cells Review The Complement System: A Powerful Modulator and Effector of Astrocyte Function in the Healthy and Diseased Central Nervous System Marcela Pekna 1,3,4,* and Milos Pekny 2,3,4 1 Laboratory of Regenerative Neuroimmunology, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, 40530 Gothenburg, Sweden 2 Laboratory of Astrocyte Biology and CNS Regeneration, Center for Brain Repair, Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, 40530 Gothenburg, Sweden; [email protected] 3 Florey Institute of Neuroscience and Mental Health, Parkville, Melbourne 3010, Australia 4 School of Medicine and Public Health, University of Newcastle, Newcastle 2308, Australia * Correspondence: [email protected]; Tel.: +46-31-786-3581 Abstract: The complement system, an effector arm of the innate immune system that plays a critical role in tissue inflammation, the elimination of pathogens and the clearance of dead cells and cell debris, has emerged as a regulator of many processes in the central nervous system, including neural cell genesis and migration, control of synapse number and function, and modulation of glial cell responses. Complement dysfunction has also been put forward as a major contributor to neurological disease. Astrocytes are neuroectoderm-derived glial cells that maintain water and ionic homeostasis, and control cerebral blood flow and multiple aspects of neuronal functioning. By virtue of their Citation: Pekna, M.; Pekny, M. The Complement System: A Powerful expression of soluble as well as membrane-bound complement proteins and receptors, astrocytes are Modulator and Effector of Astrocyte able to both send and receive complement-related signals. Here we review the current understanding Function in the Healthy and Diseased of the multiple functions of the complement system in the central nervous system as they pertain to Central Nervous System. Cells 2021, the modulation of astrocyte activity, and how astrocytes use the complement system to affect their 10, 1812. https://doi.org/10.3390/ environment in the healthy brain and in the context of neurological disease. cells10071812 Keywords: astrocytes; the complement system; C3; reactive astrocytes; reactive gliosis; neurodegen- Academic Editors: Pavel Hozák, eration; neural plasticity Elly Hol and Roy Andrew Quinlan Received: 15 June 2021 Accepted: 14 July 2021 1. Introduction Published: 17 July 2021 By virtue of its ability to sense and rapidly respond to diverse danger signals, the Publisher’s Note: MDPI stays neutral complement system plays an essential role in the innate immune responses and constitutes with regard to jurisdictional claims in the first line of defense against pathogens such as bacteria, viruses, mycoplasma, fungi, and published maps and institutional affil- protozoa. Whereas the functions of the complement system in the elimination of pathogens, iations. antigen-antibody complexes, dead cells and tissue debris, and their involvement in the regulation of the responses mediated by antibodies and cells of the adaptive immune system have been well recognized for many decades, the homeostatic and non-immune tasks of the complement proteins only recently began to be unraveled. Liver cells are the main source of complement proteins in the blood, but complement proteins are also Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. produced locally in many tissues including the central nervous system (CNS). There is This article is an open access article an exponentially growing amount of evidence for the role of the complement system in distributed under the terms and the CNS development [1–8], maintenance and restoration of CNS homeostasis [9,10], and conditions of the Creative Commons in the regulation of neural plasticity [11–14]. However, the complement system is also Attribution (CC BY) license (https:// an important driver of age-related synapse loss and cognitive decline [15] and plays a creativecommons.org/licenses/by/ principal role in the neurodegeneration processes [16–22]. Astrocytes are a major source of 4.0/). the complement system proteins, particularly of the third complement component (C3), Cells 2021, 10, 1812. https://doi.org/10.3390/cells10071812 https://www.mdpi.com/journal/cells Cells 2021, 10, 1812 2 of 15 and they stand out as a very prominent player or effector in many of the complement- mediated processes. Through a number of complement receptors expressed on their cell membrane, astrocytes are also well equipped to sense the level of complement activation in their vicinity, as well as receive and respond to complement-derived signals sent by other cells. 2. The Complement System The complement system consists of more than 50 secreted and cell membrane-bound proteins that exert their functions through highly ordered interactions. Liver cells are the main source of complement proteins in the blood. Complement proteins are also produced locally in many tissues including the CNS. The very powerful and potentially deleterious effector functions of the complement system place high demands on its control. The strict control of the complement system is achieved at two levels: activation of inactive precursors and inactivation of the active components through degradation. Many of the secreted complement proteins are produced as inactive precursors and need to be activated through conformational changes induced, for example, by binding to the right target, such as the pathogen-associated molecular patterns or antigen-antibody complex, or through proteolytic cleavage. The complement system also includes a number of fluid-phase and membrane-bound regulatory proteins that protect healthy host cells and ensure that the activation and effector functions of the active proteins and their fragments are limited both in space and in time. 2.1. Activation of the Complement System There are three canonical pathways through which the complement system can be activated: the classical pathway, the alternative pathway, and the lectin pathway. The prototypic trigger of the classical pathway is the binding of the C1 complex to the Fc moieties of antigen-bound IgG or IgM. The C1 complex consists of C1q, which serves the role of a pattern recognition molecule, associated with a tetramer of two each of the serine proteases C1r and C1s. Other ligands for the complement component C1q include molecular patterns on certain pathogens (such as Gram-positive and Gram-negative bacteria and some viruses), the C-reactive protein-phosphocholine complex, pentraxin-3, serum amyloid P component, beta-amyloid fibrils, DNA, mitochondrial membranes, as well as different targets on apoptotic cells such as phosphoserine, histones and annexins (reviewed by e.g., [23,24]). Binding of C1q to a ligand induces autoactivation of C1r followed by sequential proteolytic activation of C1s, C4 and C2, which results in the formation of activator-bound C3 convertase (C4b2a) of the classical pathway, an enzymatic complex that cleaves C3 into C3a and C3b. C3a is released into the fluid-phase and binds to the C3a receptor (C3aR) or is rapidly inactivated by carboxypeptidases that remove its C-terminal arginine residue. C3b becomes covalently bound to the activator via exposed internal thioester bond, thus irreversibly tagging and opsonizing the activator for recognition by cells expressing complement receptors (CR) 1–4 and CRIg, Figure1. The pattern recognition molecules of the lectin pathway are the collectins mannan- binding lectin and collectin-LK and ficolins H, M, and L, which recognize the sugar moieties and acetyl groups of glycoproteins and glycolipids on bacteria, viruses, fungi, and protozoa, but also host organelles, mitochondria and natural IgM bound to neo-epitopes exposed on apoptotic and necrotic host cells. Similar to the C1 complex of the classical pathway, binding of collectins or ficolins to an activator leads to the autoactivation and proteolytic activation of the serine proteases they are associated with, namely mannan-binding lectin- associated serine protease 1 and 2, followed by activation of C2 and C4 and formation of activator-bound C3 convertase C4b2a. Activation of the classical and lectin pathways thus leads to the covalent binding of C3b to the activator surface, Figure1. Cells 2021, 10, 1812 3 of 15 Cells 2021, 10, x 3 of 15 Figure 1. Complement system activation. Upon binding to a target structure, e.g.,e.g., antigen-antibodyantigen-antibody complex or as yet unidentified unidentified synaptic component, C1q triggers the activation of the classical path- way leading to formation of the C2a4b convertase and the proteolytic activationactivation ofof C3, opsonization of the target target with with C3b, C3b, and and release release of of C3a. C3a. Recognition Recognition of microbial of microbial sugar sugar moieties moieties by ficolins, by ficolins, col- collectinslectins or ormannan mannan-binding-binding lectin lectin (MBL) (MBL) in in complex complex with with mannan mannan-binding-binding lectin lectin-associated-associated serineserine protease 1 and 2 (MASP1, 2) initiates the lectin pathway. The alternative pathway is activated when protease 1 and 2 (MASP1, 2) initiates the lectin pathway. The alternative pathway is activated when spontaneous hydrolysis of the internal thioester bond in C3 leads to the conformational change of spontaneous hydrolysis of the