astrogliosis - cshl p

Astrogliosis

Michael V. Sofroniew

Department of Neurobiology, David Geffen School of Medicine, University of California,Los Angeles, California 90095

Correspondence: [email protected]

In addition to their many functions in the healthy central nervous system (CNS), astrocytesrespond to CNS damage and disease through a process called astrogliosis. For many decades,astrogliosis was sparsely studied and enigmatic. This article examines recent evidence sup-porting a definition of astrogliosis as a spectrum of heterogeneous potential changes inastrocytes that occur in a context-specific manner as determined by diverse signalingevents that vary with the nature and severityof different CNS insults. Astrogliosis is associatedwith essential beneficial functions, but under specific circumstances can lead to harmfuleffects. Potential dysfunctions of astrocytes and astrogliosis are being identified that cancontribute to, or be primary causes of, CNS disorders, leading to the notion of astrocytopa-thies. A conceptual framework is presented that allows consideration of normally occurringand dysfunctional astrogliosis and their different roles in CNS disorders.

Astrocytes exert many essential functions inthe healthy central nervous system (CNS) as

reviewed and discussed in other articles in thisvolume. In addition, astrocytes respond to allforms of CNS damage and disease with a varietyof potential changes in gene expression, cellu-lar structure, and function. Such responses arecommonly referred to as astrogliosis. Althoughastrogliosis has a long history of descriptiveanalysis beginning in the late 19th century, therewas only sparse interest in, or investigation of, itsmechanisms or functions for much of the 20thcentury. This situation changed gradually overthe last two decades when, in parallel with theexplosion of information regarding essentialastrocyte roles in the healthy CNS, interest hasgrown in understanding astrogliosis (Peknyand Nilsson 2005; Sofroniew 2009; Sofroniewand Vinters 2010; Kang and Hebert 2011). Assummarized in this article, considerable infor-

mation has now accrued regarding the mecha-nisms, functions, and impact of astrogliosis. It isnow clear that astrogliosis plays fundamentalroles in determining tissue repair and outcomeafter injury or disease, and has the potential toinfluence neural function.

WHAT IS ASTROGLIOSIS?

The term astrogliosis dates back to late 19th andearly 20th century neuroanatomists who rec-ognized that astroglia underwent pronouncedstructural changes in response to CNS damageand disease. At different times, astrogliosis hasbeen assigned various definitions but it has al-ways referred to astrocyte responses to CNS in-sults. Based on a large cross section of studies inexperimental animals and human pathologicalspecimens, we have recently proposed a moredetailed working definition of astrogliosis that

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encompasses four key features: (1) astrogliosisis a spectrum of potential molecular, cellular,and functional changes in astrocytes that occurin response to all forms and severities of CNSinjury and disease; (2) changes undergone byreactive astrocytes vary with severity of the in-sult along a graded continuum; (3) changesassociated with astrogliosis are regulated in acontext-specific manner by many differentinter- and intracellular signaling molecules;and (4) changes undergone during astrogliosishave the potential to alter astrocyte activitiesboth through gain and loss of functions (So-froniew 2009; Sofroniew and Vinters 2010).Specific aspects of these features are discussedbelow.

Various other terms are sometimes used torefer to astrocyte responses to CNS damage ordisease, and use of certain terms can vary amonginvestigators. We will use “astrogliosis” and “re-active astrocytes” as general all-inclusive de-scriptors of all forms of astrocyte responsesassociated with any form of CNS damage or dis-ease. As discussed in more detail below, theseterms encompass astrocyte responses of con-siderable diversity and heterogeneity. We willnot use “activation” or “activated astrocytes” astermsthat referexclusively to astrocyte responsesto injury or disease. Astrocytes in healthy tissuecontinually show physiological activation in theform of transient, ligand-evoked elevations inintracellular calcium ([Ca2þ]i) that represent atype of astrocyte excitability, involved in medi-ating many critical dynamic astrocyte functions,including interactions with synapses and regu-lation of blood flow as discussed in other articlesin this volume. Thus, astrocyte activation canrange from physiological contexts in healthyCNS to pathophysiologic contexts that involveresponding to CNS injury or disease. In keepingwith these definitions, there seems to be no placefor the notion of an “activated astrocyte” as asingle uniform entity.

MULTICELLULAR RESPONSESTO CNS INSULTS

Although the focus of this article is on astro-gliosis, it is important to emphasize that astro-

gliosis does not occur in isolation, but is partof a coordinated multicellular response to CNSinsults that includes multiple types of glia aswell as neurons and different types of nonneu-ral cells that are intrinsic to the CNS or thatenter from the bloodstream (Burda and Sofro-niew 2014). Different types of glia that respondto CNS insults include microglia, astrocytes,and NG2-positive oligodendrocyte progenitors(NG2-OPC). Nonneural cells intrinsic to theCNS that respond to insults include endothelia,perivascular fibroblasts, pericytes, and menin-geal cells. Cells that enter from the bloodstreamafter CNS insults include leukocytes, platelets,and other bone marrow–derived cells. Together,these cells have the capacity to produce a vastarray of intercellular signaling molecules, andthese molecules have the potential to influencethe activities and functions of different celltypes, including astrocytes. Thus, the responseto CNS insults is a complex mixture of eventsinvolving the interactions of multiple cell typesthat change over time (Burda and Sofroniew2014). Astrocytes take part in these interactionsboth by receiving instructive signals from othercells and by sending instructive signals that in-fluence other cells (Fig. 1).

ASTROGLIOSIS AS A CONTINUUMOF POTENTIAL RESPONSES

Astrogliosis has often been referred to as ifit were a single uniform entity that is essential-ly the same in all situations. This is emphaticallynot the case. A multitude of studies over thepast 20 yr have provided compelling evidencethat astrogliosis is not a simple stereotypic re-sponse, but instead is a finely tuned spectrumof potential changes that range from reversiblealterations in gene expression and cellular hy-pertrophy to pronounced cell proliferation withcompact scar formation and permanent tissuerearrangement. Available evidence points to-ward a wide range of specific molecular sig-naling mechanisms that regulate specific aspectsof astrogliosis, rather than a single stereotypicprogram that is regulated in an on–off manner(Pekny and Nilsson 2005; Sofroniew 2009; So-froniew and Vinters 2010; Kang and Hebert

M.V. Sofroniew

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2011). Although there are common featuresacross different forms and intensities of astro-gliosis, such as up-regulation of glial fibrillaryacidic protein (GFAP) and cellular hypertro-phy, even these do not occur in all or none fash-ions, but are finely regulated along a gradientof intensity that can vary from very small to

very intense changes (Fig. 2). Thus, astrogliosisis complex and multivariate, and the changesin astrocytes that are associated with astro-gliosis are induced in a context-dependentmanner as regulated by many different potentialsignaling events as summarized in the nextsections.

Domainpreservation

Astrogliosis gradient

Overlappingprocesses

CytoskeletonCytoskeletalhypertrophy Proliferated

scar astrocytesInflammatory

cells

Tissuelesion

ScarSevere diffuseModerateMildHealthy

Figure 2. Schema of astrogliosis gradient from mild to moderate to scar. In healthy CNS tissue, many astrocytesdo not express detectable levels of the cytoskeletal protein, GFAP. In mild to moderate astrogliosis, mostastrocytes up-regulate GFAP and hypertrophy their cytoskeleton but preserve individual domains. In severediffuse astrogliosis, there is also proliferation (depicted by red nuclei). Compact astroglial scars are comprised ofnewly proliferated astrocytes with densely overlapping processes that form borders to damaged tissue andinflammation.

Astrocytes send instructionsAstrocytes receive instructions

PT3 IL-10

LCN2IL-11IL-15

CXCL10CCL2

CCL7

CCL8CCL5

CXCL1

CXCL9CXCL16

IL-6

???

Bloodflow

bvbvBBBrepair

BBB leakBBB leak

FGF-2Microglia

Reactive AstrocyteReactive Astrocyte

KYN

THBS1GPC4

CSPGBDNFGDNF

NGF

GFsLIF

IGF-1

NeuronNeuron

SynapseSynapse

MMP3NOPGE

VEGF-A

NOGlut

TNF-αIL-1β

TNFαTNF-α

IL1-βINF-γ

FGF-2EGFATPK+

Glut

IL-6IL-10

wbcwbc

Microglia

Estrogen

ENDLPS

PAMPs

NH4+

AlbuminCNTF

LIFROS

GDNFAβ

NE

SHH Thrombin

NO

A B

TGF-β

ATP

Figure 1. Reactive astrocytes receive and send diverse molecular instructions. Schematic drawings depict exam-ples of diverse molecular signals that instruct reactive astrocytes (A), or that reactive astrocytes release to instructother cells (B). For abbreviations, see Table 1.

Astrogliosis

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SIMPLE CONVENIENT CATEGORIESOF ASTROGLIOSIS

Changes in astrocyte appearance, molecular ex-pression, and function that are associated withastrogliosis occur along a seamless graded con-tinuum of intensity. Nevertheless, for practicalpurposes of description, comparison, and dis-cussion, it is convenient to distinguish amongseveral simple categories of astrogliosis as delin-eated on the basis of changes in structure, mo-lecular expression, and proliferation. These cat-egories include mild to moderate astrogliosis,severe diffuse astrogliosis, and severe astroglio-sis with compact scar formation (Fig. 2).

Mild to Moderate Astrogliosis

Mild to moderate astrogliosis consists ofchanges (up or down) in astrocyte gene expres-sion together with variable degrees of hypertro-phy of cell body and stem processes, withoutsubstantive loss of individual astrocyte domainsand without astrocyte proliferation (Sofroniew2009; Sofroniew and Vinters 2010). There isincreased expression of the astrocyte intermedi-ate filament protein, GFAP, which is somewhatproportional to the degree of reactivity. Theessentially nonoverlapping astrocyte domainsfound in healthy gray matter are more or lesspreserved in mild to moderate reactive astroglio-sis in brain and spinal cord (Fig. 2) (Wilhelms-son et al. 2006; Wanner et al. 2013). Mild tomoderate astrogliosis is generally associatedwith mild nonpenetrating and noncontusivetrauma, or with diffuse innate immune activa-tion (viral infections, system bacterial infec-tions), or occurs in areas that are some distanceto focal CNS lesions. After insults that are acutesingle events, such as traumatic or ischemic in-juries, mild to moderate astrogliosis has consid-erable potential to resolve.

Severe Diffuse Astrogliosis

Severe diffuse reactive astrogliosis consists ofchanges (up or down) in gene expression withpronounced up-regulation of GFAP, cellularhypertrophy, dispersed astrocyte proliferation,and some loss of individual astrocyte domains

with overlapping of neighboring astrocyte pro-cesses (Fig. 2) (Sofroniew 2009; Sofroniew andVinters 2010). These changes can extend dif-fusely over substantive areas, and can occur invarious situations, such as chronic neurodegen-erative insults, diffuse trauma, diffuse ischemia,or certain types of infection. Because there canbe considerable tissue reorganization, the po-tential for resolution and return to normalstructure is reduced and there is a high tendencytoward long-lasting tissue reorganization (So-froniew and Vinters 2010).

Severe Astrogliosis with CompactScar Formation

Compact astroglial scars derive almost entirelyfrom newly proliferated astrocytes with elongat-ed shapes (Wanner et al. 2013), whose cell pro-cesses overlap and intertwine extensively toform compact borders that surround and de-marcate areas of tissue damage, necrosis, andinflammation after trauma, stroke, infection,autoimmune-triggered inflammatory infiltra-tion, or neurodegenerative disease (Bush et al.1999; Faulkner et al. 2004; Drogemuller et al.2008; Voskuhl et al. 2009; White et al. 2010;Wanner et al. 2013). There may be several possi-ble sources of newly divided scar-forming astro-cytes including (1) mature astrocytes that re-enter the cell cycle and proliferate (Bush et al.1999; Buffo et al. 2008; Gadea et al. 2008; Bar-dehle et al. 2013), (2) NG2 progenitor cells in thelocal parenchyma (Magnus et al. 2008), or (3)ependymal cell progenitors (Meletis et al. 2008;Barnabe-Heider et al. 2010). Astrocyte scar bor-ders directly interface with and surround a vari-ety of nonneural cell types in the central coreof tissue lesions, including perivascular-derivedfibroblasts, fibrocytes, pericytes, and other glialcells (Fig. 2) (Bundesen et al. 2003; Herrmannet al. 2008; Sofroniew 2009; Sofroniew andVinters 2010; Aldrich and Kielian 2011; Reilkoffet al. 2011; Burda and Sofroniew 2014). It isnoteworthy that astroglial scar formation is as-sociated with substantive tissue reorganizationand structural changes that are essentially per-manent and persist even when triggering insultsmay have resolved.

M.V. Sofroniew




HETEROGENEITY OF ASTROCYTESAND REACTIVE ASTROCYTES

There is growing evidence for and interest in thepotential for heterogeneity among astrocytes inhealthy CNS not only across different CNS re-gions, but also locally within the same regions(Zhang and Barres 2010; Tsai et al. 2012). Giventhat astrogliosis is not a single stereotypic re-sponse but is regulated by multiple specific sig-naling events, there is also growing awareness ofheterogeneity among reactive astrocytes at mul-tiple levels (Anderson et al. 2014). For example,adjacent to focal traumatic or ischemic lesions,there is topographic heterogeneity of astroglio-sis as regards astrocyte proliferation, morphol-ogy, and gene expression with respect to distancefrom the insult (Sofroniew and Vinters 2010;Wanner et al. 2013). In addition, analysis at thesingle cell in vivo shows that intermingled re-active astrocytes can show different expressionlevels of (1) chemokines or cytokines (Hambyet al. 2012), (2) signaling molecules, such aspSTAT3 (Herrmann et al. 2008), or (3) tran-scription factors that regulate Sonic Hedgehogsignaling (SHH) (Garcia et al. 2010). It is alsonoteworthy that different stimuli of astrocytereactivity can lead to similar degrees of GFAPup-regulation, whereas causing substantiallydifferent changes in transcriptome profiles andcell function (Hambyet al. 2012; Zamanian et al.2012). Thus, it is not possible to equate simpleand uniform measures, such as cell hypertrophyand up-regulation of GFAP expression with asingle, uniform concept of astrocyte reactivity.Indeed, certain inflammatory signals can sub-stantively alter reactive astrocyte transcriptomeprofiles without inducing further changes inGFAP (Hamby et al. 2012). These findings un-derscore the considerable potential for pheno-typic and functional heterogeneity among reac-tive astrocytes as regulated by specific signalingevents.

MULTIPLE MOLECULAR REGULATORSOF ASTROGLIOSIS

Astrogliosis is not an all-or-none response orstereotypic program regulated by a few simpleon–off molecular switches. Instead, astrogliosis

is a spectrum of potential changes that occurin a context-specific manner as determined bya myriad of specific potential signaling eventsthat vary with the nature and severity of specificCNS insults. Current evidence indicates thatspecific aspects of reactive astrogliosis can beregulated separately and individually by a widevariety of intercellular and intracellular signal-ing and regulatory molecules, as called for indifferent situations. Combinatorial exposure tomultiple signals can markedly alter astrocytetranscriptome profiles and give rise to synergis-tic effects not predicted by exposure to individ-ual stimuli (Hamby et al. 2012).

Extracellular Signals

Astrogliosis can be induced, regulated, or mod-ulated by a wide variety of extracellular mole-cules ranging from small molecules, such aspurines, transmitters, and steroid hormones,to large polypeptide growth factors, cytokines,serum proteins, or neurodegeneration associ-ated molecules like b-amyloid (Table 1). Theseinstructive signals can derive from many differ-ent sources (Fig. 1A) and can be released by celldamage or cell death, or via specific signalingmechanisms. Many cell types can release molec-ular regulators of astrogliosis, including (1) lo-cal neural and nonneural cells intrinsic to CNStissue, such as neurons, microglia, oligodendro-cyte lineage cells, endothelia, pericytes, fibro-meningeal cells, and other astrocytes, as wellas (2) nonneural cells that gain entry into theCNS, such as bone marrow–derived leukocytes,fibrocytes, and microbial infectious agents (Fig.1A) (Burda and Sofroniew 2014). Last but notleast, astrogliosis can be regulated by molecules,such as serum proteins, cytokines, or steroidhormones that are produced by cells outsideof the CNS, including microbial endotoxins,such as lipopolysaccharides (LPS) (Burda andSofroniew 2014).

Intracellular Signal Transducersand Regulators

Many extracellular molecular regulators of as-trogliosis have receptor targets that initiate in-

Astrogliosis




tracellular second messenger signaling cascades(Table 1), as reviewed elsewhere (Pekny andNilsson 2005; Sofroniew 2009; Sofroniew andVinters 2010; Kang and Hebert 2011). There isalso emerging evidence that microRNAs (miR),such as miR-21 and miR-181 (Bhalala et al. 2012;Hutchison et al. 2013), and miR regulatory en-zymes, such as Dicer (Tao et al. 2011), can mod-ulate astrogliosis and reactive astrocyte func-tions, adding yet another level of potentialregulation and specification of functions (Table1). Thus, intrinsic properties of individual as-trocytes, such as epigenetic mechanisms or ge-netic polymorphisms of receptors and secondmessengers and other regulators, may impactastrogliosis.

Selective Regulation of Specific Functionsand Effects of Astrogliosis

There is increasing interest in dissecting molec-ular signaling mechanisms that regulate specificfunctions or effects of astrogliosis so that thesemight be targeted by specific therapeutic inter-ventions (Sofroniew 2009; Hamby and Sofro-niew 2010). Considerable information is nowavailable, which reveals that some aspects of as-trogliosis can be regulated by many pathways,whereas other aspects are regulated more selec-tively. For example, expression of structural fil-aments, such as GFAP or vimentin can be in-duced by signaling pathways associated withcAMP, STAT3, NF-kB, Rho-kinase, JNK, calci-

Table 1. Selected examples of molecular regulators of astrogliosis

Categories Source Molecules

Extracellular molecular signalsDAMPs Cell damage Adenosine triphosphate (ATP), reactive oxygen

species (ROS), nitric oxide (NO), high-mobilitygroup box 1 (HGMB1), etc.

Hypoxia andmetabolic stress

Ischemia Oxygen deprivation, glucose deprivation

Transmitters Local neurons Glutamate (Glut), noradrenalin (NE)Hormones Endocrine glands Estrogens, glucocorticoids

Neurodegeneration b-amyloid (Ab)PAMPs Microbes LPS, zymosan, dsRNA (viral)

Systemic metabolic toxicity(liver failure)

Ammonium (NH4þ)

Serum proteins Bloodstream Thrombin, albumin, fibrin, etc.Cytokines and

growth factorsOther glia, local nonneural

cells, infiltrating leukocytesIL-1b, tumor necrosis factor (TNF)-a, interferon

(INF)-g, IL-6, ciliary neurotrophic factor (CNTF),leukemia inhibitory factor (LIF), transforminggrowth factor (TGF)-b, IL-10, epidermalgrowth factor (EGF), fibroblast growth factor(FGF)-2, Sonic Hedgehog (SHH), endothelin(END)

Astrocyte intrinsic signaling pathways and regulatory mechanismsSignal transducers STAT3, STAT2, STAT2, JAK2, NF-kB, IRAK, SOC3,

MAP-kinase, SOX9, Nrf2, Olig2, cAMP, Nurr1,SMAD3, SMAD4, mTOR, c-FOS, c-JUN, PKA,PKC, ERK, MyDD8, IRF1, G proteins, etc.

microRNAs miR-21, miR-181, Dicer (ribonuclease) identifiedthus far

Nomenclature for growth factors, cytokines, chemokines, receptors, and transcription factors are per The Human Gene

Compendium, GeneCards (see www.genecards.org).

DAMPs, danger-associated molecular patterns; PAMPs, pathogen-associated molecular patterns.

M.V. Sofroniew



http://www.genecards.org




um, and others (Pekny and Nilsson 2005; Sofro-niew 2009; Middeldorp and Hol 2011; Gao et al.2013). Similarly, astrocyte proliferation can beregulated by different extracellular signals in-cluding EGF, FGF, endothelin 1, Sonic Hedge-hog, the serum proteins thrombin and albumin,and others, and by intracellular signals, such asOlig2, JNK pathway, and others (Levison et al.2000; Gadea et al. 2008; Sofroniew 2009; Sirkoet al. 2013). Other aspects of astrogliosis areregulated more selectively. For example, certainpro- and anti-inflammatory functions of astro-cytes are regulated separately. Deletion or dis-ruption of NF-kB or SOC3 signaling pathwaysselectively in astrocytes diminishes recruitmentof inflammatory cells after traumatic injury andautoimmune disease (Brambilla et al. 2005,2009; Okada et al. 2006). Deletion of estrogenreceptor-a, but not estrogen receptor-b, selec-tively from astrocytes diminishes the anti-inflammatory and neuroprotective effects ofestrogen on autoimmune inflammation (Spenceet al. 2011, 2013). In contrast, deletion of STAT3or its associated membrane receptor GP130,markedly increases the spread of inflammationafter traumatic injury, autoimmune disease, orinfection (Okada et al. 2006; Drogemuller et al.2008; Herrmann et al. 2008; Haroon et al. 2011;Wanner et al. 2013). Deletion of YLK-40/BRP-39, an astrocyte produced anti-inflammatoryprotein, exacerbates autoimmune disease inmice (Bonneh-Barkay et al. 2012). miR-181 de-creases astrocyte production of inflammatorycytokines (TNF-a, IL-1b) and increases pro-duction of anti-inflammatory cytokines (IL-10) (Hutchison et al. 2013). Thus, different sig-naling mechanisms regulate different aspects ofpro- or anti-inflammatory functions of reactiveastrocytes. From a different perspective, expres-sion and function of the glutamate transporterGLT-1 can be modulated up or down duringastrogliosis depending on the nature of the in-sult and time after the insult, and this regulationcan impact outcome by influencing extracellularglutamate levels and the potential for neuronalexcitotoxicity (Bianchi et al. 2013). The mTOR-Akt-NF-kB pathway is one molecular signalingmechanism that can modulate astrocyte expres-sion of Glt-1 (Pawlak et al. 2005; Faideau et al.

2010; Ji et al. 2013). Findings such as these sup-port a model in which many different specificsignaling mechanisms can trigger different spe-cific molecular, morphological, and functionalchanges in reactive astrocytes. This model alsopredicts that the impact of astrogliosis on itshost neural tissue and associated neural func-tions will not be uniform or stereotypic, butwill vary in a context-specific manner as deter-mined by the specific signaling mechanisms as-sociated with specific insults and the environ-ment in which they are occurring.

BENEFICIAL FUNCTIONSAND MALADAPTIVE EFFECTSOF ASTROGLIOSIS

In response to the many signaling events justdescribed, reactive astrocytes have the potentialto release a large variety of molecules that im-pact nearby cells (Fig. 1B; Table 2). These mol-ecules can exert many different functions andeffects. For much of its greater than 100-yearhistory, astrogliosis has been regarded by some

Table 2. Selected examples of effector molecularreleased by reactive astrocytes

Categories Molecules

Cytokines IL-6, IL-1b, TNF-a, INF-g,CNTF, LIF, TGF-b, IL-11,IL-15

Chemokines CXCL1, CXCL9, CXCL10,CXCL12, CXCL16, CCL2,CCL5, CCL7, CCL8

Growth factors andother proteins

BDNF, NGF, GDNF, THSP1,GPC4, GPC6, FGF2,PDGFb, BMP1, VEGF-A,pentraxin 3 (PT3),a-crystallin B, etc.

Extracellular matrix MMP3, SEMA4A, TIMP1,chondroitin sulfateproteoglycans (CSPG)

Intermediatefilaments

GFAP, vimentin, nestin

Transmitters Glutamate (Glut), kynurenicacid (KYN), D-serine

Small molecules NO, prostaglandin E (PGE),ATP

Nomenclature as per The Human Gene Compendium,

GeneCards (see www.genecards.org).

Astrogliosis







investigators as a reaction that is fundamentallyharmful to functional recovery. This notion isrefuted bya large volume of in vivo experimentalstudies from many laboratories, which show thatin response to most if not all CNS insults, nor-mally occurring astrogliosis is initiated as anadaptive, beneficial process directed at woundrepair and tissue protection. Nevertheless, ex-perimental studies have also established the po-tential for potentially harmful effects of astro-gliosis under specific circumstances. Thus, it isimportant to understand that astrogliosis, likeinflammation, exerts essential beneficial func-tions but can also give rise to maladaptive effects,and that these are regulated by specific signalingmechanisms that occur in specific contexts.

Transgenic loss-of-function models havebeen particularly useful in identifying beneficialfunctions and harmful effects of astrogliosisand astrocyte scar formation (Sofroniew 2005;Sofroniew and Vinters 2010). For example,transgenic ablation or prevention of astrogliosisor astrocyte scar formation causes increased in-flammation and tissue damage and worsensfunctional outcome in all CNS insult modelsstudies thus far, including traumatic injury, is-chemic injury (stroke), infection, autoimmuneinflammation, and neurodegenerative disorders(Nawashiro et al. 1998; Bush et al. 1999; Faulk-ner et al. 2004; Myer et al. 2006; Drogemulleret al. 2008; Herrmann et al. 2008; Li et al. 2008;Voskuhl et al. 2009; Haroon et al. 2011; Macau-ley et al. 2011; Wanner et al. 2013). Nevertheless,transgenic studies also reveal the potential forcertain aspects of astrogliosis to exacerbate in-flammation after traumatic injury or autoim-mune challenge (Brambilla et al. 2005, 2009;Spence et al. 2011, 2013). Other studies showthat controlling astrocyte pH can reduce gluta-mate excitotoxicity during ischemia (Beppuet al. 2014; Sloan and Barres 2014). Large-scalegene expression evaluations show that inflam-matory mediators can drive astrocyte transcrip-tome profiles toward proinflammatory and po-tentially cytotoxic phenotypes (Hamby et al.2012; Zamanian et al. 2012) that may be bene-ficial in microbial infection but may be detri-mental if triggered during sterile (uninfected)tissue responses to trauma, stroke, degenerative

disease, or autoimmune attack, as discussed be-low (Sofroniew 2013).

Perhaps the most widely regarded potentialdetrimental effect of astrogliosis is the inhibi-tion of axon regeneration by astrocyte scars afterCNS damage (Silver and Miller 2004). Never-theless, this potential detrimental effect must beviewed in the context of the essential protectiveroles that astrocyte scars perform in restrictinginflammation and protecting healthy tissue ad-jacent to lesions as discussed above. Simply pre-venting or removing astrocyte scars is likely todo more harm than good. Attempts to manip-ulate scar formation with the intention ofimproving axon regeneration will likely needto be very specifically targeted and controlled,and, given the multiple and complex causes forfailure of CNS axon regeneration (Brosius Lutzand Barres 2014), are unlikely to be effective ontheir own.

Together, such observations provide com-pelling evidence that astrogliosis exerts a varietyof beneficial functions that are essential for lim-iting tissue damage and preserving neurologicalfunction after CNS insults but that astrogliosisalso has the potential to exert detrimental effectsas determined byspecific signaling mechanisms.Recognition of these concepts sets the stage fordissecting the physiology and pathophysiologyof astrogliosis to identify and ameliorate theconsequences of astrocyte dysfunction.

DYSFUNCTIONS OF ASTROCYTES ANDASTROGLIOSIS: TOWARD A CONCEPTOF ASTROCYTE PATHOPHYSIOLOGYAND ASTROCYTOPATHIES

There is increasing evidence for a concept ofastrocytopathies in which a disruption of nor-mal astrocyte functions in healthy tissue is theprimary cause of neurological dysfunction anddisease (Verkhratsky et al. 2012). The argumentcan be made that a full concept of astrocytopa-thies will also include disorders caused by alter-ing the process of astrogliosis (Fig. 3). As dis-cussed above, a strictly negative connotation ofastrogliosis is being replaced by a balanced viewof astrogliosis as an adaptive process generatedand conserved by evolution, which serves es-

M.V. Sofroniew




sential repair and tissue protective functions,but that in certain situations can show harm-ful effects as a direct consequence of context-inappropriate signaling interactions. This per-spective allows a conceptual framework forastrogliosis that includes both adaptive (benefi-cial) and maladaptive (harmful) forms of astro-gliosis, and allows for consideration of multipleways in which dysfunctions of astrogliosis couldbe primary causes of, or major contributorsto, CNS disorders. Recognizing and understand-ing the potential for dysfunction of astrogliosis(Fig. 3) is likely to be fundamental to dissectingthe cellular mechanisms underlying a variety ofCNS disorders. The next sections discuss clini-cal and experimental examples of ways in whichprimary dysfunctions of astrocytes or of astro-gliosis could precipitate, or contribute to, neu-rological dysfunction and disease.

ASTROCYTE GENE MUTATIONS

There are now several examples of genetic mu-tations that cause astrocyte dysfunctions thatcan lead, or contribute significantly, to neuronaldysfunction and degeneration, which in turnlead to neurological symptoms and disease. Onefirst example, Alexander disease, is caused by adominant mutation of the GFAP gene, which isexpressed in the CNS only by astroglia. Patients

show macrocephaly, severe neurological dys-function, seizures, psychomotor disturbances,and premature death (Brenner et al. 2001; Mess-ing et al. 2012). A second well, studied example isa familial form of amyotrophic lateral sclerosis(ALS) caused by a dominant gain-of-functionmutation of the gene-encoding superoxide dis-mutase (SOD) that leads to the production ofmolecules that are toxic to motor neurons. Tar-geting mutant SOD selectively to astrocytes intransgenic mice is sufficient to cause neuronaldysfunction and degeneration (Lobsiger andCleveland 2007; Nagai et al. 2007; Yamanakaet al. 2008). Nevertheless, in the full disease, mu-tant SOD produced in neurons also contributesto neuronal degeneration. In addition to theseexamples, there is recent evidence from experi-mental animal models that the genetic mutationassociated with Huntington’s disease causes dys-function of astrocytes in ways that may contrib-ute significantly to neurological symptoms andneurodegeneration. In Huntington’s disease, as-trocytes as well as neurons accumulate nuclearinclusionsofmutanthuntingtinprotein(mHtt).In transgenic mouse models, astrocytes withmHtt down-regulate the potassium channelKir4.1, leading to increased extracellular potas-sium and increased neuronal excitability, whichis likely to contribute to and exacerbate directeffects of mHtt on neurons (Tong et al. 2014). It

Normalastrocyte

Normalastrogliosis

Tissueprotectionand repair

Abnormalastrogliosis

Mutations,polymorphisms,chronic insult,

infections,high cytokines,autoimmune

attack,etc.

Astrocytewith mutation

GFAP-AlexD,SOD-fALS,mHtt-HD,

etc.

Astrocytopathywith

secondaryneural

dysfunctionand

degeneration

Astrocytopathy

Healthy tissueOutcome

Outcome

CNS insult

CNS insult

CNS insult

Outcome

Figure 3. Schema that distinguishes normal from abnormal astrogliosis and depicts different pathways that canlead to astrocytopathies.

Astrogliosis




is noteworthy that these effects occur at earlystages of symptom onset and in the absence ofastrocyte changes associated with astrogliosis(Tong et al. 2014). It is important to emphasizethat in all of these conditions, the detrimentaleffects on neuronal function and neurotoxicityare caused by genetically mutated and abnormalastrocytes rather than by the normal process ofastrogliosis. Thus, astrocyte dysfunction that isharmful can occur in the absence of astrogliosis,and astrogliosis can occur without causing harm(Fig. 3).

ASTROCYTE MOLECULARPOLYMORPHISMS

An intriguing and potentially important ques-tion is the degree to which genetic polymor-phisms could alter functions of astrocytes andastrogliosis. Available evidence suggests thatthis is likely to be the case. Apolipoprotein E(APOE) polymorphisms influence the risk ofAlzheimer’s disease, with isoform APOE4 in-creasing risk and APOE2 reducing risk. Stud-ies using various transgenic mouse modelsshow that astrocyte-secreted APOE4, but notAPOE3 or APOE2, is associated with increasedblood–brain barrier leak and increased neuro-nal degeneration (Bell et al. 2012) in a mannerthat may be relevant to Alzheimer’s disease pa-thology (Zlokovic 2011). The notion that astro-cyte intrinsic molecular polymorphisms mightimpact astrocyte functions in disease-relevantways is further supported by the example ofgenetic mutations or experimental gene manip-ulations that modulate astrocytes and astroglio-sis in ways that alter neuronal function or causeneurodegeneration as discussed above.

ASTROGLIOSIS AND CNS INFLAMMATION

Inflammation is an important component ofthe multicellular response to CNS damage anddisease that can markedly influence the balancebetween tissue loss and preservation (Burda andSofroniew 2014). There is now both clinical andexperimental evidence that astrocytes are criti-cal regulators of CNS inflammation. From aclinical perspective, recent findings show that

CNS autoimmune disease that selectively dam-ages astrocytes has a more severe course thanautoimmune disease that involves other cellulartargets. Neuromyelitis optica (NMO) is a CNSinflammatory demyelinating disease with pro-nounced tissue destruction and severe symp-toms that can include vision loss and paralysis.NMO has been causally associated with autoan-tibodies to aquaporin-4 (AQP4) on astrocytesthat mediate compliment-mediated astrocytelysis (Lennon et al. 2005; Roemer et al. 2007).Both clinical course and tissue lesions are moresevere in patients that have autoimmune-medi-ated CNS demyelination associated with anti-AQP4 autoantibodies compared with patientswith antimyelin autoantibodies (Kitley et al.2014; Sato et al. 2014). These findings stronglysuggest that AQP4 is not simply a passive auto-immune CNS antigen, but that disruption ofastrocyte functions by AQP4 antibodies exacer-bates the disease process and worsens the out-come. This notion is consistent with experimen-tal evidence that astrocytes critically restrict thespread of inflammation during autoimmuneCNS attack (Voskuhl et al. 2009; Haroon et al.2011). From an experimental perspective, it iswell documented that astrocytes can produce awide variety of pro- or anti-inflammatory mol-ecules and that specific molecular regulatorsmodulate specific astrocyte functions in wayscan increase or limit CNS inflammation. Astro-cytes produce not only a wide range of chemo-kines that open the blood–brain barrier (Argawet al. 2012) and attract inflammatory cells(Hamby et al. 2012; Zamanian et al. 2012; So-froniew 2013) but also molecules that can exertpotent suppressive effects on inflammatory cells(Kostianovsky et al. 2008). Astrocyte scars playcritical roles in limiting the spread of inflamma-tory cells from damage areas into neighboringhealthy tissue after trauma or autoimmune at-tack (Bush et al. 1999; Voskuhl et al. 2009; Wan-ner et al. 2013). Modulation of specific astrocytefunctions can eitherattenuate orexacerbate CNSinflammation (Okada et al. 2006; Herrmannet al. 2008; Brambilla et al. 2009), opening thedoor for gain or loss of astrocyte functions toimpact CNS inflammation (Dong and Benve-niste 2001; Sofroniew 2009). Together, these

M.V. Sofroniew




findings provide compelling clinical and exper-imental evidence that dysfunction of astroglio-sis can exacerbate CNS inflammation and thespread of tissue damage in various ways andcontexts.

ASTROCYTE-MEDIATED NON-CELL-AUTONOMOUS NEURONALDYSFUNCTION OR DEGENERATION

There are many ways that loss of astrocyte func-tions or disruption of astrogliosis could leadto non-cell-autonomous neuronal dysfunctionor degeneration. In healthy neural tissue, astro-cytes play critical roles for normal neuronalfunction including homeostasis of extracellu-lar fluid, ions, and transmitters, regulation ofblood flow, energy provision, and interactionswith synapses as reviewed elsewhere (Barres2008; Sofroniew and Vinters 2010). In damagedneural tissue, reactive astrocytes play criticalroles in neuroprotection, blood–brain barrierrepair, and regulation of inflammation (Sofro-niew and Vinters 2010; Burda and Sofroniew2014). Thus, perhaps not surprisingly, experi-mentally induced loss of specific functions ofastrocytes or astrogliosis can cause neuronaldysfunction and degeneration and worsen out-come after CNS trauma, ischemia, or autoim-mune attack. A pioneering example is that selec-tive deletion of the astrocyte glutamate uptaketransporter, Glt-1 (EAAT2) will lead to seizuresand excitotoxic neuronal death (Rothstein et al.1996). Further examples include (1) astrocyte-selective expression of mutant SOD causes neu-ronal dysfunction and degeneration (Lobsigerand Cleveland 2007; Nagai et al. 2007; Yamanakaet al. 2008), (2) astrocyte-selective deletion ofthe endoribonuclease, Dicer, cases of severeataxia, progressive cerebellar degeneration, sei-zures, and premature death (Tao et al. 2011), and(3) astrocyte-selective deletion of the Wnt sig-naling molecule adenopolyposis coli causesdelayed degeneration of cerebellar Purkinje neu-rons (Wang et al. 2011). Experimental disrup-tion of various astrocyte signaling molecules canalter astrogliosis and cause neuronal dysfunc-tion and tissue degeneration during traumaticinjury,ischemia,andautoimmuneattack(Okada

et al. 2006; Drogemuller et al. 2008; Herrmannet al. 2008; Li et al. 2008; Haroon et al. 2011). It isalso intriguing to consider whether chronic as-trogliosis with long-term overexpression ofGFAP may be sufficient to cause cellular dys-function and degeneration. This possibility israised not only by the clinical example Alexan-der disease with mutated GFAP discussed above,but also by evidence that chronic high level ex-pression of normal GFAP may cause pathology(Messing et al. 1998). Chronic astrogliosis canoccur in neurodegenerative disorders or whenCNS insults are comorbid with infections asdiscussed below, and its effects warrant furtherstudy. Nonetheless, it deserves emphasis that,after acute insults, such as single traumatic orischemic events that are not comorbid with in-fections, astrogliosis in perilesion tissue resolvesrelatively rapidly (within weeks) and GFAP lev-els return to normal or low levels. Last, an excit-ing new area pioneered by the Barres laboratoryis astrocyte induction and pruning of neuronalsynapses during development and in adult neu-ral plasticity (Clarke and Barres 2013). Mice de-ficient in astrocyte-specific phagocytic pathwaysfail to develop normal connections and retainexcess synapses (Chung et al. 2013). The impactof normal or anomalous astrogliosis on astro-cyte interactions with synapses remains to bedetermined but has the potential to open newways of thinking about certain CNS disorders.

PERIPHERAL INFECTIONS ANDMOLECULAR SIGNALS THAT SKEWASTROGLIOSIS TOWARD CYTOTOXICITY

Peripheral infections can generate high levelscirculating cytokines and inflammatory media-tors, such as microbial PAMPs, which can gainaccess to CNS lesions with compromisedblood–brain barrier (Burda and Sofroniew2014). Exposure of astrocytes to PAMPs, suchas lipopolysaccharide and certain cytokines,drives astrocyte transcriptome profiles towarda proinflammatory and cytotoxic potential(Hamby et al. 2012; Zamanian et al. 2012; So-froniew 2013). This response is not surprisingbecause limiting infection spread is likely tohave shaped the evolution of injury responses

Astrogliosis




in all tissues including the CNS (Burda and So-froniew 2014). If sterile CNS insults are comor-bid with peripheral infections, there is a strongpossibility that the molecular expression profileand function of reactive glia may be altered inways that can exacerbate tissue damage andcompromise neural repair (Burda and Sofro-niew 2014). In keeping with these experimentalfindings, clinical epidemiological observationsindicate that peripheral infections have a nega-tive impact on neurological outcome after spi-nal cord injury (Failli et al. 2012). The potentialimpact of concurrent low-grade infections, oreven of microbiome (Heintz and Mair 2014),on astrogliosis and responses to CNS insults islikely to be an interesting area of future research.

ASTROGLIOSIS AND NEURONALFUNCTION AND BEHAVIOR

Astrogliosis has the potential to modify astro-cyte functions in ways that influence neuronalfunctions, including behaviors. In the healthyCNS, astrocytes (1) maintain the extracellularhomeostasis of Kþ, water, pH, and transmitteruptake (Halassa and Haydon 2010; Jin et al.2013), (2) may modulate synaptic activity di-rectly via release of “gliotransmitters” (Volterraand Meldolesi 2005; Halassa and Haydon 2010;Hamilton and Attwell 2010; Henneberger et al.2010), and (3) take part in the formation andpruning of synapses (Chung et al. 2013; Clarkeand Barres 2013). Functional changes under-gone by reactive astrocytes in response to spe-cific molecular triggers can impact neurons via(1) down-regulation of glutamine synthase as-sociated with reduced inhibitory synaptic cur-rents in local neurons (Ortinski et al. 2010), (2)increased expression of xCT (Slc7a11), a cys-teine-glutamate transporter associated with in-creased glutamate signaling, seizures, and exci-totoxicity (Jackman et al. 2010; Buckinghamet al. 2011), and (3) changes in the expressionof multiple GPCRs and G proteins and calciumsignaling evoked by their ligands (Hamby et al.2012). There is increasing evidence for astrocyteparticipation in complex behaviors includingsleep (Halassa and Haydon 2010), pain (Hansenand Malcangio 2013), mood, depression (Ha-

lassa and Haydon 2010; Paradise et al. 2012;Czeh and Di Benedetto 2013; Martin et al.2013), and certain childhood behavioral disor-ders with altered synapse development (Ste-phan et al. 2012; Clarke and Barres 2013). As-trocytes are primary targets of cytokines andinflammatory mediators increasingly implicat-ed not only in sickness behaviors, such as socialwithdrawal, reduced activity, loss of appetite,and cognitive disturbances, but also in certainkinds of sleep disturbances, mood disturbances,major depressive disorders, and CNS develop-mental disorders (Dantzer et al. 2008; Dowlatiet al. 2010; Irwin and Cole 2011; Jurgens et al.2012; Patterson 2012; Sofroniew 2013). Mod-ulation of astrocyte physiology and functionby cytokines and inflammatory mediators hasthe potential to impact such behaviors (Millerand O’Callaghan 2005; Sofroniew 2013). Al-though such interactions are only beginning tobe studied, early information suggests a strongpotential for identifying new ways in which CNScellular responses to injury or disease impactsystems-level neural functions and behaviors(Sofroniew 2013).

ASTROGLIOSIS AS A THERAPEUTIC TARGET

There is increasing recognition that molecularmechanisms associated with specific functionsand effects of astrocytes and astrogliosis maybe potential targets for novel therapeutic strat-egies for CNS disorders (Hamby and Sofroniew2010). As emphasized throughout this article,astrogliosis exerts essential beneficial functionsbut can also give rise to harmful effects in spe-cific contexts as determined by specific signalingevents. Thus, useful therapeutic strategies willneed to be specifically targeted so as to preserveor augment beneficial effects of astrogliosiswhile blocking or reducing harmful ones. Theonce prevalent view that wholesale blockade ofastrogliosis or astroglial scar formation could bea therapeutic strategy is no longer tenable andwould likely do more harm than good. Specificaspects of astrogliosis that are being explored aspotential targets for therapeutic manipulationsinclude mechanisms that regulate glutamate,enzymes that generate or neutralize reactive ox-

M.V. Sofroniew




ygen species, and production of certain cyto-kines (Hamby and Sofroniew 2010). Althoughdetailed examination is beyond the scope ofthis article, astrocyte regulation of glutamateclearance and the potential role of astrocytesand astrogliosis in glutamate excitotoxicity afterischemia (Beppu et al. 2014; Sloan and Barres2014) and during neurodegenerative disease(Maragakis and Rothstein 2006) are of particu-lar interest. Pharmacological manipulation ofexpression or activity of astrocyte glutamatetransporters is being explored, and moleculeshave been identified that enhance astrocyte-me-diated glutamate uptake sufficiently to provideneuroprotection in animal models of stroke andneurodegenerative disorders (Rothstein et al.2005; Fontana et al. 2007).

CONCLUDING REMARKS

Astrogliosis in response to CNS damage anddisease has been recognized for well over 100years. Recent progress shows that astrogliosis isa complex and multifaceted process that canrange from subtle and reversible alterations ingene expression and morphology to the pro-nounced and long-lasting changes associatedwith scar formation. Responses of astrocytes toCNS insults are controlled in a context-depen-dent manner by specific signaling mechanismsthat mediate numerous essential beneficialfunctions, but under certain circumstances canlead to harmful effects. Simplistic notions thatastrogliosis and scar formation are maladaptive,uniformly detrimental responses, and that com-plete blockade of reactive astrogliosis per se willbe beneficial, are refuted by findings from manylaboratories. Essential functions of astrogliosisand scar formation include the protection ofneural cells, the restriction of inflammationand infection, and the preservation of tissueand function. Dysfunctions of astrocytes andastrogliosis can also occur, either through gainof abnormal effects or loss of normal functions,and contribute to, or be primary causes of, avariety of CNS disorders. As a result, astrocytesand astrogliosis are increasingly recognized aspotential targets for novel therapeutic strategies.Effective therapies will need to be directed at

augmenting or attenuating specific aspects ofastrogliosis.

ACKNOWLEDGMENTS

Work in the author’s laboratory is supported bygrants from the National Institutes of Health,The Dr. Miriam and Sheldon G. Adelson Med-ical Foundation, and Wings for Life.

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M.V. Sofroniew




November 7, 20142015; doi: 10.1101/cshperspect.a020420 originally published onlineCold Spring Harb Perspect Biol

Michael V. Sofroniew Astrogliosis

Subject Collection Glia

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Matthew N. Rasband and Elior Peles

Oligodendrocyte Development and PlasticityDwight E. Bergles and William D. Richardson

Microglia in Health and DiseaseRichard M. Ransohoff and Joseph El Khoury Support

Oligodendrocytes: Myelination and Axonal

Mikael Simons and Klaus-Armin NaveThe Astrocyte: Powerhouse and Recycling Center

Bruno Weber and L. Felipe Barros Central Nervous System GliaDrosophila

Marc R. Freeman

Development and PlasticityMicroglia Function in Central Nervous System

Dorothy P. Schafer and Beth StevensSynapse: Adaptable, Multitasking Glial CellsPerisynaptic Schwann Cells at the Neuromuscular

Chien-Ping Ko and Richard Robitaille

the Central Nervous SystemOligodendrocyte Development and Myelination in Transcriptional and Epigenetic Regulation of

Ben Emery and Q. Richard Lu

and EliminationAstrocytes Control Synapse Formation, Function,

Won-Suk Chung, Nicola J. Allen and Cagla Eroglu

ControversiesOrigin of Microglia: Current Concepts and Past

Florent Ginhoux and Marco Prinz

Schwann Cell MyelinationJames L. Salzer

Remyelination−−Glia Disease and RepairRobin J.M. Franklin and Steven A. Goldman Repair

Schwann Cells: Development and Role in Nerve

LloydKristján R. Jessen, Rhona Mirsky and Alison C.

Astrocytes in Neurodegenerative DiseaseHemali Phatnani and Tom Maniatis

Perineurial GliaSarah Kucenas

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