Exploring the Role of Chemokine Receptor 6 ( Ccr6 ) in the BXD Mouse Model of Gulf War Illness.

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 betweenCCR6and 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 identifiedCcr6as a candidate gene underlying individual differences in susceptibility to GWI. TheCcr6gene iscis-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 ofCcr6to CORT+DFP is also significantly different (p< 0.0001) between the parental strains, suggestingCcr6is affected by both host genetic background and chemical treatments. Pearson product-moment correlation analysis revealed 1473Ccr6-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 ofCcr6in the PFC. We further established a protein-protein interaction subnetwork for theCcr6-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 thatCcr6is one of promising GWI biomarkers.