Dataset Information

Peripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damage.

ABSTRACT:

Background

The continuum of pro- and anti-inflammatory response elicited by traumatic brain injury (TBI) is suggested to play a key role in the outcome of TBI; however, the underlying mechanisms remain ill -defined.

Methods

Here, we demonstrate that using bone marrow chimeric mice and systemic inhibition of EphA4 receptor shifts the pro-inflammatory milieu to pro-resolving following acute TBI.

Results

EphA4 expression is increased in the injured cortex as early as 2 h post-TBI and on CX3CR1^gfp-positive cells in the peri-lesion. Systemic inhibition or genetic deletion of EphA4 significantly reduced cortical lesion volume and shifted the inflammatory profile of peripheral-derived immune cells to pro-resolving in the damaged cortex. These findings were consistent with in vitro studies showing EphA4 inhibition or deletion altered the inflammatory state of LPS-stimulated monocyte/macrophages towards anti-inflammatory. Phosphoarray analysis revealed that EphA4 may regulate pro-inflammatory gene expression by suppressing the mTOR, Akt, and NF-κB pathways. Our human metadata analysis further demonstrates increased EPHA4 and pro-inflammatory gene expression, which correlates with reduced AKT concurrent with increased brain injury severity in patients.

Conclusions

Overall, these findings implicate EphA4 as a novel mediator of cortical tissue damage and neuroinflammation following TBI.

SUBMITTER: Kowalski EA

PROVIDER: S-EPMC6844068 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Publications

Peripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damage.

Kowalski Elizabeth A EA Chen Jiang J Hazy Amanda A Fritsch Lauren E LE Gudenschwager-Basso Erwin Kristobal EK Chen Michael M Wang Xia X Qian Yun Y Zhou Mingjun M Byerly Matthew M Pickrell Alicia M AM Matson John B JB Allen Irving Coy IC Theus Michelle H MH

Journal of neuroinflammation 20191111 1

<h4>Background</h4>The continuum of pro- and anti-inflammatory response elicited by traumatic brain injury (TBI) is suggested to play a key role in the outcome of TBI; however, the underlying mechanisms remain ill -defined.<h4>Methods</h4>Here, we demonstrate that using bone marrow chimeric mice and systemic inhibition of EphA4 receptor shifts the pro-inflammatory milieu to pro-resolving following acute TBI.<h4>Results</h4>EphA4 expression is increased in the injured cortex as early as 2 h post- ...[more]

PMID: 31711546

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Project description:Peripheral arterial disease (PAD) is a common complication associated with diabetes, which can lead to foot ischemia. The condition is often accompanied by infection and necrosis, ultimately leading to diabetic foot ulcers and the risk of amputation. Brown adipose tissue (BAT) and its secreted cytokines play an essential role in the regulation of glucose homeostasis, the modulation of inflammatory responses, and vascular endothelial cell proliferation. The transplantation of BAT into ischemic regions may offer therapeutic benefits in alleviating the symptoms associated with PAD. A diabetic mouse model was established via intraperitoneal administration of streptozocin. Subsequently, a diabetic lower limb ulcer model was constructed by transection of the femoral artery and ligation of the femoral vein. BAT harvested from the subscapular region of the mouse was employed as an adipose graft. The research utilized Laser Doppler monitoring, Western blot analysis, hematoxylin-eosin (HE) staining, immunofluorescence staining, and enzyme-linked immunosorbent assay (ELISA) to evaluate blood flow recovery in ischemic regions, histopathological changes, angiogenesis and tissue remodeling, inflammatory responses, and M1/M2 macrophage polarization. BAT transplantation significantly enhanced blood flow recovery in ischemic regions of diabetic lower limb ulcer mice while concurrently reducing necrotic tissue. Pathological analyses demonstrate that BAT transplantation mitigates ischemic tissue damage, stimulates angiogenesis, and supports tissue remodeling. Furthermore, the Western blotting, immunofluorescence, and ELISA results revealed that BAT transplantation significantly reduces inflammatory levels in ischemic tissues, increases the expression of angiogenic factors, and promotes the polarization of macrophages from the M1 to the M2 phenotype. The research has demonstrated that BAT transplantation can mitigate ischemic injury in diabetic lower limb ulcer mice, attenuate inflammatory responses, and facilitate the restoration of blood flow. These effects may be linked to alterations in macrophage polarization.

Dataset Information

Peripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damage.

Background

Methods

Results

Conclusions

Publications

Peripheral loss of EphA4 ameliorates TBI-induced neuroinflammation and tissue damage.

Similar Datasets

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