Interleukin-1 Receptor Antagonist as Therapy for Traumatic Brain Injury

Abstract

Traumatic brain injury is a common type of acquired brain injury of varying severity carrying potentially deleterious consequences for the afflicted individuals, families, and society. Following the initial, traumatically induced insult, cellular injury processes ensue. These are believed to be amenable to treatment. Among such injuries, neuroinflammation has gained interest and has become a specific focus for both experimental and clinical researchers. Neuroinflammation is elicited almost immediately following trauma, and extend for a long time, possibly for years, after the primary injury. In the acute phase, the inflammatory response is characterized by innate mechanisms such as the activation of microglia which among else mediates cytokine production. Among the earliest cytokines to emerge are the interleukin- (IL-) 1 family members, comprising, for example, the agonist IL-1β and its competitive antagonist, IL-1 receptor antagonist (IL-1ra). Because of its early emergence following trauma and its increased concentrations also after human TBI, IL-1 has been hypothesized to be a tractable treatment target following TBI. Ample experimental data supports this, and demonstrates restored neurological behavior, diminished lesion zones, and an attenuated inflammatory response following IL-1 modulation either through IL-1 knock-out experiments, IL-1β inhibition, or IL-1ra treatment. Of these, IL-1ra treatment is likely the most physiological. In addition, recombinant human IL-1ra (anakinra) is already approved for utilization across a few rheumatologic disorders. As of today, one randomized clinical controlled trial has utilized IL-1ra inhibition as an intervention and demonstrated its safety. Further clinical trials powered for patient outcome are needed in order to demonstrate efficacy. In this review, we summarize IL-1 biology in relation to acute neuroinflammatory processes following TBI with a particular focus on current evidence for IL-1ra treatment both in the experimental and clinical context.

Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI

“…Though IL-ra did not exhibit significant group differences in the LMMs, it was included in the model predicting CT+ status at admission and 2 weeks and was the only inflammation marker to show a positive association with intracranial findings. IL-ra is an endogenous receptor antagonist of IL-1ra [ 74 ] that is under investigation as a therapeutic target for TBI [ 75 , 76 ]. Its elevation in CT+ could therefore reflect endogenous repair mechanisms, although given it was only included in some CT models (but not MRI models), the clinical/biological relevance of this effect remains unclear.…”

Recent Research Trends in Neuroinflammatory and Neurodegenerative Disorders

“…Hormonal changes post-TBI reflect a disrupted endocrine system and may be predictive for patient outcomes including levels of plasma copeptin, nesfatin-1, and resistin [ 79 ]. A recent paper reported that IL-1 receptor antagonists as therapy for TBI [ 86 ]. Recent reports indicate that hyperbaric oxygen therapy (HBOT) was safe and beneficial in treating TBI including chronic sequelae of TBI [ 87 , 88 ].…”

Emerging functions and therapeutic targets of IL‐38 in central nervous system diseases

“…After effective anti-inflammatory treatment, the expression levels of these cytokines were remarkably reduced, and cognitive dysfunction was effectively improved. [7][8][9][10][11][12][13] Of further note, IL-36 receptor antagonist (IL-36Rα) and IL-38, two anti-inflammatory cytokines with similar functions in IL-1F reduced neuronal death and improved cognitive function defects by down-regulating the expression levels of IL-1β, tumor necrosis factor α (TNFα), and IL-6. 14,15 Therefore, targeting inflammatory cytokines is a promising new therapy for the treatment of CNS diseases and injuries.…”