The role of HFE genotype in macrophage phenotype
Abstract Background Iron regulation is essential for cellular energy production. Loss of cellular iron homeostasis has critical implications for both normal function and disease progression. The H63D variant of the HFE gene is the most common gene variant in Caucasians. The resulting mutant protein...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-02-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-018-1057-0 |
| _version_ | 1819078567390085120 |
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| author | Anne M. Nixon Elizabeth Neely Ian A. Simpson James R. Connor |
| author_facet | Anne M. Nixon Elizabeth Neely Ian A. Simpson James R. Connor |
| author_sort | Anne M. Nixon |
| collection | DOAJ |
| description | Abstract Background Iron regulation is essential for cellular energy production. Loss of cellular iron homeostasis has critical implications for both normal function and disease progression. The H63D variant of the HFE gene is the most common gene variant in Caucasians. The resulting mutant protein alters cellular iron homeostasis and is associated with a number of neurological diseases and cancer. In the brain, microglial and infiltrating macrophages are critical to maintaining iron homeostasis and modulating inflammation associated with the pathogenic process in multiple diseases. This study addresses whether HFE genotype affects macrophage function and the implications of these findings for disease processes. Methods Bone marrow macrophages were isolated from wildtype and H67D HFE knock-in mice. The H67D gene variant in mice is the human equivalent of the H63D variant. Upon differentiation, the macrophages were used to analyze iron regulatory proteins, cellular iron release, migration, phagocytosis, and cytokine expression. Results The results of this study demonstrate that the H67D HFE genotype significantly impacts a number of critical macrophage functions. Specifically, fundamental activities such as proliferation in response to iron exposure, L-ferritin expression in response to iron loading, secretion of BMP6 and cytokines, and migration and phagocytic activity were all found to be impacted by genotype. Furthermore, we demonstrated that exposure to apo-Tf (iron-poor transferrin) can increase the release of iron from macrophages. In normal conditions, 70% of circulating transferrin is unsaturated. Therefore, the ability of apo-Tf to induce iron release could be a major regulatory mechanism for iron release from macrophages. Conclusions These studies demonstrate that the HFE genotype impacts fundamental components of macrophage phenotype that could alter their role in degenerative and reparative processes in neurodegenerative disorders. |
| first_indexed | 2024-12-21T19:15:09Z |
| format | Article |
| id | doaj.art-363b5954ddf74a6d863e27df3b2b0e69 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-21T19:15:09Z |
| publishDate | 2018-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-363b5954ddf74a6d863e27df3b2b0e692022-12-21T18:53:05ZengBMCJournal of Neuroinflammation1742-20942018-02-0115111110.1186/s12974-018-1057-0The role of HFE genotype in macrophage phenotypeAnne M. Nixon0Elizabeth Neely1Ian A. Simpson2James R. Connor3Department of Neurosurgery, The Pennsylvania State University College of Medicine, M.S. Hershey Medical CenterDepartment of Neurosurgery, The Pennsylvania State University College of Medicine, M.S. Hershey Medical CenterDepartment of Neural and Behavior Science, The Pennsylvania State University College of Medicine, M.S. Hershey Medical CenterDepartment of Neurosurgery, The Pennsylvania State University College of Medicine, M.S. Hershey Medical CenterAbstract Background Iron regulation is essential for cellular energy production. Loss of cellular iron homeostasis has critical implications for both normal function and disease progression. The H63D variant of the HFE gene is the most common gene variant in Caucasians. The resulting mutant protein alters cellular iron homeostasis and is associated with a number of neurological diseases and cancer. In the brain, microglial and infiltrating macrophages are critical to maintaining iron homeostasis and modulating inflammation associated with the pathogenic process in multiple diseases. This study addresses whether HFE genotype affects macrophage function and the implications of these findings for disease processes. Methods Bone marrow macrophages were isolated from wildtype and H67D HFE knock-in mice. The H67D gene variant in mice is the human equivalent of the H63D variant. Upon differentiation, the macrophages were used to analyze iron regulatory proteins, cellular iron release, migration, phagocytosis, and cytokine expression. Results The results of this study demonstrate that the H67D HFE genotype significantly impacts a number of critical macrophage functions. Specifically, fundamental activities such as proliferation in response to iron exposure, L-ferritin expression in response to iron loading, secretion of BMP6 and cytokines, and migration and phagocytic activity were all found to be impacted by genotype. Furthermore, we demonstrated that exposure to apo-Tf (iron-poor transferrin) can increase the release of iron from macrophages. In normal conditions, 70% of circulating transferrin is unsaturated. Therefore, the ability of apo-Tf to induce iron release could be a major regulatory mechanism for iron release from macrophages. Conclusions These studies demonstrate that the HFE genotype impacts fundamental components of macrophage phenotype that could alter their role in degenerative and reparative processes in neurodegenerative disorders.http://link.springer.com/article/10.1186/s12974-018-1057-0IronMacrophagesMicrogliaHFEH63DH67D |
| spellingShingle | Anne M. Nixon Elizabeth Neely Ian A. Simpson James R. Connor The role of HFE genotype in macrophage phenotype Journal of Neuroinflammation Iron Macrophages Microglia HFE H63D H67D |
| title | The role of HFE genotype in macrophage phenotype |
| title_full | The role of HFE genotype in macrophage phenotype |
| title_fullStr | The role of HFE genotype in macrophage phenotype |
| title_full_unstemmed | The role of HFE genotype in macrophage phenotype |
| title_short | The role of HFE genotype in macrophage phenotype |
| title_sort | role of hfe genotype in macrophage phenotype |
| topic | Iron Macrophages Microglia HFE H63D H67D |
| url | http://link.springer.com/article/10.1186/s12974-018-1057-0 |
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