Neuroinflammation Following Traumatic Brain Injury: Take It Seriously or Not

Zheng, Ruizhe; Lee, Kuin-yu; Qi, Zengxin; Wang, Zhe; Xu, Zeyu; Wu, Xuehai; Mao, Ying

doi:10.3389/fimmu.2022.855701

Cited by 43 publications

(34 citation statements)

References 122 publications

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“…TBI triggers a rapid astrocytic response to brain trauma [ 12 , 46 – 49 ]. Although an increased number of astrocytes in post-trauma brains have been shown to seal the disrupted BBB to a certain extent [ 50 ], an excessive increase in the number of astrocytes may lead to an overabundance of pro-inflammatory responses that result in axonal injury, vascular disruption, and local ischemia in post-traumatic brains [ 47 , 49 ]. Previous studies have demonstrated that high levels of serum GFAP and S100B (an astrocyte marker) may function as predictors for increased mortality and unfavorable outcomes in TBI [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic deletion of Krüppel-like factor 11 aggravates traumatic brain injury

Zhou

Sun

Hamblin

et al. 2022

J Neuroinflammation

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Background The long-term functional recovery of traumatic brain injury (TBI) is hampered by pathological events, such as parenchymal neuroinflammation, neuronal death, and white matter injury. Krüppel-like transcription factor 11 (KLF 11) belongs to the zinc finger family of transcription factors and actively participates in various pathophysiological processes in neurological disorders. Up to now, the role and molecular mechanisms of KLF11 in regulating the pathogenesis of brain trauma is poorly understood. Methods KLF11 knockout (KO) and wild-type (WT) mice were subjected to experimental TBI, and sensorimotor and cognitive functions were evaluated by rotarod, adhesive tape removal, foot fault, water maze, and passive avoidance tests. Brain tissue loss/neuronal death was examined by MAP2 and NeuN immunostaining, and Cresyl violet staining. White matter injury was assessed by Luxol fast blue staining, and also MBP/SMI32 and Caspr/Nav1.6 immunostaining. Activation of cerebral glial cells and infiltration of blood-borne immune cells were detected by GFAP, Iba-1/CD16/32, Iba-1/CD206, Ly-6B, and F4/80 immunostaining. Brian parenchymal inflammatory cytokines were measured with inflammatory array kits. Results Genetic deletion of KLF11 worsened brain trauma-induced sensorimotor and cognitive deficits, brain tissue loss and neuronal death, and white matter injury in mice. KLF11 genetic deficiency in mice also accelerated post-trauma astrocytic activation, promoted microglial polarization to a pro-inflammatory phenotype, and increased the infiltration of peripheral neutrophils and macrophages into the brain parenchyma. Mechanistically, loss-of-KLF11 function was found to directly increase the expression of pro-inflammatory cytokines in the brains of TBI mice. Conclusion KLF11 acts as a novel protective factor in TBI. KLF11 genetic deficiency in mice aggravated the neuroinflammatory responses, grey and white matter injury, and impaired long-term sensorimotor and cognitive recovery. Elucidating the functional importance of KLF11 in TBI may lead us to discover novel pharmacological targets for the development of effective therapies against brain trauma.

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Section: Discussionmentioning

confidence: 99%

Genetic deletion of Krüppel-like factor 11 aggravates traumatic brain injury

Zhou

Sun

Hamblin

et al. 2022

J Neuroinflammation

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“…Recovery after mTBI varies among the patient population with some patients displaying better outcome measures than others. These differences in outcomes may be attributed to pre-existing conditions, genetic factors or concurrent polytrauma [ 36 , 74 ]. However, less attention has been paid to the effect of secondary insults during the chronic phase of mTBI on outcome measures, and the consequences are not well understood.…”

Section: Discussionmentioning

confidence: 99%

Impact of gulf war toxic exposures after mild traumatic brain injury

Ferguson

McCartan

Browning

et al. 2022

acta neuropathol commun

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Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of traumatic brain injury (TBI) remains an area of study that has received little attention thus far. We studied the effects of pyridostigmine bromide (an anti-nerve agent) and permethrin (a pesticide) exposure in a mouse model of repetitive mild TBI (r-mTBI), with 5 impacts over a 9-day period, followed by Gulf War (GW) toxicant exposure for 10 days beginning 30 days after the last head injury. We then assessed the chronic behavioral and pathological sequelae 5 months after GW agent exposure. We observed that r-mTBI and GWI cumulatively affect the spatial memory of mice in the Barnes maze and result in a shift of search strategies employed by r-mTBI/GW exposed mice. GW exposure also produced anxiety-like behavior in sham animals, but r-mTBI produced disinhibition in both the vehicle and GW treated mice. Pathologically, GW exposure worsened r-mTBI dependent axonal degeneration and neuroinflammation, increased oligodendrocyte cell counts, and increased r-mTBI dependent phosphorylated tau, which was found to colocalize with oligodendrocytes in the corpus callosum. These results suggest that GW exposures may worsen TBI-related deficits. Veterans with a history of both GW chemical exposures as well as TBI may be at higher risk for worse symptoms and outcomes. Subsequent exposure to various toxic substances can influence the chronic nature of mTBI and should be considered as an etiological factor influencing mTBI recovery.

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“…The process is difficult to stop after the danger signal is no longer present, consequently, neutrophils indiscriminately cause brain tissue damage ( 33 , 34 ). Other studies have shown that the infiltration of T lymphocytes, monocytes, B cells and microglia after polarization plays a complex role in TBI, causing different effects, such as repair or aggravation of brain injury, at different periods ( 11 , 12 , 35 , 36 ). Therefore, the infiltration of inflammatory cells after TBI and downstream reactions play indispensable roles in TBI.…”

Section: Discussionmentioning

confidence: 99%

Systemic immune inflammation index and peripheral blood carbon dioxide concentration at admission predict poor prognosis in patients with severe traumatic brain injury

et al. 2023

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BackgroundRecent studies have shown that systemic inflammation responses and hyperventilation are associated with poor outcomes in patients with severe traumatic brain injury (TBI). The aim of this retrospective study was to investigate the relationships between the systemic immune inflammation index (SII = platelet × neutrophil/lymphocyte) and peripheral blood CO2 concentration at admission with the Glasgow Outcome Score (GOS) at 6 months after discharge in patients with severe TBI.MethodsWe retrospectively analyzed the clinical data for 1266 patients with severe TBI at three large medical centers from January 2016 to December 2021, and recorded the GOS 6 months after discharge. The receiver operating characteristic (ROC) curve was used to determine the best cutoff values for SII, CO2, neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and lymphocyte to monocyte ratio (LMR), and chi-square tests were used to evaluate the relationships among SII, CO2 and the basic clinical characteristics of patients with TBI. Multivariate logistic regression analysis was used to determine the independent prognostic factors for GOS in patients with severe TBI. Finally, ROC curve, nomogram, calibration curve and decision curve analyses were used to evaluate the value of SII and coSII-CO2 in predicting the prognosis of patients with severe TBI. And we used the multifactor regression analysis method to build the CRASH model and the IMPACT model. The CRASH model included age, GCS score (GCS, Glasgow Coma Scale) and Pupillary reflex to light: one, both, none. The IMPACT model includes age, motor score and Pupillary reflex to light: one, both, none.ResultsThe ROC curves indicated that the best cutoff values of SII, CO2, PLR, NLR and LMR were 2651.43×109, 22.15mmol/L, 190.98×109, 9.66×109 and 1.5×109, respectively. The GOS at 6 months after discharge of patients with high SII and low CO2 were significantly poorer than those with low SII and high CO2. Multivariate logistic regression analysis revealed that age, systolic blood pressure (SBP), pupil size, subarachnoid hemorrhage (SAH), SII, PLR, serum potassium concentration [K+], serum calcium concentration [Ca2+], international normalized ratio (INR), C-reactive protein (CRP) and co-systemic immune inflammation index combined with carbon dioxide (coSII-CO2) (P < 0.001) were independent prognostic factors for GOS in patients with severe TBI. In the training group, the C-index was 0.837 with SII and 0.860 with coSII-CO2. In the external validation group, the C-index was 0.907 with SII and 0.916 with coSII-CO2. Decision curve analysis confirmed a superior net clinical benefit with coSII-CO2 rather than SII in most cases. Furthermore, the calibration curve for the probability of GOS 6 months after discharge showed better agreement with the observed results when based on the coSII-CO2 rather than the SII nomogram. According to machine learning, coSII-CO2 ranked first in importance and was followed by pupil size, then SII.ConclusionsSII and CO2 have better predictive performance than NLR, PLR and LMR. SII and CO2 can be used as new, accurate and objective clinical predictors, and coSII-CO2, based on combining SII with CO2, can be used to improve the accuracy of GOS prediction in patients with TBI 6 months after discharge.

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Neuroinflammation Following Traumatic Brain Injury: Take It Seriously or Not

Cited by 43 publications

References 122 publications

Genetic deletion of Krüppel-like factor 11 aggravates traumatic brain injury

Genetic deletion of Krüppel-like factor 11 aggravates traumatic brain injury

Impact of gulf war toxic exposures after mild traumatic brain injury

Systemic immune inflammation index and peripheral blood carbon dioxide concentration at admission predict poor prognosis in patients with severe traumatic brain injury

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