Interferon‐β Modulates Inflammatory Response in Cerebral Ischemia

Abstract

BackgroundStroke is a leading cause of death in the world. In >80% of strokes, the initial acute phase of ischemic injury is due to the occlusion of a blood vessel resulting in severe focal hypoperfusion, excitotoxicity, and oxidative damage. Interferon‐β (IFNβ), a cytokine with immunomodulatory properties, was approved by the US Food and Drug Administration for the treatment of relapsing‐remitting multiple sclerosis for more than a decade. Its anti‐inflammatory properties and well‐characterized safety profile suggest that IFNβ has therapeutic potential for the treatment of ischemic stroke.Methods and ResultsWe investigated the therapeutic effect of IFNβ in the mouse model of transient middle cerebral artery occlusion/reperfusion. We found that IFNβ not only reduced infarct size in ischemic brains but also lessened neurological deficits in ischemic stroke animals. Further, multiple molecular mechanisms by which IFNβ modulates ischemic brain inflammation were identified. IFNβ reduced central nervous system infiltration of monocytes/macrophages, neutrophils, CD4+ T cells, and γδ T cells; inhibited the production of inflammatory mediators; suppressed the expression of adhesion molecules on brain endothelial cells; and repressed microglia activation in the ischemic brain.ConclusionsOur results demonstrate that IFNβ exerts a protective effect against ischemic stroke through its anti‐inflammatory properties and suggest that IFNβ is a potential therapeutic agent, targeting the reperfusion damage subsequent to the treatment with tissue plasminogen activator.

Microglia have a more extensive and divergent response to interferon‐α compared with astrocytes

“…While some studies have found that IFN-I protects against ischemic stroke and can reduce lesion size and leukocyte infiltration into the CNS (In acio et al, 2015;Kuo et al, 2016), others have observed the opposite (Zhang et al, 2017). In line with this latter study, Kavanagh and colleagues have recently demonstrated a causal relationship between IFN-I and microvascular changes including thrombotic microangiopathy in the CNS (Kavanagh et al, 2016).…”

Microglial Interferon Signaling and White Matter

“…Consistent with these findings, genetic deficiency of CD14, required for microglial production of type I IFNs, results in marked increases in post-MCAO infarct volume [58]. IFNβ modulates inflammatory processes in stroke, in part by suppressing inflammatory cytokine production and reducing microglial activation, resulting in reduced infarct volume and improved neurobehavioral outcomes [92]. Both of these outcomes are important in experimental stroke research.…”

Therapeutic spectrum of interferon‐β in ischemic stroke

“…IFN‐β significantly helps in obviating neuro‐inflammatory conditions of the central nervous system and improves the pathogenesis of many neurological conditions. A report suggested its role in decreasing neuronal cell death and increasing functional recovery attenuating inflammation after stroke onset (Kuo et al, ).…”

“…Type I IFNs (IFN‐α and IFN‐β) exhibit a wide breadth of biological activities (antiviral, anti‐inflammatory, and anti‐proliferative) (Kuo et al, ). The latter occurs via cytotoxic stimulation of numerous cells of the immune system such as natural killer cells, monocytes, T cells, macrophages, and dendritic cells.…”

“…Interferon‐β (IFN‐β), a broadly expressed cytokine, was approved by the US FDA in the past for the relapsing‐remitting multiple sclerosis (RRMS) treatment for more than a decade (Kuo et al, ). IFN‐β drives innate immunity, acting in response to pathogenic attack or injury via activation of both pro‐and anti‐inflammatory cytokines.…”