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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456958/ https://www.ncbi.nlm.nih.gov/pubmed/32922257 http://dx.doi.org/10.3389/fnins.2020.00818 |
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author | Gao, Jun Xu, Fuyi Starlard-Davenport, Athena Miller, Diane B. O’Callaghan, James P. Jones, Byron C. Lu, Lu |
author_facet | Gao, Jun Xu, Fuyi Starlard-Davenport, Athena Miller, Diane B. O’Callaghan, James P. Jones, Byron C. Lu, Lu |
author_sort | Gao, Jun |
collection | PubMed |
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. |
format | Online Article Text |
id | pubmed-7456958 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-74569582020-09-11 Exploring the Role of Chemokine Receptor 6 (Ccr6) in the BXD Mouse Model of Gulf War Illness Gao, Jun Xu, Fuyi Starlard-Davenport, Athena Miller, Diane B. O’Callaghan, James P. Jones, Byron C. Lu, Lu Front Neurosci Neuroscience 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. Frontiers Media S.A. 2020-08-14 /pmc/articles/PMC7456958/ /pubmed/32922257 http://dx.doi.org/10.3389/fnins.2020.00818 Text en Copyright © 2020 Gao, Xu, Starlard-Davenport, Miller, O’Callaghan, Jones and Lu. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Gao, Jun Xu, Fuyi Starlard-Davenport, Athena Miller, Diane B. O’Callaghan, James P. Jones, Byron C. Lu, Lu Exploring the Role of Chemokine Receptor 6 (Ccr6) in the BXD Mouse Model of Gulf War Illness |
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 | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456958/ https://www.ncbi.nlm.nih.gov/pubmed/32922257 http://dx.doi.org/10.3389/fnins.2020.00818 |
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