Astrocytes: Integrative Regulators of Neuroinflammation in Stroke and Other Neurological Diseases

Abstract

Astrocytes regulate neuroinflammatory responses after stroke and in other neurological diseases. Although not all astrocytic responses reduce inflammation, their predominant function is to protect the brain by driving the system back to homeostasis after injury. They receive multidimensional signals within the central nervous system and between the brain and the systemic circulation. Processing this information allows astrocytes to regulate synapse formation and maintenance, cerebral blood flow, and blood-brain barrier integrity. Similarly, in response to stroke and other central nervous system disorders, astrocytes detect and integrate signals of neuronal damage and inflammation to regulate the neuroinflammatory response. Two direct regulatory mechanisms in the astrocyte arsenal are the ability to form both physical and molecular barriers that seal the injury site and localize the neuroinflammatory response. Astrocytes also indirectly regulate the inflammatory response by affecting neuronal health during the acute injury and axonal regrowth. This ability to regulate the location and degree of neuroinflammation after injury, combined with the long time course of neuroinflammation, makes astrocytic signaling pathways promising targets for therapies.

Transgenic expression of HuR increases vasogenic edema and impedes functional recovery in rodent ischemic stroke

“…At 72 hours after injury, an increase in GFAP immunoreactivity was observed at the infarct periphery (Figure 1 A – C) which is consistent with typical injury-mediated astrocyte activation [9]. In Tg mice, an enrichment of FLAG-positive astrocytes was observed 72 hours after ischemia (Figure 1 D, E; Figure 2).…”

“…Upon central nervous system (CNS) injury, astrocytes act as first responders and become activated in injured tissue where they play different, and at times conflicting, roles [2, 29, 31]. On the one hand, astrocytes provide energy substrates to neurons, remove excitotoxins in the microenvironment, and promote recovery; on the other, once activated, they initiate an inflammatory response [9, 13, 31] which becomes amplified through the production of chemokines and recruitment of additional glial cells and immune cells [13, 35]. Following ischemia, activated astrocytes are present at the infarct borderzone within the first week, during the peak inflammatory response [9].…”

Role of neuroinflammation in ischemic stroke

“…[38] These two cells are key players in the multicellular response to central nervous system (CNS) trauma and disease, including the immune reactions. [39,40] TLRs, the well-defined pattern recognition receptors of the immune system, [41] can initiate an immune response upon exposure to harmful microorganisms [42] and play a key role in macrophage activation. Neuronal TLR's play a central role in connecting the interactions between the immune system and the nervous system.…”

Glial scars are permeable to the neurotoxic environment of chronic stroke infarcts

“…Activated astrocytes respond rapidly to ischemic stroke by upregulating genes for intermediate filaments such as glial fibrillary acidic protein (GFAP), calcium-binding protein B (S100B), vimentin, and nestin (Pekny and Nilsson, 2005; Farina et al, 2007; Cekanaviciute and Buckwalter, 2016). These changes in gene expression are accompanied by proliferation and migration towards the injured area.…”

“…The injury is then walled off by a front line of reactive astrocytes interspersed with activated microglia/macrophages, resulting in a glial scar. The physical barrier function of the glial scar is reinforced by the production of extracellular matrix proteins such as fibronectin, laminin, and chondroitin sulphate proteoglycans (Cekanaviciute and Buckwalter, 2016). Together, these mechanisms create a barrier that corrals inflammatory cells present within the core of the injury (Bush et al, 1999; Wanner et al, 2013).…”