Reactive Astrocytes Form Scar-Like Perivascular Barriers to Leukocytes during Adaptive Immune Inflammation of the CNS

Abstract

Factors that regulate leukocyte entry and spread through CNS parenchyma during different types of CNS insults are incompletely understood. Reactive astrocytes have been implicated in restricting the spread of leukocytes from damaged into healthy parenchyma during the acute and local innate inflammatory events that follow CNS trauma, but the roles of reactive astrocytes during the chronic and widespread CNS inflammation associated with adaptive or acquired immune responses are uncertain. Here, we investigated the effects of transgenically targeted ablation of proliferating, scar-forming reactive astrocytes on the acquired immune inflammation associated with experimental autoimmune encephalitis (EAE). In wild-type mice with EAE, we found that reactive astrocytes densely surrounded perivascular clusters of leukocytes in a manner reminiscent of astrocyte scar formation after CNS trauma. Transgenically targeted ablation of proliferating astrocytes disrupted formation of these perivascular scars and was associated with a pronounced and significant increase in leukocyte entry into CNS parenchyma, including immunohistochemically identified macrophages, T lymphocytes and neutrophils. This exacerbated inflammation was associated with a substantially more severe and rapidly fulminant clinical course. These findings provide experimental evidence that reactive astrocytes form scar-like perivascular barriers that restrict the influx of leukocytes into CNS parenchyma and protect CNS function during peripherally initiated, acquired immune inflammatory responses in the CNS. The findings suggest that loss or disruption of astrocyte functions may underlie or exacerbate the inflammation and pathologies associated with autoimmune diseases of the CNS, including multiple sclerosis.

Upregulation of Vascular Endothelial Growth Factor Receptor-3 in the Spinal Cord of Lewis Rats with Experimental Autoimmune Encephalomyelitis

“…Elimination of macrophages or microglia suppresses clinical and histopathological manifestations in rodent models of MS (Brosnan et al 1981;Huitinga et al 1990;Bauer et al 1995;Polfliet et al 2002;Heppner et al 2005), and infiltrating blood-borne monocytes trigger EAE progression to the severe form of the disease (Ajami et al 2011). In addition, astrocytes, CNS-resident glial cells, play an active role in the pathogenesis of EAE and MS (Voskuhl et al 2009;Toft-Hansen et al 2011), and their activation is a prominent feature in EAE and MS (Aquino et al 1988;Liedtke et al 1998).…”

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“…At the same time, the glial scar provides a barrier against inflammation to limit secondary injury, and this is beneficial [10,11] . Cheng He of the Second Military Medical University (Shanghai) [12] discusses the complex role of the glial scar in influencing axon regeneration and neuroinflammation.…”

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“…In contrast, accumulating evidence indicates that local astroglial activation is neuroprotective in EAE. Using transgenic mice with targeted ablation of proliferating scar-forming astrocytes it has been shown that severity of EAE is enhanced and that leukocyte and macrophage entry into the CNS parenchyma is significantly increased (Voskuhl et al 2009). Recent evidence additionally indicates that demyelination and oligodendrocyte degeneration follows inflammation-induced astrocyte dysfunction (Sharma et al 2010).…”