Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination

Abstract

Astrocytes respond to insult with a process of cellular activation known as reactive astrogliosis. One of the key signals regulating this phenomenon is the transcription factor nuclear factor-kappa B (NF-κB), which is responsible for modulating inflammation, cell survival, and cell death. In astrocytes, following trauma or disease, the expression of NF-κB-dependent genes is highly activated. We previously demonstrated that inactivation of astroglial NF-κB in vivo (GFAP-IκBα-dn mice) leads to improved functional outcome in experimental autoimmune encephalomyelitis (EAE), and this is accompanied by reduction of pro-inflammatory gene expression in the CNS. Here we extend our studies to show that recovery from EAE in GFAP-IκBα-dn mice is associated with reduction of peripheral immune cell infiltration into the CNS at the chronic phase of EAE. This is not dependent on a less permeable blood-brain barrier, but rather on a reduced immune cell mobilization from the periphery. Furthermore, once inside the CNS, the ability of T cells to produce pro-inflammatory cytokines is diminished during acute disease. In parallel, we found that the number of total and activated microglial cells is reduced, suggesting that functional improvement in GFAP-IκBα-dn mice is dependent upon reduction of the overall inflammatory response within the CNS sustained by both resident and infiltrating cells. This results in preservation of myelin compaction and enhanced remyelination, as shown by electron microscopy analysis of the spinal cord. Collectively our data indicate that astrocytes are key players in driving CNS inflammation and are directly implicated in the pathophysiology of EAE, since blocking their pro-inflammatory capability results in protection from the disease.

Glial regulation of the blood-brain barrier in health and disease

“…Depending on the type and severity of disturbance in the CNS, astrocytes can undergo both lossof-function (e.g., failure of glutamate uptake [117,121]) and/ or gain-of-function (production of a wide range of molecules including cytokines [122][123][124]). These changes cannot only regulate CNS vasculature remodeling but also cause activation of infiltrating immune cells and/or induce changes in neurons and oligodendrocytes [2,[125][126][127]. In the following section, we will discuss the regulation of the BBB by reactive astrocytes in the context of the neuroinflammatory disease multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE).…”

Dihydrotestosterone as a Protective Agent in Chronic Experimental Autoimmune Encephalomyelitis

“…However, it is important to highlight that a decrease in the astrocytic activation coupled with a reduced production of proinflammatory mediators has recently been hypothesized to be responsible for the decreased expression of MHC-II marker in microglia. This in turn produces less recruitment of inflammatory species from the periphery in the chronic phase of the disease, finally reducing EAE severity and improving functional recovery [66] . In our model, DHT treatment was able to reduce inflammatory parameters, bringing back GFAP staining in EAE rats to control values, suggesting that this event could be a key element for EAE recovery.…”

Astrocytes Are Primed by Chronic Neurodegeneration to Produce Exaggerated Chemokine and Cell Infiltration Responses to Acute Stimulation with the Cytokines IL-1β and TNF-α

“…IL-1RI and TNF-R p55 expression are elevated in the ME7-diseased brain , likely increasing sensitivity to these immune activators. Similarly, astrocytic NFB inhibition decreases chemokine expression (Brambilla et al, 2014) and it is plausible that increased astrocytic expression of NFB subunits, and consequent increased transcriptional activation, may underpin exaggerated astrocyte responses to acute stimulation. That astrocytic NFB activation is a key event in these exaggerated responses could be tested using selective inactivation of astroglial NFB via expression of dominant-negative IB␣ under astrocyte-specific promoter control (Brambilla et al, 2005).…”

“…Similarly, astrocytic NFB inhibition decreases chemokine expression (Brambilla et al, 2014) and it is plausible that increased astrocytic expression of NFB subunits, and consequent increased transcriptional activation, may underpin exaggerated astrocyte responses to acute stimulation. That astrocytic NFB activation is a key event in these exaggerated responses could be tested using selective inactivation of astroglial NFB via expression of dominant-negative IB␣ under astrocyte-specific promoter control (Brambilla et al, 2005). Nonetheless, we also show evidence of post-transcriptional control in the current study: despite similar transcription of CXCL1 mRNA in IL-1-challenged ME7 and NBH animals, ME7 astrocytes translated CXCL1 to a much greater extent than those of NBH animals.…”