Keywords

1 Introduction

Astrocytes are intriguing and remarkable cells controlling virtually every facet of central nervous system (CNS) functions. Astrocytes work together with neurons, microglia, oligodendrocytes, endothelial cells, and other cells to ensure harmonious function within the unique environment of the CNS. For example, astrocytes form the tripartite synapse where they take up glutamate as well as synthesize and release glutamine for use by neurons for conversion to glutamate, together ensuring proper neurotransmission. Additionally, astrocytes release trophic factors including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and others. Astrocyte end-feet interact with the neurovasculature and influence blood–brain barrier (BBB) function. The many diverse functions of astrocytes are too complex and numerous to describe in detail here; however, there are a number of excellent reviews describing the phenotypic and functional characteristics of astrocytes [1–5].

The focus of this chapter is to describe the role of astrocytes in neuroinflammation in the context of neurodegenerative diseases. Microglia are typically thought of as the main innate immunity effector cell in the CNS because of their macrophage-like phenotype, robust inflammatory responses, and ability to present antigen via major histocompatibility complex (MHC) class II. It is now appreciated that astrocytes have important innate immune functions as well [6]. In response to injury, infection, disease, or any disturbance, astrocytes undergo a phenotypic change known as astrogliosis. Widely characterized as the increased expression of the intermediate filament protein glial fibrillary acidic protein (GFAP), astrogliosis involves a host of transcriptional, translational, and phenotypic changes aimed at resolving and limiting damage to the CNS [2]. GFAP is expressed at variable levels in unstimulated astrocytes and forms a fibrous network typical of cytoskeletal proteins (Fig. 1). Additionally, astrocytes express pattern recognition receptors (PRR), although their repertoire is more restricted than that of microglia. Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns and astrocytes express TLR2, TLR3, TLR4, TLR5, and TLR9. TLR3, which recognizes double-stranded RNA, appears to be the most abundant TLR expressed by astrocytes [6]. In addition, astrocytes express nucleotide-binding oligomerization domain (NOD) proteins that recognize bacterial components [7]. Astrocytes can also sense and respond to damage-associated molecular patterns (DAMPs) such as ATP through purinergic receptors and the multi-protein NLRP2 inflammasome [8, 9]. Astrocytes respond to interferons (IFN) and a wide array of cytokines and chemokines. When stimulated, astrocytes in turn produce many cytokines and chemokines including IL-1, IL-6, LIF, CNTF, IL-8, IL-10, IFN-α, IFN-β, M-CSF, GM-CSF, TNF-α, TGF-β, CCL2, CCL3, CCL4, CCL5, CCL20, CXCL10, and CXCL12 [10–12]. In addition, inflammatory stimulation of astrocytes can lead to the production of the free radical nitric oxide (NO) which is toxic to neurons and oligodendrocytes and may promote neurodegeneration [13]. While astrocytes contribute to the local inflammatory response, they are also essential to limit and resolve CNS inflammation. Following traumatic brain injury (TBI), as well as other insults, astrocytes proliferate and form a glial scar around the injury [2]. The selective ablation of proliferating astrocytes following TBI in mice results in a prolonged inflammatory response and increased neuronal degeneration [14]. In acute conditions such as injury or infection, the astrocytic response is paramount to reestablish homeostasis in the CNS. However, in chronic conditions such as neurodegenerative diseases, astrocytes may eventually contribute to pathology.

Fig. 1
figure 1

GFAP expression in murine astrocytes. Astrocytes were isolated from the telencephalon of P1 pups and expanded in culture for 14 days. Cells were then stained for GFAP (red) and nuclei (DAPI, blue) and imaged by confocal microscopy. Notice the mesh-like network of GFAP

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2 Astrocytes in Multiple Sclerosis

Multiple sclerosis (MS) is a debilitating T cell-mediated autoimmune disease in which leukocytes (T cells, macrophages, neutrophils, and others) invade the CNS, leading to demyelination and axonal degeneration, eventually resulting in permanent disability. The etiology of MS is complex, involving genetic, environmental, and geographic factors, and usually develops in young adults (20–40 years of age) with a bias toward females [15]. MS initially manifests as highly variable transient episodes disrupting sensory and/or motor function, followed by full or partial recovery and disease remission (relapsing-remitting MS). In conjunction with symptoms, inflammatory lesions are also observed in the brain and spinal cord. MS lesions are areas of demyelination and inflammation involving invading peripheral leukocytes as well as resident glial cells. Cytokines and chemokines are key players in this inflammatory attack. Cytokines including IFN-γ, IL-17, and IL-6 are elevated in MS lesions as are the C-C chemokines CCL2, CCL3, CCL4, CCL5, CCL7, and CXCL12 [16–18]. MS patients have multiple attacks causing incremental damage to the CNS, and many patients progress to secondary progressive MS, where remission and recovery are reduced [19, 20]. Additionally, cognitive impairment is observed in at least 50 % of MS patients, contributing to disability and reduced quality of life [21]. Treatments for MS including IFN-β, glatiramer acetate, fingolimod, and others have greatly improved the quality of life for many MS patients; however, not all patients respond to or can tolerate these treatments [22, 23]. As such, new therapeutic targets for the treatment of MS are greatly needed.

The animal model of MS, experimental autoimmune encephalomyelitis (EAE), has greatly facilitated understanding the immunological interactions with the CNS. Although EAE is by no means a perfect replica of human MS, it shares many similar pathological features. EAE can be induced in a number of animals including nonhuman primates, rabbits, guinea pigs, hamsters, rats, and mice with an array of protocols and CNS antigens [24, 25]. Most current research utilizes the murine model. EAE, like MS, is a demyelinating disease involving perivascular infiltration of peripheral immune cells and axonal degeneration, manifesting with physical symptoms in a relapsing-remitting and/or progressive fashion. T helper (Th) cells, specifically IFN-γ-producing Th1 cells and IL-17-producing Th17 cells, are the main effector cells in the initiation of EAE [26].

In postmortem studies of MS lesions, markers of Th1 and Th17 cells have been described, among other cell types [27]. Coincident with infiltration of leukocytes, astrocyte damage and hypertrophy have been observed in MS lesions [28]. Moreover, astrogliosis is present in the CNS of MS patients [1]. These examples highlight an abundance of data that suggest astrocytes are important players in the pathogenesis of MS. This has been supported by studies in EAE. Astrocyte activation, as measured by GFAP expression, correlates with or precedes the onset of clinical symptoms [29–31]. Additionally, there is astrocyte proliferation within the white matter of the spinal cord [32]. Astrocytes in MS and EAE produce the potent leukocyte-attracting chemokines CCL2 [33, 34] and CCL20 [12, 35] among others, and disruption of either of the receptors for these chemokines, CCR2 and CCR6, respectively, results in amelioration of EAE [36, 37]. While astrocytes produce chemoattractants, they also form a barrier around perivascular lesions in EAE to block further leukocyte infiltration into the healthy parenchyma [38]. IL-6 is a multifaceted proinflammatory cytokine that is elevated in the CNS following injury or in diseases including MS [39]. Astrocytes are a major source of endogenous IL-6 in the CNS, and IL-6 drives its own expression through autocrine signaling in conjunction with the soluble IL-6 receptor (trans-signaling) [40, 41]. Transgenic mice expressing IL-6 under the control of the GFAP promoter alters EAE disease such that inflammatory leukocytes invade mainly the cerebellum rather than the spinal cord [42]. Disruption of gp130, the common signal-transducing receptor for the IL-6 family of cytokines, in astrocytes leads to exacerbated EAE, indicating that astrocytes also have a key role in limiting disease [43]. Additionally, the importance of astrocytes in EAE was further established in a recent study which demonstrated that intact IL-17 signaling in astrocytes is required for induction of disease [44]. Moreover, IL-17 enhances IL-6-induced IL-6 and CCL20 expression in astrocytes [45, 46]. This likely reflects the cooperative actions of the IL-6-induced transcription factor STAT3 and the IL-17-induced transcription factor NF-κB [47, 48]. Disruption of NF-κB activity in astrocytes ameliorates CNS inflammation and EAE disease severity [49, 50]. In MS and EAE, Th1 cells and Th17 cells contribute to the pathogenesis of disease. However, IL-4-producing Th2 cells and T regulatory cells (Tregs) are protective in EAE models [51, 52]. Thus, the repertoire of T cells interacting with the CNS is critical to the outcome of disease, and astrocytes influence this through production of chemoattractant molecules. For example, during EAE, astrocytes produce CXCL10 which recruits T cells, the monocyte chemoattractant CCL2, as well as CCL20 that can recruit both Th17 cells and Tregs [34, 35, 53, 54]. Additionally, as nonprofessional antigen-presenting cells, astrocytes, in an IFN-γ-inducible fashion, can express major histocompatibility complex (MHC class II) and present myelin-derived autoantigens to encephalitogenic T cells [55–57], potentially providing a stimulus for reactivation of T cells in the CNS. Collectively, these studies indicate that astrocytes are active participants in MS and EAE pathology and are potential therapeutic targets.

3 Astrocytes in Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that robs individuals of their memory and reduces cognitive function. Extracellular amyloid β (Aβ) deposition and tau-containing neurofibrillary tangles (NFTs) are hallmarks of AD pathology [58]. However, beginning with Alois Alzheimer’s initial description of AD more than 100 years ago, alterations in glial cells have also been appreciated [59]. Upon postmortem analysis, brains from patients with AD display clear astrogliosis, and the levels of GFAP inversely correlate with cognitive function [60, 61]. Astrocytes influence several features of AD. Astrocytes are thought to phagocytosis Aβ [62], and blockade of astrocyte activation in a transgenic AD mouse model increases Aβ plaque burden [63]. The exact mechanisms leading to gliosis in AD is not well understood. Fibrillar Aβ1-42 can stimulate pattern recognition receptors, including the lipopolysaccharide (LPS) coreceptor CD14 and the NOD-like receptor NALP3, leading to microglial activation and production of IL-1β [64, 65]. Similarly, astrocytes express TLRs and NLRs which may engage Aβ1-42 and promote astrogliosis, but this has not yet been formally demonstrated. However, several molecules have been implicated in mediating various astrocytic responses to Aβ including low-density lipoprotein receptors, aquaporin-4, adenosine A2A receptor, as well as the scavenger receptors CD36 and CD47 [66–69]. More recently, Aβ was shown to interact with the α7 nicotinic acetylcholine receptor and promote astrocytic glutamate release [70, 71]. While astrogliosis is initially beneficial, the long-term production of cytokines and chemokines may be deleterious and promote AD pathology.

Glial-derived IL-1 and IL-6 are important proinflammatory cytokines elevated in the brain of patients with AD [72, 73]. From animal studies, we have learned that these cytokines may be active participants in AD pathology. Transgenic AD mice (Tg2576) that express an APP mutant associated with early onset familial AD have increased IL-6 in the brain that precedes detectable Aβ plaques [74]. Moreover, IL-6 expression, in the same transgenic mouse model, persists into the established disease state with IL-6-producing astrocytes observed near Aβ deposits [75]. Mice overexpressing IL-6 in astrocytes have learning defects, suggesting that IL-6 may exacerbate cognitive decline [76]. Moreover, IL-1β directs astrocytes to produce IL-6 [77]. As mentioned previously, astrocytes are a potent source of chemokines that likely help to recruit and direct the peripheral monocytes observed in the AD brain [78]. Direct injection of IL-1β into the rat forebrain leads to prolonged astrocyte activation with concomitant increases in GABA and glutamate [79]. Elevated glutamate may be associated with the ability of Aβ1-42 to reduce astrocyte-dependent glutamate clearance [80]. Astrocytes stimulated with IL-1β also secrete S100B [81]. Secreted S100B has cytokine-like functions and at low concentrations is neurotrophic. However, extracellular S100B is elevated in neurological disorders including AD, and at higher concentrations S100B can promote neuronal cell death [82]. Further, antibody-mediated blockade of IL-1β in 3 × Tg-AD mice, which express mutants of APP, presenilin, and tau, reduces S100B expression, tau pathology, and disease pathology [83, 84]. Nitric oxide may also play an important role in AD. Mixed glial cultures respond to Aβ peptides with increased production of IL-1β and TNF-α that leads to increased expression of iNOS and synthesis of nitric oxide [85]. In AD astrocytes appear to be the main source of nitric oxide [86]. Nitric oxide is neurotoxic and may facilitate neurodegeneration in AD [87, 88]. Moreover, stimulation with the microglial- and astrocyte-derived cytokines IL-β, TNF-α, and IFN-γ can also stimulate nitric oxide production with subsequent neurotoxicity from astrocytes [89]. Astrocytes can also modulate microglial function through the production of soluble cytokines and chemokines. Astrocyte-produced S100B can stimulate activation of microglia that includes the production of IL-1β [90], potentially reinforcing or promoting astrogliosis. Additionally, inflammatory cytokines, as well as Aβ fibrils, can also stimulate astrocyte- and neuron-dependent APP expression and Aβ production [91–93]. Ultimately, the interactions between cytokines (particularly IL-1) with neurons, microglia, and astrocytes drive a cycle of inflammation and Aβ production that culminates in neurological dysfunction and cognitive decline [94].

4 Astrocytes in Parkinson’s Disease

Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra (SN) and the associated physical manifestations. In addition to dopaminergic neurodegeneration, neuropathology includes the accumulation of α-synuclein-containing Lewy bodies, activated microglia, infiltrating CD4+ and CD8+ T cells, and increased numbers of astrocytes surrounding dopaminergic neurons [95–97]. Elevated levels of cytokines including TNF-α, TGF-β1, IL-1β, IL-6, IL-2, IFN-γ, and reactive oxygen/nitrogen species are also observed in brains from PD patients [98]. These findings (and many others) indicate an ongoing, non-resolving inflammatory reaction in the brain of PD patients.

Several animal models suggest that inflammation is important in the pathogenesis of PD. Mice expressing human α-synuclein driven by the thy1 promoter display activated microglia and elevated TNF-α as early as 1 month of age in the striatum [99]. Importantly, the striatum contains axon terminals emanating from the SN as part of the nigrostriatal pathway. These findings support the idea that inflammation maybe a key participant in neurodegeneration and not just a consequence of tissue damage [99]. In toxin-induced models, including MPTP and 6-OHDA, inflammatory cytokines and activated microglia are present [100]. MPTP intoxication leads to prolonged (years) glial activation, suggesting glial cells are involved in the pathological outcome. Direct injection of LPS is toxic to dopaminergic neurons [101], indicating that inflammation, even in the absence of disease, can recapitulate the cell death seen in PD. Additionally, LPS can synergize with MPTP to induce dopaminergic neuronal cell death in neuron-glia cocultures [102]. LPS-induced neuronal death is likely indirect. In support of this are in vitro studies demonstrating that microglia and astrocytes work in concert to drive neurotoxicity in response to LPS [103].

Astrocyte accumulation of α-synuclein is observed in the PD brain [104], and recent findings suggest that α-synuclein can be transmitted from neurons to surrounding cells [105]. Indeed, astrocytes can take up α-synuclein via endocytosis. Not only do astrocytes take up α-synuclein, but an inflammatory reaction is stimulated that includes production of IL-6 and TNF-α as well as chemokines and matrix metalloproteinases (MMPs) [105]. Moreover, transgenic mice expressing a mutant α-synuclein associated with familial PD, A53T α-synuclein, in astrocytes display paralysis and mortality. This is associated with widespread gliosis and increased expression of TNF-α, IL-1β, and IL-6 in the brainstem. Conditioned media from the A53T α-synuclein-expressing astrocytes stimulated IL-1β and Cox1 expression in microglia [106]. These findings suggest that the effects of α-synuclein on astrocytes may contribute to the pathology of PD.

Astrocytes can have both protective and neurotoxic effects. Alpha-synuclein can enhance IL-1β-induced CXCL10 expression in astroglial cultures through mRNA stabilization [107]. CXCL10 is toxic to neurons; this has been demonstrated in the cholinergic LAN-2 cell line and in mixed human fetal neurons [108, 109]. While the dark pigment found in the SN, neuromelanin, attenuates astrocyte-derived CXCL10 [107], the direct influence of CXCL10 on dopaminergic neurons has not been examined. Astrocyte expression of the antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) in the Thy1-hSYNA53T mice protects motor neurons, reduces synuclein aggregates in the brain and spinal cord, and enhances overall survival. Additionally, Nrf2 expression reduces gliosis [110].

The exact mechanisms responsible for activation of the glial reaction in PD are unknown. Gliosis is observed in PD patients and most animal models and once active a self-perpetuating inflammatory reaction may result. In adult macaques injected with MPTP, persistent astrogliosis is observed as well as elevated IFN-γ and TNF-α in the SN. Mice lacking either IFN-γ or TNF-α have attenuated gliosis following MPTP treatment [111].

Some mutations associated with familial forms of PD have been shown to alter inflammatory responses. Cortical slices from PINK1−/− mice have increased production of TNF-α, IL-1β, and IL-6 [112]. The cytokines produced suggest activation of microglia and astrocytes, although it should be noted that PINK−/− astrocytes are dysfunctional in their proliferative capacity and do not have elevated GFAP expression [113]. Astrocytes deficient for DJ-1 are more sensitive to LPS-induced inflammatory gene expression [114]. Mutations in Nurr1 are associated with a rare form of PD. Nurr1 suppresses inflammation in microglia and astrocytes through repression of NF-κB, and loss of Nurr1 enhances astrocyte-derived neurotoxic molecules [103]. This indicates that astrocytes are involved in both sporadic and familial PD.

5 Astrocytes in Huntington’s Disease

In contrast to most neurodegenerative diseases in which the etiology is unknown, we know that Huntington’s disease (HD) is caused by a CAG expansion (poly Q) in the huntingtin gene, leading to neuronal loss in the striatum and cortex [115, 116]. As with other neurodegenerative diseases, inflammation is likely a key player in HD. Immune activation is detectable in the periphery and CNS of HD patients. Elevated plasma levels of IL-6, IL-8, IL-4, IL-10, TNF-α, and IL-5 have been shown in HD patients compared to healthy controls. Similarly, IL-6 and IL-8 levels are elevated in the CSF and in striatal tissue [117]. In addition to elevated cytokines, cellular alterations including microglial activation and astrogliosis are present in HD [118].

The role of astrocytes in HD is multifaceted, involving the production of inflammatory mediators as well as the potential loss of neuronal support. The expression of mutant huntingtin is not restricted to neurons; it is also expressed in astrocytes and peripherally. The targeted expression of mutant htt (160Q) in astrocytes leads to neurological and motor dysfunction [119], suggesting that astrocytes can directly influence HD pathology. A key function of astrocytes is to support neurons through the secretion of neurotrophins and buffering of extracellular glutamate. Evidence from HD mouse models suggests that astrocyte dysfunction may be an important aspect of the disease. Astrocytes produce BDNF, and this was found to be impaired in astrocytes expressing a mutant huntingtin fragment (htt552-100Q) [120]. Others have shown that astrocyte-produced BDNF provides therapeutic benefit. Astrocyte-targeted overexpression of BDNF attenuated quinolinate-induced lesions [121]. Additionally, viral delivery of BDNF driven by the GFAP promoter delayed disease progression in the R6/2 HD mouse model which expresses the 5′end of human huntingtin with 115-150 CAG repeats [122, 123]. Similarly, delivery of GDNF protects neurons and reduces disease severity [124, 125]. In vitro, astrocyte-conditioned media protect a striatal neuronal cell line expressing huntingtin Q111 from oxidative and excitotoxic cell death [126].

Evidence suggests that excitotoxic injury is an underlying mechanism of striatal neuronal loss in HD [127]. The uptake of glutamate, the main excitatory neurotransmitter, is impaired in the prefrontal cortex of HD patients [128]. Expression of mutant huntingtin in astrocytes reduces glutamate transporter expression and impairs the ability of astrocytes to take up glutamate. Moreover, in a coculture system, mutant htt-expressing astrocytes were less efficient at protecting neurons from glutamate-induced excitotoxicity [129]. In an in vivo model in which striatal astrocytes express mutant htt, reduced expression of glutamate transporters GLAST and GLT-1 as well as impaired glutamate uptake was observed. In addition, these mice displayed astrogliosis and neuronal dysfunction [130]. The ability of mutant htt to impair astrocyte-dependent glutamate handling may potentiate neuronal death in HD.

Despite evidence of microglial, astrocytic, and complement activation in the brains of HD patients, few studies have examined the contribution of glial cells to inflammation in HD [131]. In line with previous studies that mutant htt impairs astrocyte function, astrocytes from R6/2 mice express and secrete less CCL5 (RANTES). Impaired secretion results in aberrant accumulation of CCL5 in astrocytes and is observed in HD mouse models and in HD patients [132]. CCL5 has neurotrophic effects and its reduction may contribute to HD pathogenesis [132]. A recent study has examined the inflammatory responses in HD mice and astrocytes. In Hdh150Q mice, acute LPS treatment leads to enhanced TNF-α and IL-1β production in the cortex, striatum, and periphery [133]. Not only is the initial inflammatory reaction greater in the mutant htt mice, it is also prolonged. The enhanced inflammation was associated with excessive NF-κB activation in astrocytes. A single injection of LPS resulted in chronic inflammation and accelerated disease in the R6/2 mice. In addition, isolated R6/2 astrocytes stimulated with LPS produced higher levels of nitric oxide and were more toxic to isolated neurons [133].

6 Astrocytes in ALS

Amyotrophic lateral sclerosis (ALS) is caused by the selective degeneration of motor neurons resulting in progressive paralysis and premature death. In most cases, ALS is sporadic with unknown etiology. In a small number of cases, ALS is caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Through the use of SOD1 mutant mice, the mechanisms and cells involved in pathogenesis have been examined, and the non-cell autonomous processes involved in ALS have gained attention. Collectively, it appears that disease onset is determined by motor neurons, most likely through mutant SOD1-dependent damage; however, other cells including microglia and astrocytes are important in overall disease progression [134]. Consistently, ALS patients display activated microglia and astrocytes and increased expression of proinflammatory cytokines [135].

Glial activation is observed in the postmortem analysis of patients with ALS and in ALS animal models. It is likely that astrocytes and microglia work together, along with other cells types such as peripheral leukocytes, to modulate disease pathology. Using a SOD1G37R mouse model in which mutant SOD1 could be deleted from astrocytes, Yamanaka and colleagues demonstrated that disease onset was unaffected, but disease progression was greatly attenuated [136]. Although astrogliosis, based on GFAP expression, was not reduced by astrocyte-selective ablation of SOD1G37R, microgliosis was diminished. Concomitant with reduced microglial activation was a reduction in the expression of iNOS. These studies indicate that mutant SOD1-expressing astrocytes can influence disease progression in part through modulation of microglia [136]. Expression of SOD1G37R in astrocytes elicits an inflammatory response and toxicity toward motor neurons in coculture. This includes elevated expression of iNOS and NOX2 with increased production of nitric oxide and reactive oxygen, respectively. The antioxidant apocynin attenuated astrocyte-produced ROS and motor neuron toxicity [137]. Accordingly, motor neurons are sensitive to NO-induced cell death, most likely through reaction with superoxide to form highly reactive peroxynitrite [138]. Additionally, astrocytes derived from both familial and sporadic ALS patients are toxic to motor neurons. This toxicity was associated with upregulation of a number of astrocyte-produced inflammatory molecules including several C-C and C-X-C chemokines, TNF and IL-8 [139]. Similarly, mutant SOD1-expressing mouse astrocytes are toxic to primary motor neurons in coculture [140]. Expression of SOD1G93A alters inflammatory gene expression in astrocytes leading to upregulation of CCL8, CXCL7, and CCL5 [141]. In addition the prostaglandin D2 (PGD2) receptor was markedly increased. While these chemokines do not mediate the astrocyte-dependent toxicity toward motor neurons, blockade of the PGD2 receptor attenuated cell death, suggesting that prostaglandins may have role in motor neuron death [141].

IFN-γ has also been implicated in the demise of motor neurons. SOD1G93A-expressing astrocytes produce IFN-γ, and antibody-mediated neutralization of IFN-γ blocks astrocyte-dependent toxicity toward motor neurons in this model [142]. The toxic effects of IFN-γ are mediated in part through stimulation of the TNF family member, LIGHT (TNFSF14), from motor neurons which binds the lymphotoxin-β receptor (LT-βR) in an autocrine fashion, activating a pro-death signaling cascade. Consistent with a role for astrocytes in driving disease progression, deletion of LIGHT delays disease progress but not onset [142]. Type I IFNs may also have a role through stimulation of interferon-stimulated genes (ISGs) in astrocytes. ISG15 was reported to be elevated in human ALS and mouse spinal cords. Deletion of IFNAR1 delayed disease progress but not onset in SOD1G93A mice [143]. Thus, astrocyte-dependent production and responses to IFNs may have important roles in the progression of ALS.

7 Conclusions

Astrocytes have a key role in controlling inflammatory responses in the CNS (Fig. 2). Here, we have focused on astrocytes in only the most prevalent neurodegenerative diseases. It is worth noting that activated astrocytes and increased inflammatory cytokines are observed in many other neurodegenerative diseases including prion diseases [144] and lysosomal storage diseases [145]. While astrocytes have numerous beneficial functions [1–4, 6, 146–148], it seems that long-term perpetual stimulation, as likely occurs in neurodegenerative diseases, may exacerbate disease. Thus, we must continue to define the physiological and pathological functions of astrocytes as they may hold the key to new therapies.

Fig. 2
figure 2

Astrocytes orchestrate CNS inflammation. In neurodegenerative diseases, astrocytes respond to soluble factors including protein/peptide oligomers produced by neurons and inflammatory cytokines and chemokines produced by endogenous microglia and invading peripheral leukocytes. In response, astrocytes activate transcription factors such as NF-κB and STATs that leads to the production of a plethora of molecules which dictate the behavior and/or recruitment of the surrounding cells. The astrocyte-directed response may be beneficial through release of anti-inflammatory mediators and growth factors, or it may promote neurodegeneration through production of ROS and proinflammatory mediators

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