Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation
Abstract Background Midkine (MK) is a multifunctional cytokine found upregulated in the brain in the presence of different disorders characterized by neuroinflammation, including neurodegenerative disorders and ischemia. The neuroinflammatory response to traumatic brain injury (TBI) represents a key...
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doaj-d785c2432dd841c7857e243fab2ed7fc2021-01-31T16:05:04ZengBMCJournal of Neuroinflammation1742-20942020-01-0117111210.1186/s12974-020-1709-8Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammationSeiya Takada0Harutoshi Sakakima1Takahiro Matsuyama2Shotaro Otsuka3Kazuki Nakanishi4Kosuke Norimatsu5Yuki Itashiki6Akira Tani7Kiyoshi Kikuchi8Department of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima UniversityDepartment of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima UniversityDepartment of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima UniversityDepartment of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima UniversityDepartment of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima UniversityDepartment of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima UniversityDepartment of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima UniversityDepartment of Physical Therapy, School of Health Sciences, Faculty of Medicine, Kagoshima UniversityDivision of Brain Science, Department of Physiology, Kurume University School of MedicineAbstract Background Midkine (MK) is a multifunctional cytokine found upregulated in the brain in the presence of different disorders characterized by neuroinflammation, including neurodegenerative disorders and ischemia. The neuroinflammatory response to traumatic brain injury (TBI) represents a key secondary injury factor that can result in further neuronal injury. In the present study, we investigated the role of endogenous MK in secondary injury, including neuroinflammation, immune response, and neuronal apoptosis activity, after TBI. Methods Wild type (Mdk+/+) and MK gene deficient (Mdk−/−) mice were subjected to fluid percussion injury for TBI models and compared at 3, 7, and 14 days after TBI, in terms of the following: brain tissue loss, neurological deficits, microglia response, astrocytosis, expression of proinflammatory M1 and anti-inflammatory M2 microglia/macrophage phenotype markers, and apoptotic activity. Results As opposed to Mdk+/+ mice, Mdk−/− mice reported a significantly reduced area of brain tissue loss and an improvement in their neurological deficits. The ratios of the Iba1-immunoreactive microglia/macrophages in the perilesional site were significantly decreased in Mdk−/− than in the Mdk+/+ mice at 3 days after TBI. However, the ratios of the glial fibrillary acidic protein immunoreactive area were similar between the two groups. The M1 phenotype marker (CD16/32) immunoreactive areas were significantly reduced in Mdk−/− than in the Mdk+/+ mice. Likewise, the mRNA levels of the M1 phenotype markers (TNF-α, CD11b) were significantly decreased in Mdk−/− mice than in Mdk+/+ mice. Furthermore, flow cytometry analysis identified the M2 markers, i.e., CD163+ macrophages cells and arginase-1+ microglia cells, to be significantly higher in Mdk−/− than in Mdk+/+ mice. Finally, the ratios of apoptotic neurons were significantly decreased in the area surrounding the lesion in Mdk−/− than in Mdk+/+ mice following TBI. Conclusion Our findings suggest that MK-deficiency reduced tissue infiltration of microglia/macrophages and altered their polarization status thereby reducing neuroinflammation, neuronal apoptosis, and tissue loss and improving neurological outcomes after TBI. Therefore, targeting MK to modulate neuroinflammation may represent a potential therapeutic strategy for TBI management.https://doi.org/10.1186/s12974-020-1709-8MidkineTraumatic brain injuryMicroglia/macrophagesM1/M2 phenotypeNeuroinflammation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Seiya Takada Harutoshi Sakakima Takahiro Matsuyama Shotaro Otsuka Kazuki Nakanishi Kosuke Norimatsu Yuki Itashiki Akira Tani Kiyoshi Kikuchi |
spellingShingle |
Seiya Takada Harutoshi Sakakima Takahiro Matsuyama Shotaro Otsuka Kazuki Nakanishi Kosuke Norimatsu Yuki Itashiki Akira Tani Kiyoshi Kikuchi Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation Journal of Neuroinflammation Midkine Traumatic brain injury Microglia/macrophages M1/M2 phenotype Neuroinflammation |
author_facet |
Seiya Takada Harutoshi Sakakima Takahiro Matsuyama Shotaro Otsuka Kazuki Nakanishi Kosuke Norimatsu Yuki Itashiki Akira Tani Kiyoshi Kikuchi |
author_sort |
Seiya Takada |
title |
Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation |
title_short |
Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation |
title_full |
Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation |
title_fullStr |
Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation |
title_full_unstemmed |
Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation |
title_sort |
disruption of midkine gene reduces traumatic brain injury through the modulation of neuroinflammation |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2020-01-01 |
description |
Abstract Background Midkine (MK) is a multifunctional cytokine found upregulated in the brain in the presence of different disorders characterized by neuroinflammation, including neurodegenerative disorders and ischemia. The neuroinflammatory response to traumatic brain injury (TBI) represents a key secondary injury factor that can result in further neuronal injury. In the present study, we investigated the role of endogenous MK in secondary injury, including neuroinflammation, immune response, and neuronal apoptosis activity, after TBI. Methods Wild type (Mdk+/+) and MK gene deficient (Mdk−/−) mice were subjected to fluid percussion injury for TBI models and compared at 3, 7, and 14 days after TBI, in terms of the following: brain tissue loss, neurological deficits, microglia response, astrocytosis, expression of proinflammatory M1 and anti-inflammatory M2 microglia/macrophage phenotype markers, and apoptotic activity. Results As opposed to Mdk+/+ mice, Mdk−/− mice reported a significantly reduced area of brain tissue loss and an improvement in their neurological deficits. The ratios of the Iba1-immunoreactive microglia/macrophages in the perilesional site were significantly decreased in Mdk−/− than in the Mdk+/+ mice at 3 days after TBI. However, the ratios of the glial fibrillary acidic protein immunoreactive area were similar between the two groups. The M1 phenotype marker (CD16/32) immunoreactive areas were significantly reduced in Mdk−/− than in the Mdk+/+ mice. Likewise, the mRNA levels of the M1 phenotype markers (TNF-α, CD11b) were significantly decreased in Mdk−/− mice than in Mdk+/+ mice. Furthermore, flow cytometry analysis identified the M2 markers, i.e., CD163+ macrophages cells and arginase-1+ microglia cells, to be significantly higher in Mdk−/− than in Mdk+/+ mice. Finally, the ratios of apoptotic neurons were significantly decreased in the area surrounding the lesion in Mdk−/− than in Mdk+/+ mice following TBI. Conclusion Our findings suggest that MK-deficiency reduced tissue infiltration of microglia/macrophages and altered their polarization status thereby reducing neuroinflammation, neuronal apoptosis, and tissue loss and improving neurological outcomes after TBI. Therefore, targeting MK to modulate neuroinflammation may represent a potential therapeutic strategy for TBI management. |
topic |
Midkine Traumatic brain injury Microglia/macrophages M1/M2 phenotype Neuroinflammation |
url |
https://doi.org/10.1186/s12974-020-1709-8 |
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