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.

Keywords: Anakinra; Interleukin-1; Interleukin-1 receptor antagonist; Neurocritical care; Neuroinflammation; Neurotrauma; Personalized medicine; Randomized controlled clinical trial; Secondary insult; Traumatic brain injury.

Fig. 1

IL-1 signaling in the CNS. IL-1 ligands such as IL-1α, IL-1β, and IL-1ra binds to either one of the two IL-1 receptors IL-1R1 or IL-1R2. IL-1β is synthesized upon inflammasome activation, typically within microglia and released. Upon binding to IL-1R1 (located at neurons, astrocytes, and endothelial cells), IL-1β elicits an intracellular signaling cascade, dependent on dimerization to the IL-1 receptor accessory protein. Ultimately, this leads to transcription of mediators pertaining to various pathways, e.g. NFκB, AP-1, and JNK. IL-1ra is a competitive IL-1 antagonist and hinders further IL-1 signaling. IL-1R2 is a decoy receptor, which also inhibits IL-1 signaling. Abbreviations: AP-1, activator protein 1; IL-, interleukin; IL-1R, interleukin receptor type; IL-1ra, IL-1 receptor antagonist, IL-1RAcP, IL-1 receptor accessory protein; JNK, c-Jun N-terminal kinase; NFκB, nuclear factor kappa light-chain-enhancer of activated B cells

Fig. 2

IL-1 synthesis and downstream effects following traumatic brain injury. Upon trauma, tissue destruction leads to the release of DAMPs from dying cells and leakage of inflammatory mediators such as complement across a disrupted BBB. This elicits innate CNS immune responses through binding of DAMPs to PRRs. Across these events, microglia is a core CNS specific immune cell. Various PRRs elicit different immune responses. In the inset, a priming and activation stimulus are depicted, typically necessary to activate the inflammasome within microglia. This yields cleavage of pro-IL1β into its active form. Inflammasome activation can also yield pyroptosis, through which even more IL-1β is expected to leak into the extracellular room. Here, IL-1β effectuates numerous biological processes, of both deleterious and beneficial character for the injured CNS. Abbreviations: AP-1, activator protein 1; ASC, apoptosis-associated speck-like protein containing a caspase recruiting domain; BBB, blood-brain barrier; CNS, central nervous system; DAMP, damage-associated molecular pattern; IL- interleukin; IL-1ra, IL-1 receptor antagonist; JNK, c-Jun N-terminal kinase; NGF, nerve growth factor; NFκB, nuclear factor kappa light-chain-enhancer of activated B cells; NLR, nucleotide-binding oligomerization domain-like receptor; PRR, pattern recognition receptor; TBI, traumatic brain injury; TLR, Toll-like receptor