RESUMEN
Neuroinflammation contributes to secondary injury cascades following traumatic brain injury (TBI), with alternating waves of inflammation and resolution. Interleukin-1 (IL-1), a critical neuroinflammatory mediator originating from brain endothelial cells, microglia, astrocytes, and peripheral immune cells, is acutely overexpressed after TBI, propagating secondary injury and tissue damage. IL-1 affects blood-brain barrier permeability, immune cell activation, and neural plasticity. Despite the complexity of cytokine signaling post-TBI, we hypothesize that IL-1 signaling specifically regulates neuroinflammatory response components. Using a closed-head injury (CHI) TBI model, we investigated IL-1's role in the neuroinflammatory cascade with a new global knock-out (gKO) mouse model of the IL-1 receptor (IL-1R1), which efficiently eliminates all IL-1 signaling. We found that IL-1R1 gKO attenuated behavioral impairments 14 weeks post-injury and reduced reactive microglia and astrocyte staining in the neocortex, corpus callosum, and hippocampus. We then examined whether IL-1R1 loss altered acute neuroinflammatory dynamics, measuring gene expression changes in the neocortex at 3, 9, 24, and 72 h post-CHI using the NanoString Neuroinflammatory panel. Of 757 analyzed genes, IL-1R1 signaling showed temporal specificity in neuroinflammatory gene regulation, with major effects at 9 h post-CHI. IL-1R1 signaling specifically affected astrocyte-related genes, selectively upregulating chemokines like Ccl2, Ccl3, and Ccl4, while having limited impact on cytokine regulation, such as Tnfα. This study provides further insight into IL-1R1 function in amplifying the neuroinflammatory cascade following CHI in mice and demonstrates that suppression of IL-1R1 signaling offers long-term protective effects on brain health.
Asunto(s)
Lesiones Traumáticas del Encéfalo , Traumatismos Cerrados de la Cabeza , Receptores Tipo I de Interleucina-1 , Animales , Ratones , Lesiones Traumáticas del Encéfalo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Células Endoteliales/metabolismo , Traumatismos Cerrados de la Cabeza/complicaciones , Inflamación/metabolismo , Interleucina-1/metabolismo , Ratones Endogámicos C57BL , Microglía/metabolismo , Enfermedades Neuroinflamatorias , Receptores Tipo I de Interleucina-1/metabolismoRESUMEN
Epilepsy is a chronic disorder of the nervous system characterized by recurrent seizures. Inflammation is one of the six major causes of epilepsy, and its role in the pathogenesis of epilepsy is gaining increasing attention. Two signaling pathways, the high mobility group box-1 (HMGB1)/toll-like receptor 4 (TLR4) and interleukin-1ß (IL-1ß)/interleukin-1 receptor 1 (IL-1R1) pathways, have become the focus of research in recent years. These two signaling pathways have potential as biomarkers in the prediction, prognosis, and targeted therapy of epilepsy. This review focuses on the association between epilepsy and the neuroinflammatory responses mediated by these two signaling pathways. We hope to contribute further in-depth studies on the role of HMGB1/TLR4 and IL-1ß/IL-1R1 signaling in epileptogenesis and provide insights into the development of specific agents targeting these two pathways.
RESUMEN
Several barriers separate the central nervous system (CNS) from the rest of the body. These barriers are essential for regulating the movement of fluid, ions, molecules, and immune cells into and out of the brain parenchyma. Each CNS barrier is unique and highly dynamic. Endothelial cells, epithelial cells, pericytes, astrocytes, and other cellular constituents each have intricate functions that are essential to sustain the brain's health. Along with damaging neurons, a traumatic brain injury (TBI) also directly insults the CNS barrier-forming cells. Disruption to the barriers first occurs by physical damage to the cells, called the primary injury. Subsequently, during the secondary injury cascade, a further array of molecular and biochemical changes occurs at the barriers. These changes are focused on rebuilding and remodeling, as well as movement of immune cells and waste into and out of the brain. Secondary injury cascades further damage the CNS barriers. Inflammation is central to healthy remodeling of CNS barriers. However, inflammation, as a secondary pathology, also plays a role in the chronic disruption of the barriers' functions after TBI. The goal of this paper is to review the different barriers of the brain, including (1) the blood-brain barrier, (2) the blood-cerebrospinal fluid barrier, (3) the meningeal barrier, (4) the blood-retina barrier, and (5) the brain-lesion border. We then detail the changes at these barriers due to both primary and secondary injury following TBI and indicate areas open for future research and discoveries. Finally, we describe the unique function of the pro-inflammatory cytokine interleukin-1 as a central actor in the inflammatory regulation of CNS barrier function and dysfunction after a TBI.
Asunto(s)
Barrera Hematoencefálica/metabolismo , Barrera Hematorretinal/metabolismo , Lesiones Traumáticas del Encéfalo/metabolismo , Mediadores de Inflamación/metabolismo , Inflamación/metabolismo , Interleucina-1/metabolismo , Meninges/metabolismo , Animales , Antiinflamatorios/farmacología , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/patología , Barrera Hematorretinal/efectos de los fármacos , Barrera Hematorretinal/inmunología , Barrera Hematorretinal/patología , Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Lesiones Traumáticas del Encéfalo/inmunología , Lesiones Traumáticas del Encéfalo/patología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Mediadores de Inflamación/antagonistas & inhibidores , Interleucina-1/antagonistas & inhibidores , Meninges/efectos de los fármacos , Meninges/inmunología , Meninges/patología , Receptores Tipo I de Interleucina-1/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Interleukin-1 receptor 1 (IL-1R1) inhibition is a potential strategy for treating patients with chronic obstructive pulmonary disease (COPD). MEDI8968, a fully human monoclonal antibody, binds selectively to IL-1R1, inhibiting activation by IL-1α and IL-1ß. We studied the efficacy and safety/tolerability of MEDI8968 in adults with symptomatic, moderate-to-very severe COPD. METHODS: This was a phase II, randomised, double-blind, placebo-controlled, multicentre, parallel-group study. Subjects aged 45-75 years and receiving standard maintenance therapy with ≥2 exacerbations in the past year were randomised 1:1 to receive placebo or MEDI8968 300 mg (600 mg intravenous loading dose) subcutaneously every 4 weeks, for 52 weeks. The primary endpoint was the moderate/severe acute exacerbations of COPD (AECOPD) rate (week 56 post-randomisation). Secondary endpoints were severe AECOPD rate and St George's Respiratory Questionnaire-COPD (SGRQ-C) score (week 56 post-randomisation). RESULTS: Of subjects randomised to placebo (n = 164) and MEDI8968 (n = 160), 79.3% and 75.0%, respectively, completed the study. There were neither statistically significant differences between treatment groups in moderate/severe AECOPD rate ([90% confidence interval]: 0.78 [0.63, 0.96], placebo; 0.71 [0.57, 0.90], MEDI8968), nor in severe AECOPD rate or SGRQ-C scores. Post-hoc analysis of subject subgroups (by baseline neutrophil count or tertiles of circulating neutrophil counts) did not alter the study outcome. The incidence of treatment-emergent adverse events (TEAEs) with placebo and MEDI8968 treatment was similar. The most common TEAE was worsening of COPD. CONCLUSIONS: In this phase II study, MEDI8968 did not produce statistically significant improvements in AECOPD rate, lung function or quality of life. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01448850 , date of registration: 06 October 2011.
Asunto(s)
Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/metabolismo , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/diagnósticoRESUMEN
Taking into consideration the previous evidence of revealing the relationship of early life adversity, major depressive disorder (MDD), and stress-linked immunological changes, we recruited 22 MDD patients with childhood trauma exposures (CTE), 21 MDD patients without CTE, and 22 healthy controls without CTE, and then utilized a novel cytokine antibody array methodology to detect potential biomarkers underlying MDD in 120 peripheral cytokines and to evaluate the effect of CTE on cytokine changes in MDD patients. Although 13 cytokines were identified with highly significant differences in expressions between MDD patients and normal controls, this relationship was significantly attenuated and no longer significant after consideration of the effect of CTE in MDD patients. Depressed individuals with CTE (TD patients) were more likely to have higher peripheral levels of those cytokines. Severity of depression was associated with plasma levels of certain increased cytokines; meanwhile, the increased cytokines led to a proper separation of TD patients from normal controls during clustering analyses. Our research outcomes add great strength to the relationship between depression and cytokine changes and suggest that childhood trauma may play a vital role in the co-appearance of cytokine changes and depression.