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.

中文翻译：

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探索趋化因子受体 6 (Ccr6) 在海湾战争疾病 BXD 小鼠模型中的作用

海湾战争病 (GWI) 是一种慢性和多症状疾病，具有持续的神经免疫症状。趋化因子受体 6 (CCR6) 已被证明与人类的几种炎症疾病有关。然而，尚未研究 CCR6 与 GWI 神经炎症之间的因果关系。通过使用来自 31 个 C57BL/6J X DBA/2J (BXD) 重组近交 (RI) 小鼠品系及其亲本品系的前额叶皮层 (PFC) 的 RNA-seq 数据，在三个化学处理组 - 盐水对照 (CTL)、二异丙基氟磷酸盐 (DFP) 下)，以及皮质酮结合二异丙基氟磷酸酯 (CORT+DFP)，我们将 Ccr6 鉴定为潜在的个体 GWI 易感性差异的候选基因。Ccr6 基因受顺式调控，其表达与 CORT+DFP 处理显着相关。在 CORT+DFP 组中，其在 BXD 小鼠 PFC 中的平均转录本丰度降低了 1.6 倍（p < 0.0001）。Ccr6 对 CORT+DFP 的反应在亲本菌株之间也有显着差异（p < 0.0001），表明 Ccr6 受宿主遗传背景和化学处理的影响。Pearson 积矩相关分析揭示了 1473 个 Ccr6 相关基因 (p < 0.05)。在免疫、炎症、细胞因子和神经系统相关类别中观察到这些基因的富集。此外，我们还发现五种中枢神经系统相关表型和粪便皮质酮浓度与 PFC 中 Ccr6 的表达具有显着相关性（p < 0.05）。我们进一步为 Ccr6 相关基因建立了蛋白质-蛋白质相互作用子网络，它提供了对 G 蛋白偶联受体、激肽释放酶-激肽系统和神经活性配体-受体相互作用的深入了解。该分析可能定义了 GWI 的异质性和复杂性。因此，我们的结果表明 Ccr6 是一种有前途的 GWI 生物标志物。