Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press 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), astrocytes respond 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 in astrocytes that occur in a context-specific manner as determined by diverse signaling events that vary with the nature and severity of different CNS insults. Astrogliosis is associated with essential beneficial functions, but under specific circumstances can lead to harmful effects. Potential dysfunctions of astrocytes and astrogliosis are being identified that can contribute 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 occurring and dysfunctional astrogliosis and their different roles in CNS disorders. strocytes exert many essential functions in mation has now accrued regarding the mecha- Athe healthy central nervous system (CNS) as nisms, functions, and impact of astrogliosis. It is reviewed and discussed in other articles in this now clear that astrogliosis plays fundamental volume. In addition, astrocytes respond to all roles in determining tissue repair and outcome forms of CNS damage and disease with a variety after injury or disease, and has the potential to of potential changes in gene expression, cellu- influence neural function. lar structure, and function. Such responses are commonly referred to as astrogliosis. Although astrogliosis has a long history of descriptive WHAT IS ASTROGLIOSIS? analysis beginning in the late 19th century, there The term astrogliosis dates back to late 19th and was only sparse interest in, or investigation of, its early 20th century neuroanatomists who re- mechanisms or functions for much of the 20th cognized that astroglia underwent pronounced century. This situation changed gradually over structural changes in response to CNS damage the last two decades when, in parallel with the and disease. At different times, astrogliosis has explosion of information regarding essential been assigned various definitions but it has al- astrocyte roles in the healthy CNS, interest has ways referred to astrocyte responses to CNS in- grown in understanding astrogliosis (Pekny sults. Based on a large cross section of studies in and Nilsson 2005; Sofroniew 2009; Sofroniew experimental animals and human pathological and Vinters 2010; Kang and Hebert 2011). As specimens, we have recently proposed a more summarized in this article, considerable infor- detailed working definition of astrogliosis that Editors: Ben A. Barres, Marc R. Freeman, and Beth Stevens Additional Perspectives on Glia available at www.cshperspectives.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a020420 1 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press M.V. Sofroniew encompasses four key features: (1) astrogliosis gliosis does not occur in isolation, but is part is a spectrum of potential molecular, cellular, of a coordinated multicellular response to CNS and functional changes in astrocytes that occur insults that includes multiple types of glia as in response to all forms and severities of CNS well as neurons and different types of non-neu- injury and disease; (2) changes undergone by ral cells that are intrinsic to the CNS or that reactive astrocytes vary with severity of the in- enter from the bloodstream (Burda and Sofro- sult along a graded continuum; (3) changes niew 2014). Different types of glia that respond associated with astrogliosis are regulated in a to CNS insults include microglia, astrocytes, context-specific manner by many different and NG2-positive oligodendrocyte progenitors inter- and intracellular signaling molecules; (NG2-OPC). Non-neural cells intrinsic to the and (4) changes undergone during astrogliosis CNS that respond to insults include endothelia, have the potential to alter astrocyte activities perivascular fibroblasts, pericytes, and menin- both through gain and loss of functions (So- geal cells. Cells that enter from the bloodstream froniew 2009; Sofroniew and Vinters 2010). after CNS insults include leukocytes, platelets, Specific aspects of these features are discussed and other bone marrow–derived cells. Together, below. these cells have the capacity to produce a vast Various other terms are sometimes used to array of intercellular signaling molecules, and refer to astrocyte responses to CNS damage or these molecules have the potential to influence disease, and use of certain terms can vary among the activities and functions of different cell investigators. Wewill use “astrogliosis” and “re- types, including astrocytes. Thus, the response active astrocytes” as general all-inclusive de- to CNS insults is a complex mixture of events scriptors of all forms of astrocyte responses involving the interactions of multiple cell types associated with any form of CNS damage or dis- that change over time (Burda and Sofroniew ease. As discussed in more detail below, these 2014). Astrocytes take part in these interactions terms encompass astrocyte responses of con- both by receiving instructive signals from other siderable diversity and heterogeneity. We will cells and by sending instructive signals that in- not use “activation” or “activated astrocytes” as fluence other cells (Fig. 1). termsthatreferexclusively toastrocyteresponses to injury or disease. Astrocytes in healthy tissue ASTROGLIOSIS AS A CONTINUUM continually show physiological activation in the OF POTENTIAL RESPONSES form of transient, ligand-evoked elevations in 2þ intracellular calcium ([Ca ]i) that represent a Astrogliosis has often been referred to as if type of astrocyte excitability, involved in medi- it were a single uniform entity that is essential- ating many critical dynamic astrocyte functions, ly the same in all situations. This is emphatically including interactions with synapses and regu- not the case. A multitude of studies over the lation of blood flow as discussed in other articles past 20 yr have provided compelling evidence in this volume. Thus, astrocyte activation can that astrogliosis is not a simple stereotypic re- range from physiological contexts in healthy sponse, but instead is a finely tuned spectrum CNS to pathophysiologic contexts that involve of potential changes that range from reversible responding to CNS injury or disease. In keeping alterations in gene expression and cellular hy- with these definitions, there seems to be no place pertrophy to pronounced cell proliferation with for the notion of an “activated astrocyte” as a compact scar formation and permanent tissue single uniform entity. rearrangement. Available evidence points to- ward a wide range of specific molecular sig- naling mechanisms that regulate specific aspects MULTICELLULAR RESPONSES of astrogliosis, rather than a single stereotypic TO CNS INSULTS program that is regulated in an on–off manner Although the focus of this article is on astro- (Pekny and Nilsson 2005; Sofroniew 2009; So- gliosis, it is important to emphasize that astro- froniew and Vinters 2010; Kang and Hebert 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a020420 Downloaded from http://cshperspectives.cshlp.org/ on October 5, 2021 - Published by Cold Spring Harbor Laboratory Press Astrogliosis ABAstrocytes receive instructions Astrocytes send instructions Synapse Microglia Synapse Microglia FGF-2 IL-10 + NO ATP PT3 K ATP FGF-2 EGF TNF-α TNF-α KYN NO LCN2 TNFα Glut INF-γ Glut IL-11IL-15 IL-1β β IL1- CXCL10 THBS1 NE Reactive Astrocyte Reactive Astrocyte CCL2 GPC4 CCL7 wbc ROS IL-6 wbc CSPG CXCL1 IL-10 LIF BDNF IL-6 CCL8 GDNF TGF-β GDNF CCL5 β NGF CXCL9 A Estrogen CXCL16 NH + bv ??? bv 4 GFs NO BBB CNTF Albumin END LIF MMP3 PGE repair SHH Thrombin LPS IGF-1 VEGF-A PAMPs BBB leak Blood Neuron BBB leak Neuron flow 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 instruct other cells (B). For abbreviations, see Table 1. 2011). Although there are common features very intense changes (Fig. 2). Thus, astrogliosis across different forms and intensities of astro- is complex and multivariate, and the changes gliosis, such as up-regulation of glial fibrillary in astrocytes that are associated with astro- acidic protein (GFAP) and cellular hypertro- gliosis are induced in a context-dependent phy, even these do not occur in all or none fash- manner as regulated by many different potential ions, but are finely regulated along a gradient signaling events as summarized in the next of intensity that can vary from very small to sections. Astrogliosis gradient Healthy Mild Moderate Severe diffuse Scar Tissue lesion Domain Overlapping preservation processes Cytoskeletal Cytoskeleton hypertrophy Proliferated Inflammatory