted mouse brain inflammation at 1 h post-SCI. Anti-CISD2 antibody treatment exacerbated SCI-induced inflammation in mouse spine and brain. Lipopolysaccharide-stimulated siCISD2-transfected EOC microglial cells exhibited proinflammatory phenotypes (enhanced M1 polarization, decreased M2 polarization, and increased intranuclear NF-κB p65 translocation). Plasma and CSF CISD2 levels were increased in three patients with CNS insult post-therapeutic hypothermia. CISD2 levels were negatively correlated with plasma and CSF levels of inflammatory mediators. CISD2 inhibition and potentiation experiments in cells, animals, and humans revealed CISD2 as a biomarker for CNS insult and upregulation of CISD2 anti-inflammatory properties as a potential therapeutic strategy for CNS insult.