Abstract
Gulf War illness (GWI) is a chronic and multi-symptomatic disorder with persistent neuroimmune symptomatology. Chemokine receptor 6 (CCR6) has been shown to be involved in several inflammation disorders in humans. However, the causative relationship between CCR6 and neuroinflammation in GWI has not yet been investigated. By using RNA-seq data of prefrontal cortex (PFC) from 31 C57BL/6J X DBA/2J (BXD) recombinant inbred (RI) mouse strains and their parental strains under three chemical treatment groups – saline control (CTL), diisopropylfluorophosphate (DFP), and corticosterone combined with diisopropylfluorophosphate (CORT+DFP), we identified Ccr6 as a candidate gene underlying individual differences in susceptibility to GWI. The Ccr6 gene is cis-regulated and its expression is significantly correlated with CORT+DFP treatment. Its mean transcript abundance in PFC of BXD mice decreased 1.6-fold (p < 0.0001) in the CORT+DFP group. The response of Ccr6 to CORT+DFP is also significantly different (p < 0.0001) between the parental strains, suggesting Ccr6 is affected by both host genetic background and chemical treatments. Pearson product-moment correlation analysis revealed 1473 Ccr6-correlated genes (p < 0.05). Enrichment of these genes was seen in the immune, inflammation, cytokine, and neurological related categories. In addition, we also found five central nervous system-related phenotypes and fecal corticosterone concentration have significant correlation (p < 0.05) with expression of Ccr6 in the PFC. We further established a protein-protein interaction subnetwork for the Ccr6-correlated genes, which provides an insight on the interaction of G protein-coupled receptors, kallikrein-kinin system and neuroactive ligand-receptors. This analysis likely defines the heterogeneity and complexity of GWI. Therefore, our results suggest that Ccr6 is one of promising GWI biomarkers.
Highlights
Gulf War illness (GWI) is the term used to describe a chronic and multi-symptomatic disorder affecting returning military veterans of the 1990–1991 Gulf War (Binns et al, 2014)
Results showed that Ccr6 significantly decreased in the CORT+DFP group when compared with CTL group (Fold change = 1.60, p < 0.0001) and DFP group (Fold change = 1.42, p < 0.05) (Figure 1B), respectively
We identified a Ccr6 Protein-Protein Interactions (PPI) subnetwork that includes 38 genes enriched in G protein-coupled receptor (GPCR) signaling pathways and cytosolic calcium ion concentration signaling pathway
Summary
Gulf War illness (GWI) is the term used to describe a chronic and multi-symptomatic disorder affecting returning military veterans of the 1990–1991 Gulf War (Binns et al, 2014). Accumulated neuroimaging studies have demonstrated abnormalities in the brains of veterans with GWI (Binns et al, 2014) including strong evidence for neuroinflammation (Alshelh et al, 2020). Studies revealed that brain chemistry is abnormal mainly in prefrontal cortex (PFC) and different subregions that mediate various characteristics of the chronic pain, such as sensory and affective dimensions, anxiety and depression (Apkarian et al, 2005). Heterogeneous symptom presentation and lack of biomarkers in PFC that identify a distinct pathophysiological process in GWI still remain challenging
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