Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury

Abstract Background Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial/macrophage activation and neuroinflammation are key cellular events following TBI, but the regulatory and functional mechanisms are still not well understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, regulates multiple features of microglial/macrophage physiology. However, its function in regulating the innate immune response and microglial/macrophage M1/M2 polarization in TBI has not been addressed. The present study aimed to evaluate the role of Mer in regulating microglial/macrophage M1/M2 polarization and neuroinflammation following TBI. Methods The controlled cortical impact (CCI) mouse model was employed. Mer siRNA was intracerebroventricularly administered, and recombinant protein S (PS) was intravenously applied for intervention. The neurobehavioral assessments, RT-PCR, Western blot, magnetic-activated cell sorting, immunohistochemistry and confocal microscopy analysis, Nissl and Fluoro-Jade B staining, brain water content measurement, and contusion volume assessment were performed. Results Mer is upregulated and regulates microglial/macrophage M1/M2 polarization and neuroinflammation in the acute stage of TBI. Mechanistically, Mer activates the signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1/3 (SOCS1/3) pathway. Inhibition of Mer markedly decreases microglial/macrophage M2-like polarization while increases M1-like polarization, which exacerbates the secondary brain damage and sensorimotor deficits after TBI. Recombinant PS exerts beneficial effects in TBI mice through Mer activation. Conclusions Mer is an important regulator of microglial/macrophage M1/M2 polarization and neuroinflammation, and may be considered as a potential target for therapeutic intervention in TBI.

Download Full-text

Mer regulates microglial M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury

10.21203/rs.3.rs-29587/v1 ◽

2020 ◽

Author(s):

haijian wu ◽

jingwei zheng ◽

shenbin xu ◽

yuanjian fang ◽

anwen shao ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Tyrosine Kinases ◽

Protein S ◽

Acute Stage ◽

Cytokine Signaling ◽

Beneficial Effects ◽

M2 Polarization ◽

Fluoro Jade B ◽

Pathway Inhibition

Abstract Background: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial activation and neuroinflammation are key cellular events following TBI, but the regulatory and functional mechanisms are still not well understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, regulates multiple features of microglial physiology. However, its function in regulating the innate immune response and microglial M1/M2 polarization in TBI has not been addressed. The present study aimed to evaluate the role of Mer in regulating microglial M1/M2 polarization and neuroinflammation following TBI. Methods: The controlled cortical impact (CCI) mouse model was established. Mer siRNA was intracerebroventricularly administered and recombinant protein S (PS) was intravenously applied for intervention. The neurobehavioral assessments, RT-PCR, Western blot, immunohistochemistry and confocal microscopy analysis, Nissl and Fluoro-Jade B staining, brain water content measurement, and contusion volume assessment were performed. Results: Mer is upregulated and regulates microglial M1/M2 polarization and neuroinflammation in the acute stage of TBI. Mechanistically, Mer activates the signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1/3 (SOCS1/3) pathway. Inhibition of Mer markedly decreases microglial M2 polarization while increases M1 polarization, which exacerbates the secondary brain damage and sensorimotor deficits after TBI. Recombinant PS exerts beneficial effects in TBI mice through Mer activation. Conclusions: Mer is an important regulator of microglial M1/M2 polarization and neuroinflammation, and may be considered as a potential target for therapeutic intervention in TBI.

Download Full-text

Use of hemoglobin-based oxygen-carrying solution–201 to improve resuscitation parameters and prevent secondary brain injury in a swine model of traumatic brain injury and hemorrhage

Journal of Neurosurgery ◽

10.3171/jns/2008/108/3/0575 ◽

2008 ◽

Vol 108 (3) ◽

pp. 575-587 ◽

Cited By ~ 34

Author(s):

Guy Rosenthal ◽

Diane Morabito ◽

Mitchell Cohen ◽

Annina Roeytenberg ◽

Nikita Derugin ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Mr Imaging ◽

Swine Model ◽

Secondary Brain Injury ◽

Large Animal ◽

Fluoro Jade B ◽

Significant Difference ◽

Impact Injury ◽

The Brain

Object Traumatic brain injury (TBI) often occurs as part of a multisystem trauma that may lead to hemorrhagic shock. Effective resuscitation and restoration of oxygen delivery to the brain is important in patients with TBI because hypotension and hypoxia are associated with poor outcome in head injury. We studied the effects of hemoglobin-based oxygen-carrying (HBOC)–201 solution compared with lactated Ringer (LR) solution in a large animal model of brain injury and hemorrhage, in a blinded prospective randomized study. Methods Swine underwent brain impact injury and hemorrhage to a mean arterial pressure (MAP) of 40 mm Hg. Twenty swine were randomized to undergo resuscitation with HBOC-201 (6 ml/kg) or LR solution (12 ml/kg) and were observed for an average of 6.5 ± 0.5 hours following resuscitation. At the end of the observation period, magnetic resonance (MR) imaging was performed. Histological studies of swine brains were performed using Fluoro-Jade B, a marker of early neuronal degeneration. Results Swine resuscitated with HBOC-201 had higher MAP, higher cerebral perfusion pressure (CPP), improved base deficit, and higher brain tissue oxygen tension (PbtO2) than animals resuscitated with LR solution. No significant difference in total injury volume on T2-weighted MR imaging was observed between animals resuscitated with HBOC-201 solution (1155 ± 374 mm3) or LR solution (1246 ± 279 mm3; p = 0.55). On the side of impact injury, no significant difference in the mean number of Fluoro-Jade B–positive cells/hpf was seen between HBOC-201 solution (61.5 ± 14.7) and LR solution (48.9 ± 17.7; p = 0.13). Surprisingly, on the side opposite impact injury, a significant increase in Fluoro-Jade B–positive cells/hpf was seen in animals resuscitated with LR solution (42.8 ± 28.3) compared with those resuscitated with HBOC-201 solution (5.6 ± 8.1; p < 0.05), implying greater neuronal injury in LR-treated swine. Conclusions The improved MAP, CPP, and PbtO2 observed with HBOC-201 solution in comparison with LR solution indicates that HBOC-201 solution may be a preferable agent for small-volume resuscitation in brain-injured patients with hemorrhage. The use of HBOC-201 solution appears to decrease cellular degeneration in the brain area not directly impacted by the primary injury. Hemoglobin-based oxygen-carrying–201 solution may act by improving cerebral blood flow or increasing the oxygen-carrying capacity of blood, mitigating a second insult to the injured brain.

Download Full-text

The effect of attention training program on the attention ability on daily activity in patients with acute stage of traumatic brain injury

International Journal of Evidence-Based Healthcare ◽

10.1097/01.xeb.0000455253.39024.bd ◽

2014 ◽

Vol 12 (3) ◽

pp. 222

Author(s):

M. R. Weng ◽

L. C. Lin

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Training Program ◽

Daily Activity ◽

Acute Stage ◽

Attention Training

Download Full-text

Long-term beneficial effects of hematopoietic growth factors on brain repair in the chronic phase of severe traumatic brain injury

Experimental Neurology ◽

10.1016/j.expneurol.2020.113335 ◽

2020 ◽

Vol 330 ◽

pp. 113335

Author(s):

Xuecheng Qiu ◽

Suning Ping ◽

Michele Kyle ◽

Lawrence Chin ◽

Li-Ru Zhao

Keyword(s):

Traumatic Brain Injury ◽

Growth Factors ◽

Brain Injury ◽

Severe Traumatic Brain Injury ◽

Chronic Phase ◽

Hematopoietic Growth Factors ◽

Brain Repair ◽

Beneficial Effects

Download Full-text

Mesenchymal stem cell therapy for the treatment of traumatic brain injury: progress and prospects

Reviews in the Neurosciences ◽

10.1515/revneuro-2019-0002 ◽

2019 ◽

Vol 30 (8) ◽

pp. 839-855 ◽

Cited By ~ 10

Author(s):

Mahasweta Das ◽

Karthick Mayilsamy ◽

Shyam S. Mohapatra ◽

Subhra Mohapatra

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neuronal Damage ◽

Neuronal Loss ◽

Tumor Formation ◽

Functional Improvement ◽

Preclinical Research ◽

Mortality And Morbidity ◽

Mesenchymal Stem Cell Therapy ◽

Beneficial Effects

Abstract Traumatic brain injury (TBI) is a major cause of injury-related mortality and morbidity in the USA and around the world. The survivors may suffer from cognitive and memory deficits, vision and hearing loss, movement disorders, and different psychological problems. The primary insult causes neuronal damage and activates astrocytes and microglia which evokes immune responses causing further damage to the brain. Clinical trials of drugs to recover the neuronal loss are not very successful. Regenerative approaches for TBI using mesenchymal stem cells (MSCs) seem promising. Results of preclinical research have shown that transplantation of MSCs reduced secondary neurodegeneration and neuroinflammation, promoted neurogenesis and angiogenesis, and improved functional outcome in the experimental animals. The functional improvement is not necessarily related to cell engraftment; rather, immunomodulation by molecular factors secreted by MSCs is responsible for the beneficial effects of this therapy. However, MSC therapy has a few drawbacks including tumor formation, which can be avoided by the use of MSC-derived exosomes. This review has focused on the research works published in the field of regenerative therapy using MSCs after TBI and its future direction.

Download Full-text

Effects of Transient Receptor Potential Cation 5 (TRPC5) Inhibitor, NU6027, on Hippocampal Neuronal Death after Traumatic Brain Injury

International Journal of Molecular Sciences ◽

10.3390/ijms21218256 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8256 ◽

Cited By ~ 1

Author(s):

Min Kyu Park ◽

Bo Young Choi ◽

A Ra Kho ◽

Song Hee Lee ◽

Dae Ki Hong ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Neuronal Death ◽

Transient Receptor Potential ◽

Neuronal Cell Death ◽

Neuronal Cell ◽

Treated Group ◽

Therapeutic Window ◽

Permanent Disability ◽

Fluoro Jade B

Traumatic brain injury (TBI) can cause physical, cognitive, social, and behavioral changes that can lead to permanent disability or death. After primary brain injury, translocated free zinc can accumulate in neurons and lead to secondary events such as oxidative stress, inflammation, edema, swelling, and cognitive impairment. Under pathological conditions, such as ischemia and TBI, excessive zinc release, and accumulation occurs in neurons. Based on previous research, it hypothesized that calcium as well as zinc would be influx into the TRPC5 channel. Therefore, we hypothesized that the suppression of TRPC5 would prevent neuronal cell death by reducing the influx of zinc and calcium. To test our hypothesis, we used a TBI animal model. After the TBI, we immediately injected NU6027 (1 mg/kg, intraperitoneal), TRPC5 inhibitor, and then sacrificed animals 24 h later. We conducted Fluoro-Jade B (FJB) staining to confirm the presence of degenerating neurons in the hippocampal cornus ammonis 3 (CA3). After the TBI, the degenerating neuronal cell count was decreased in the NU6027-treated group compared with the vehicle-treated group. Our findings suggest that the suppression of TRPC5 can open a new therapeutic window for a reduction of the neuronal death that may occur after TBI.

Download Full-text