Reversible Demyelination, Blood-Brain Barrier Breakdown, and Pronounced Neutrophil Recruitment Induced by Chronic IL-1 Expression in the Brain

Abstract

Interleukin-1␤ (IL-1) expression is associated with a spectrum of neuroinflammatory processes related to chronic neurodegenerative diseases. The single-bolus microinjection of IL-1 into the central nervous system (CNS) parenchyma gives rise to delayed and localized neutrophil recruitment, transient blood-brain barrier (BBB) breakdown, but no overt damage to CNS integrity. However, acute microinjections of IL-1 do not mimic the chronic IL-1 expression, which is a feature of many CNS diseases. To investigate the response of the CNS to chronic IL-1 expression, we injected a recombinant adenovirus expressing IL-1 into the striatum. At the peak of IL-1 expression (days 8 and 14 post-injection), there was a marked recruitment of neutrophils, vasodilatation, and breakdown of the BBB. Microglia and astrocyte activation was evident during the first 14 days post-injection. At days 8 and 14, extensive demyelination was observed but the number of neurons was not affected by any treatment. Finally, at 30 days, signs of inflammation were no longer present, there was evidence of tissue reorganization, the BBB was intact, and the process of remyelination was noticeable. In summary, our data show that chronic expression of IL-1, in contrast to its acute delivery, can reversibly damage CNS integrity and implicates this cytokine or downstream components as major mediators of demyelination in chronic inflammatory and demyelinating diseases.

Chronic Interleukin-1β Expression in Mouse Brain Leads to Leukocyte Infiltration and Neutrophil-Independent Blood–Brain Barrier Permeability without Overt Neurodegeneration

“…5 A, B,D). This observation is in general agreement with the literature in vivo, which suggests that IL-1␤ expression is not capable of neurotoxicity by itself but may serve to lower the threshold for additional injury (Rothwell, 2003;Ferrari et al, 2004;Hailer et al, 2005). Indeed, when expressed in concert with CNS injuries such as ischemia or excitotoxicity, IL-1␤ can produce marked exacerbations of neuronal injury in the affected regions (Allan et al, 2005;Patel et al, 2006).…”

“…Neutrophils are an important feature of the mammalian acute phase response and are quickly cleared within days after injury (Nathan, 2006). Neutrophil infiltration has not been reported beyond 3 weeks after targeting of IL-1␤ to the rodent brain, either after single bolus injection or expression by an adenoviral vector (Anthony et al, 1997(Anthony et al, , 1998Ferrari et al, 2004). Our results suggest that persistent infiltration of neutrophils is taking place in the IL-1␤ XAT mice, because neutrophils are incapable of surviving more than a few days after leaving the circulation (Simon, 2003).…”

“…The proinflammatory cytokine interleukin-1␤ (IL-1␤) is rapidly induced after experimental brain injuries, and has emerged as a powerful driving force for leukocyte recruitment to the CNS (Gibson et al, 2004). IL-1␤ alone is capable of overriding the intrinsic resistance of the CNS to leukocyte infiltration, resulting in acute cellular recruitment to the brain parenchyma (Anthony et al, 1997;Proescholdt et al, 2002;Ferrari et al, 2004;Ching et al, 2005;Depino et al, 2005). Additionally, blocking the actions of IL-1␤ using the IL-1 receptor antagonist (IL-1ra) results in significant reductions in parenchymal leukocyte infiltration after injury (Garcia et al, 1995;Yang et al, 1998).…”

Identification of a microglia phenotype supportive of remyelination

“…In contrast, remyelination is also seriously delayed and affected when microglia/macrophages are not present (Kotter et al, 2005;Li et al, 2005). Genetic ablation of the two classical proinflammatory cytokines, tumor necrosis factor alpha (TNFa) and interleukin-1 beta (IL-1b), which after application in the CNS cause neuroinflammation and subsequent demyelination (Ferrari et al, 2004;Redford et al, 1995), had no effect on demyelination in the cuprizone model, but significantly impeded remyelination due to inadequate recruitment and differentiation of OPCs (Arnett et al, 2001;Mason et al, 2001). This clearly outlines the complex nature of the relationship between inflammation and remyelination.…”

The Role of Death Domains Superfamily in Multiple Sclerosis Pathogenesis

“…On the other hand, IL-1β, as a proinflammatory cytokine initiates differentiation of Th17, thus IL-1RI-deficient mice are resistant to EAE induction [71]. Furthermore, like the IL-17 and IL-22, IL-1β can enhance BBB disruption; promote microglia and astrocyte activation and stimulate the demyelination process [72].…”