Systemic Inflammation Alters the Kinetics of Cerebrovascular Tight Junction Disruption after Experimental Stroke in Mice

Abstract

Systemic inflammatory events, such as infection, increase the risk of stroke and are associated with worse outcome, but the mediators of this clinically important effect are unknown. Our aim here was to elucidate mechanisms contributing to the detrimental effects of systemic inflammation on mild ischemic brain injury in mice. Systemic inflammation was induced in mice by peripheral interleukin-1␤ (IL-1␤) challenge and focal cerebral ischemia by transient middle cerebral artery occlusion (MCAo). Systemic inflammation caused an alteration in the kinetics of blood-brain barrier (BBB) disruption through conversion of a transient to a sustained disruption of the tight junction protein, claudin-5, and also markedly exacerbated disruption to the cerebrovascular basal lamina protein, collagen-IV. These alterations were associated with a systemic inflammation-induced increase in neurovascular gelatinolytic activity that was mediated by a fivefold increase in neutrophil-derived matrix metalloproteinase-9 (MMP-9) in the brains of IL-1␤-challenged mice after MCAo. Specific inhibition of MMP-9 abrogated the effects of systemic inflammation on the sustained but not the acute disruption of claudin-5, which was associated with phosphorylation of cerebrovascular myosin light chain. MMP-9 inhibition also attenuated the deleterious impact of systemic inflammation on brain damage, edema, neurological deficit, and incidence of hemorrhagic transformation. These data indicate that a transformation from transient to sustained BBB disruption caused by enhanced neutrophil-derived neurovascular MMP-9 activity is a critical mechanism underlying the exacerbation of ischemic brain injury by systemic inflammation. These mechanisms may contribute to the poor clinical outcome in stroke patients presenting with antecedent infection.

Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

“…Indeed, peripheral IL-6 is implicated in atherosclerosis (Schuett et al, 2009), which, together with increased neuroinflammation, may lead to alterations in vascular permeability before stroke and/or influence BBB breakdown after stroke. This is supported by our recent data indicating that an acute systemic inflammatory challenge alters the kinetics of BBB disruption after experimental stroke, an effect that is both neutrophil and MMP-9 dependent (McColl et al, 2007;McColl et al, 2008), and by previous studies confirming the role of MMP-9 in BBB disruption and hemorrhagic transformation experimentally and clinically (Castellanos et al, 2003;Gasche et al, 1999;McColl et al, 2010). An important role for neutrophils and MMP-9 in ischemic injury in the presence of systemic inflammation is confirmed in this study, more neutrophils being seen in Cp rats.…”

Magnetic Resonance Imaging Reveals Therapeutic Effects of Interferon-Beta on Cytokine-Induced Reactivation of Rat Model of Multiple Sclerosis

“…8 Previously, we demonstrated reactivation of a focal myelin oligodendrocyte glycoprotein-induced experimental allergic encephalomyelitis lesion in the rat brain following systemic bacterial endotoxin injection. 9 Our findings parallel the disease-modifying effects of systemic inflammation on chronic neurodegeneration in models of Prion disease, 10 stroke, [11][12][13] MS, 14 and Parkinson's disease. 15,16 These findings together highlight an important generic role for innate immune-brain interactions in acute and chronic neurological dysfunction.…”

The Immune System in Stroke: Clinical Challenges and Their Translation to Experimental Research

“…Preceding infection is (although not uniformly) also associated with worse clinical outcome (Emsley and Hopkins 2008a; Grau et al 1995;Macko et al 1996). In mice, administration of LPS prior to MCAo results in worse neurological outcome, cerebral edema and increased BBB injury (McColl et al 2008(McColl et al , 2007Denes et al 2011a). After endotoxin treatment, blood-derived leukocytes, primarily neutrophils have been shown to contribute to BBB injury via MMP-9 production that results in altered expression of endothelial tight junction proteins (McColl et al 2008).…”

“…In mice, administration of LPS prior to MCAo results in worse neurological outcome, cerebral edema and increased BBB injury (McColl et al 2008(McColl et al , 2007Denes et al 2011a). After endotoxin treatment, blood-derived leukocytes, primarily neutrophils have been shown to contribute to BBB injury via MMP-9 production that results in altered expression of endothelial tight junction proteins (McColl et al 2008). Endotoxin administration also results in rapid systemic upregulation of pro-inflammatory cytokines and chemokines, such as IL-1β, TNFα, IL-6, CXCL1 (KC), RANTES (CCL5) and MCP-1 that is apparent in both the circulation and the brain prior to cerebral ischemia (Denes et al 2011a).…”