Infliximab Can Improve Traumatic Brain Injury by Suppressing the Tumor Necrosis Factor Alpha Pathway

Zhou, Yunfeng; Fan, Ruihua; Botchway, Benson O. A.; Zhang, Yong; Liu, Xuehong

doi:10.1007/s12035-021-02293-1

Cited by 15 publications

(5 citation statements)

References 91 publications

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“…This cohort (henceforth collectively defined as “Melbourne Cohort”) is independent of the Kaifeng Cohort and has been the object of publication before 41 ; clinical and demographic characteristics are briefly summarized in Supplementary Table 3 . We used a Single-Molecule Array (SIMOA) platform to determine the concentration of IL-13 and, as a proxy of inflammation 42 , of TNF-α in CSF samples obtained within 24 h of TBI (comparably to the Kaifeng Cohort); for a distinct subset of patients. Serial samples were available from day 0 (within 24 h of trauma), day 1 and day 4 and these samples were independently analyzed.…”

Section: Resultsmentioning

confidence: 99%

Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection

Heuvel

Rehman

et al. 2023

Nat Commun

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Immune system molecules are expressed by neurons, yet their functions are often unknown. We have identified IL-13 and its receptor IL-13Ra1 as neuronal, synaptic proteins in mouse, rat, and human brains, whose engagement upregulates the phosphorylation of NMDAR and AMPAR subunits and, in turn, increases synaptic activity and CREB-mediated transcription. We demonstrate that increased IL-13 is a hallmark of traumatic brain injury (TBI) in male mice as well as in two distinct cohorts of human patients. We also provide evidence that IL-13 upregulation protects neurons from excitotoxic death. We show IL-13 upregulation occurring in several cohorts of human brain samples and in cerebrospinal fluid (CSF). Thus, IL-13 is a physiological modulator of synaptic physiology of neuronal origin, with implications for the establishment of synaptic plasticity and the survival of neurons under injury conditions. Furthermore, we suggest that the neuroprotection afforded through the upregulation of IL-13 represents an entry point for interventions in the pathophysiology of TBI.

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Section: Resultsmentioning

confidence: 99%

Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection

Heuvel

Rehman

et al. 2023

Nat Commun

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“…In the capillary and venous segments, the capillary wall cells, especially the pericapillary cells, are surrounded by the basal lamina and play a major role in the regulation of blood flow in the microcirculation through neurovascular coupling 13 , 17 , 34 , 35 . In stroke disease models, intense contraction of pericytes in the ischemic core as well as in the penumbra is observed in the early stage 11 , 36 , 37 .…”

Section: Discussionmentioning

confidence: 99%

“…A large number of ROS/RNS products generated by this pathway can induce lipid peroxidation of the cell membrane, resulting in the destruction of phospholipid-dependent enzymes and ion channels, and the loss of function of capillary wall cells, leading to microcirculatory blood flow disturbance, BBB damage and brain swelling. Infliximab (IFX), a monoclonal antibody bound to TNF-α, has anti-inflammatory, anti-oxidative stress and anti-apoptosis effects, and is believed to alleviate the damage caused by hypoxia, ischemia, edema and vascular changes in the acute phase of TBI 17 . TNF-α is involved in various stages of TBI, and blocking TNF-α has been shown to promote neural function recovery after TBI, and is considered as a potential therapeutic target, but its mechanism has not been fully clarified 18 , 19 .…”

Section: Introductionmentioning

confidence: 99%

Assessment of cerebrovascular alterations induced by inflammatory response and oxidative–nitrative stress after traumatic intracranial hypertension and a potential mitigation strategy

Zhang,

Chen,

Chen

et al. 2024

Sci Rep

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The rapid perfusion of cerebral arteries leads to a significant increase in intracranial blood volume, exposing patients with traumatic brain injury to the risk of diffuse brain swelling or malignant brain herniation during decompressive craniectomy. The microcirculation and venous system are also involved in this process, but the precise mechanisms remain unclear. A physiological model of extremely high intracranial pressure was created in rats. This development triggered the TNF-α/NF-κB/iNOS axis in microglia, and released many inflammatory factors and reactive oxygen species/reactive nitrogen species, generating an excessive amount of peroxynitrite. Subsequently, the capillary wall cells especially pericytes exhibited severe degeneration and injury, the blood–brain barrier was disrupted, and a large number of blood cells were deposited within the microcirculation, resulting in a significant delay in the recovery of the microcirculation and venous blood flow compared to arterial flow, and this still persisted after decompressive craniectomy. Infliximab is a monoclonal antibody bound to TNF-α that effectively reduces the activity of TNF-α/NF-κB/iNOS axis. Treatment with Infliximab resulted in downregulation of inflammatory and oxidative–nitrative stress related factors, attenuation of capillary wall cells injury, and relative reduction of capillary hemostasis. These improved the delay in recovery of microcirculation and venous blood flow.

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“…Additional TNF-binding drugs include infliximab, a chimeric monoclonal anti-TNF antibody that has been used to reduce inflammation associated with a variety of chronic diseases and conditions [69,70]. Marketed as Remicade ® , infliximab functions to target TNF, attenuating inflammation by binding to Fc receptors to decrease the activation of monocyte and caspase-3induced oxidative stress [71,72]. While infliximab has been widely used for chronic diseases, its potential therapeutic role in neuroinflammation, like etanercept, warrants exploration.…”

Section: Tnf As a Therapeutic Targetmentioning

confidence: 99%

The Role of Tnf and Soluble Tnf Receptors (TNFR1/2) as Therapeutic Targets for Inflammation Secondary to Intracerebral Stroke and Hemorrhage

Alshaibi,

Ekanayake,

Barlow

et al. 2024

Preprint

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Most neurodegenerative diseases, including Alzheimer's disease, ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage are associated with inflammation. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine that regulates cerebral infarction in stroke pathology, and its action is influenced by the bioavailability of its membrane-bound receptors, TNFR1 and TNFR2, and microglial activation. During the initial onset of these diseases, the soluble variant of the cytokine presents with prolonged and excessive activation of TNFR1, resulting in cell death and long-term neurological impairments. Therapeutic interventions for neurodegenerative diseases have targeted TNF to limit the onset of neuroinflammation. First-generation therapeutics have been demonstrated to inhibit membrane-bound TNF to TNFR2 receptor binding, resulting in severe side effects such as infections and cancer. As such, second-generation drugs, including XPro1595, have been developed to selectively inhibit soluble TNF and impede the effects of TNFR1 while still allowing for TNFR2 activation. Early results in murine TBI models demonstrate reduced glial reactivity by 50%, reduced dendritic degeneration by 30%, increased plasticity by 15%, and improved functional outcomes by 20% post-TBI. This scoping review of TNF receptors in various neurodegenerative diseases seeks to evaluate current and future therapeutic strategies as well as highlight potential strategies to eliminate confounding variables present in the current literature.

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Infliximab Can Improve Traumatic Brain Injury by Suppressing the Tumor Necrosis Factor Alpha Pathway

Cited by 15 publications

References 91 publications

Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection

Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection

Assessment of cerebrovascular alterations induced by inflammatory response and oxidative–nitrative stress after traumatic intracranial hypertension and a potential mitigation strategy

The Role of Tnf and Soluble Tnf Receptors (TNFR1/2) as Therapeutic Targets for Inflammation Secondary to Intracerebral Stroke and Hemorrhage

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