TNF-α Impairs Pericyte-Mediated Cerebral Microcirculation via the NF-κB/iNOS Axis after Experimental Traumatic Brain Injury

Abstract

BackgroundSecondary structural and functional abnormalities of the neurovascular unit are important pathological mechanisms following traumatic brain injury (TBI). The tumor necrosis factor α (TNF-α)/nuclear factor-κB (NF-κB) pathway regulates neuroin ammation and oxidative damage, which may act as triggers for pathological processes after TBI. However, the role of TNF-α/NF-κB in pericyte-mediated cerebral microcirculation are currently unknown. MethodsWe assessed the activity and mechanisms of the TNF-α/NF-κB signaling axis on pericyte-mediated microcirculation using the mouse controlled cortical impact model and BV2 cells. Immuno uorescent staining and western blot analysis were used to detect activation of the TNF-α/NF-κB signaling pathway and the expression of inducible nitric oxide synthase (iNOS) to evaluate the effects of the TNF-α speci c inhibitor in iximab (IFX). Modi ed neurological severity scores, Garcia test, Nissl staining, and TUNEL staining were employed to determine the neuroprotective effects of IFX supplementation. The relative blood ow values in the capillary areas surrounding the impinging lesion were observed by Laser speckle contrast imaging. The impact of IFX on pericyte markers was assessed to evaluate whether pericyte damage was dependent on the TNF-α/NF-κB/iNOS axis to gain further insight into the mechanisms underlying the development of the microcirculation disturbance after TBI. ResultsMicroglia were activated after TBI, and the expression of NF-κB, iNOS, a disintegrin and metalloproteinase 17, in ammatory factors, and free radicals increased around the injury areas. After lipopolysaccharide treatment, the expression of TNF-α and downstream NF-κB/iNOS in BV2 cells was signi cantly upregulated. Pharmacological inhibition of TNF-α via IFX signi cantly reduced NF-κB p65 phosphorylation and nuclear translocation and downregulated iNOS expression. Meanwhile, we found that speci c inhibition of TNF-α reversed pericyte marker loss, and improved pericyte function and cerebral microcirculation perfusion after TBI, which could attenuate in ammation and oxidative damage, reduce neuronal cell damage and apoptosis, and play a neuroprotective role. ConclusionThe results of this study suggested that microglia activated and released TNF-α after TBI, which promoted neuroin ammation and oxidative stress by activating downstream NF-κB/iNOS signals, and

Bibliometric study of neuroinflammation in autism spectrum disorder

“…Current studies suggest that NF-kB is a convergence of multiple pathways in the pathogenesis of ASD, such as high expression of interleukin-17 receptor A potentially increasing the expression of NF-kB through activating the NF-kB pathway ( 21 ) or Toll-like receptor signal transduction ( 19 ). NF-kB is activated in response to these stressor stimuli, which drives the overexpression of pro-inflammatory genes (including cytokines, chemokines, and adhesion molecule expression), and plenty of pro-inflammatory factors are produced, including IL-1 and TNF-α, which in turn act as activators of NF-kB, creating a complex positive feedback that keeps NF-kB in a hyper-activated state, subsequently leading to a vicious cycle of excessive and uncontrolled neuroinflammation ( 52 ). Keyword burst is an essential means of investigating the evolution of academic research hotspots, and the intestinal microbiota and immune system have been continuous bursting keywords since 2019, which is consistent with the development of the microbiome-gut-brain axis hypothesis in the field of ASD neuroinflammation, and the intestinal microflora regulates changes in immunity and inflammation through the gut–brain axis, influencing the occurrence and development of ASD ( 53 ).…”

The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders

“…iNOS has been detected in nerve damage caused by various factors and is closely associated with neuroinflammation and neuropathic pain [168]. The expression of iNOS has also been found in diverse central nervous system diseases, such as Alzheimer's disease, Parkinson's disease, ischemic brain injury, and traumatic brain injury [169][170][171][172]. However, the specific mechanisms through which iNOS influences the damage and long-term prognosis of these diseases are not yet fully understood, as compared to other molecules.…”

“…The neuroinflammation in the central nervous system caused by iNOS is closely linked to microglia. During traumatic neuroinflammation, microglia-produced TNF-α activates the NF-κB/iNOS pathway, leading to alterations in brain microcirculation function [172] (Figure 1). This type of nerve injury is primarily characterized by damage to the blood-brain barrier.…”

What Are the Roles of Pericytes in the Neurovascular Unit and Its Disorders?

“…[75][76][77]131 As shown in traumatic injury models, microglial-released TNF-α initiates a nuclear factor kappa B pathway-inducible NO synthase cascade that results in pericyte damage. 132…”