Interferons in Traumatic Brain and Spinal Cord Injury: Current Evidence for Translational Application

Abstract

This review article provides a general perspective of the experimental and clinical work surrounding the role of type-I, type-II, and type-III interferons (IFNs) in the pathophysiology of brain and spinal cord injury. Since IFNs are themselves well-known therapeutic targets (as well as pharmacological agents), and anti-IFNs monoclonal antibodies are being tested in clinical trials, it is timely to review the basis for the repurposing of these agents for the treatment of brain and spinal cord traumatic injury. Experimental evidence suggests that IFN-α may play a detrimental role in brain trauma, enhancing the pro-inflammatory response while keeping in check astrocyte proliferation; converging evidence from genetic models and neutralization by monoclonal antibodies suggests that limiting IFN-α actions in acute trauma may be a suitable therapeutic strategy. Effects of IFN-β administration in spinal cord and brain trauma have been reported but remain unclear or limited in effect. Despite the involvement in the inflammatory response, the role of IFN-γ remains controversial: although IFN-γ appears to improve the outcome of traumatic spinal cord injury, genetic models have produced either beneficial or detrimental results. IFNs may display opposing actions on the injured CNS relative to the concentration at which they are released and strictly dependent on whether the IFN or their receptors are targeted either via administration of neutralizing antibodies or through genetic deletion of either the mediator or its receptor. To date, IFN-α appears to most promising target for drug repurposing, and monoclonal antibodies anti IFN-α or its receptor may find appropriate use in the treatment of acute brain or spinal cord injury.

Decoding the transcriptional response to ischemic stroke in young and aged mouse brain

“…An outstanding feature of differential response of aged animals to ischemic stroke was upregulation of IFN-I pathway ( Figure 2B, 3A, 5A-E, S2, S3B), which persisted for at least 14 days ( Figure 6E). IFN-Is are antiviral cytokines with pleiotropic roles 129 implicated in a number of CNS pathologies including multiple sclerosis 130,131 , Aicardi-Goutières syndrome, amyotrophic lateral sclerosis 132 , Alzheimer's disease 59,133,134 , spinal cord injury 135 , traumatic brain injury 136,137 and ischemic stroke 100,103,138 . Therefore, we have explored INF-I signaling in more detail and found that two IFN-I regulatory modules are activated by stroke irrespective of age, but only the canonical STATdependent module is differentially activated in aged animals ( Figure 6B-D), likely contributing to an increased neurotoxicity 100 .…”

Systemic Inflammation Persists the First Year after Mild Traumatic Brain Injury: Results from the Prospective Trondheim Mild Traumatic Brain Injury Study

“…On the other hand, LOC was positively associated with admission IFN-c. IFN-c is upregulated in the brain following TBI, but there is ongoing discussion about whether IFN-c elevation is beneficial or detrimental. 43,44 A large positive association of other injuries with TNF was demonstrated. These results are unsurprising, as TNF release has been reported in response to bone fractures and virtually all forms of ischemia/reperfusion injury in the acute phase.…”

The Therapeutic Potential of Conditioned Medium from Human Breast Milk Stem Cells in Treating Spinal Cord Injury

“…Spinal cord injury (SCI) is a serious neurological condition that impacts a patient's ability to function [1]. SCI is a result of the primary injury, which occurs as a direct consequence of trauma and the secondary injury, which occurs following the onset of reactive processes such as inflammation, ischemia, free radical production, apoptosis, and necrosis in the spinal cord [2].…”