NDLI: Disruption of Midkine gene reduces traumatic brain injury through the modulation of neuroinflammation

Content Provider	Springer Nature : BioMed Central
Author	Takada, Seiya Sakakima, Harutoshi Matsuyama, Takahiro Otsuka, Shotaro Nakanishi, Kazuki Norimatsu, Kosuke Itashiki, Yuki Tani, Akira Kikuchi, Kiyoshi
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.
Related Links	https://jneuroinflammation.biomedcentral.com/counter/pdf/10.1186/s12974-020-1709-8.pdf
Ending Page	12
Page Count	12
Starting Page	1
File Format	HTM / HTML
ISSN	17422094
DOI	10.1186/s12974-020-1709-8
Journal	Journal of Neuroinflammation
Issue Number	1
Volume Number	17
Language	English
Publisher	BioMed Central
Publisher Date	2020-01-29
Access Restriction	Open
Subject Keyword	Neurosciences Neurology Neurobiology Immunology Midkine Traumatic brain injury Microglia/macrophages M1/M2 phenotype Neuroinflammation
Content Type	Text
Resource Type	Article
Subject	Neuroscience Immunology Cellular and Molecular Neuroscience Neurology
Journal Impact Factor	9.3/2023
5-Year Journal Impact Factor	9.8/2023

Sl.	Authority	Responsibilities	Communication Details
1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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