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 between CCR6 and neuroinflammation in GWI has not...
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Frontiers Media S.A.
2020-08-01
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| Series: | Frontiers in Neuroscience |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fnins.2020.00818/full |
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| author | Jun Gao Jun Gao Fuyi Xu Athena Starlard-Davenport Diane B. Miller James P. O’Callaghan Byron C. Jones Lu Lu |
| author_facet | Jun Gao Jun Gao Fuyi Xu Athena Starlard-Davenport Diane B. Miller James P. O’Callaghan Byron C. Jones Lu Lu |
| author_sort | Jun Gao |
| collection | DOAJ |
| description | 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. |
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| language | English |
| last_indexed | 2024-12-10T23:29:18Z |
| publishDate | 2020-08-01 |
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| spelling | doaj.art-c8813c0449524db48a329f682419fbd62022-12-22T01:29:28ZengFrontiers Media S.A.Frontiers in Neuroscience1662-453X2020-08-011410.3389/fnins.2020.00818568728Exploring the Role of Chemokine Receptor 6 (Ccr6) in the BXD Mouse Model of Gulf War IllnessJun Gao0Jun Gao1Fuyi Xu2Athena Starlard-Davenport3Diane B. Miller4James P. O’Callaghan5Byron C. Jones6Lu Lu7Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN, United StatesInstitute of Animal Husbandry and Veterinary Science, Shanghai Academy of Agricultural Sciences, Shanghai, ChinaDepartment of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN, United StatesHealth Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV, United StatesHealth Effects Laboratory Division, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV, United StatesDepartment of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN, United StatesDepartment of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN, United StatesGulf 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.https://www.frontiersin.org/article/10.3389/fnins.2020.00818/fullCcr6GWIDFPCORTBXD strainRNA-seq |
| spellingShingle | Jun Gao Jun Gao Fuyi Xu Athena Starlard-Davenport Diane B. Miller James P. O’Callaghan Byron C. Jones Lu Lu Exploring the Role of Chemokine Receptor 6 (Ccr6) in the BXD Mouse Model of Gulf War Illness Frontiers in Neuroscience Ccr6 GWI DFP CORT BXD strain RNA-seq |
| title | Exploring the Role of Chemokine Receptor 6 (Ccr6) in the BXD Mouse Model of Gulf War Illness |
| title_full | Exploring the Role of Chemokine Receptor 6 (Ccr6) in the BXD Mouse Model of Gulf War Illness |
| title_fullStr | Exploring the Role of Chemokine Receptor 6 (Ccr6) in the BXD Mouse Model of Gulf War Illness |
| title_full_unstemmed | Exploring the Role of Chemokine Receptor 6 (Ccr6) in the BXD Mouse Model of Gulf War Illness |
| title_short | Exploring the Role of Chemokine Receptor 6 (Ccr6) in the BXD Mouse Model of Gulf War Illness |
| title_sort | exploring the role of chemokine receptor 6 ccr6 in the bxd mouse model of gulf war illness |
| topic | Ccr6 GWI DFP CORT BXD strain RNA-seq |
| url | https://www.frontiersin.org/article/10.3389/fnins.2020.00818/full |
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