Interleukin-1 and acute brain injury

Abstract

Inflammation is the key host-defense response to infection and injury, yet also a major contributor to a diverse range of diseases, both peripheral and central in origin. Brain injury as a result of stroke or trauma is a leading cause of death and disability worldwide, yet there are no effective treatments, resulting in enormous social and economic costs. Increasing evidence, both preclinical and clinical, highlights inflammation as an important factor in stroke, both in determining outcome and as a contributor to risk. A number of inflammatory mediators have been proposed as key targets for intervention to reduce the burden of stroke, several reaching clinical trial, but as yet yielding no success. Many factors could explain these failures, including the lack of robust preclinical evidence and poorly designed clinical trials, in addition to the complex nature of the clinical condition. Lack of consideration in preclinical studies of associated co-morbidities prevalent in the clinical stroke population is now seen as an important omission in previous work. These co-morbidities (atherosclerosis, hypertension, diabetes, infection) have a strong inflammatory component, supporting the need for greater understanding of how inflammation contributes to acute brain injury. Interleukin (IL)-1 is the prototypical pro-inflammatory cytokine, first identified many years ago as the endogenous pyrogen. Research over the last 20 years or so reveals that IL-1 is an important mediator of neuronal injury and blocking the actions of IL-1 is beneficial in a number of experimental models of brain damage. Mechanisms underlying the actions of IL-1 in brain injury remain unclear, though increasing evidence indicates the cerebrovasculature as a key target. Recent literature supporting this and other aspects of how IL-1 and systemic inflammation in general contribute to acute brain injury are discussed in this review.

Clinical Trials of Immunomodulation in Ischemic Stroke

“…Stroke causes upregulation of the IL-1 receptor and its ligands in animal models [41], with expression of IL-1α seen in microglia within 4 h postreperfusion [42]. Furthermore, exogenous administration of IL-1β exacerbates ischaemic damage in rodent models, with the absence of IL-1α or IL-1β in knockout mice ameliorating damage [43]. A recent meta-analysis showed that IL1Ra administration was associated with a 38.2 % reduction in mean infarct volume across 16 published preclinical studies [44].…”

Attenuation of Blood-Brain Barrier Breakdown and Hyperpermeability by Calpain Inhibition

“…IL-1␤ is the most implicated pro-inflammatory cytokine in various pathologies of the central nervous system, including TBI (6,7). Interleukin-1 (IL-1) inhibition has beneficial effects as demonstrated in experimental models of brain damage (6). IL-1␤ induces BBB breakdown in rat brain endothelial cells and also increases human brain microvascular endothelial cell permeability (8).…”

“…IL-1␤ is the most implicated pro-inflammatory cytokine in various pathologies of the central nervous system, including TBI (6,7). Interleukin-1 (IL-1) inhibition has beneficial effects as demonstrated in experimental models of brain damage (6).…”

Effect of Interleukin-1Beta (IL-1<i>β</i>) on the Cortical Neurons Survival and Neurites Outgrowth

“…Insults to the brain are known to cause a myriad of downstream effects, including the release of cytokines by astrocytes and resultant reactive gliosis [7] [8]. Cytokines are thought to be a major mediator of reactive gliosis [9].…”

“…IL-1β is a pro-inflammatory cytokine that exerts an important role in developing brains as a maintenance and growth-promoting factor [10] [11] and in migration of cortical neurons [12]. IL-1β is secreted by activated astroglia and microglia in brain, where it exerts a diverse range of activities on immune function and coordination of many aspects of the acute phase response to trauma and infection [8] [10]. Inflammation is the key hostdefense response to infection and injury but is also thought to be a major contributor to a diverse range of diseases.…”