Mechanisms of Inflammation

Leading Edge Review Mechanisms Underlying Inflammation in Neurodegeneration Christopher K. Glass,1,2,* Kaoru Saijo,1 Beate Winner,3 Maria Carolina Marchetto,3 and Fred H. Gage3,* 1Department of Cellular and Molecular Medicine 2Department of Medicine University of California, San Diego, La Jolla, CA 92093, USA 3Laboratory of Genetics, Salk Institute for Biological Studies, La Jolla, CA 92037, USA *Correspondence: [email protected] (C.K.G.), [email protected] (F.H.G.) DOI 10.1016/j.cell.2010.02.016 Inflammation is associated with many neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and multiple sclerosis. In this Review, we discuss inducers, sensors, transducers, and effectors of neuroinflammation that contribute to neu- ronal dysfunction and death. Although inducers of inflammation may be generated in a disease- specific manner, there is evidence for a remarkable convergence in the mechanisms responsible for the sensing, transduction, and amplification of inflammatory processes that result in the production of neurotoxic mediators. A major unanswered question is whether pharmacological inhibition of inflammation pathways will be able to safely reverse or slow the course of disease. Introduction glial cell with support functions) and neurons. Under physiolog- Virchow’s seminal descriptions of activated microglia antici- ical conditions, microglia exhibit a deactivated phenotype that pated by more than a century the current interest in roles of is associated with the production of anti-inflammatory and neu- the innate and adaptive immune systems in diverse forms of rotrophic factors (Streit, 2002). Microglia switch to an activated neurodegenerative disease. Microglia, a type of glial cell, are phenotype in response to pathogen invasion or tissue damage macrophages that are resident in the brain and spinal cord and and thereby promote an inflammatory response that serves form the frontline defense of the innate immune system. Direct to further engage the immune system and initiate tissue repair. evidence for an innate inflammatory response in Alzheimer’s In most cases, this response is self-limiting, resolving once infec- disease (AD) was described nearly 20 years ago (reviewed in tion has been eradicated or the tissue damage has been Akiyama, 1994), and subsequent studies have documented repaired. inflammatory components in Parkinson’s disease (PD), amyotro- Sustained inflammation resulting in tissue pathology implies phic lateral sclerosis (ALS), multiple sclerosis (MS), and a growing persistence of an inflammatory stimulus or a failure in normal number of other nervous system pathologies. Although inflam- resolution mechanisms. A persistent stimulus may result from mation may not typically represent an initiating factor in neurode- environmental factors or the formation of endogenous factors generative disease, there is emerging evidence in animal models (e.g., protein aggregates) that are perceived by the immune sys- that sustained inflammatory responses involving microglia and tem as ‘‘stranger’’ or ‘‘danger’’ signals. Inflammatory responses astrocytes contribute to disease progression. A major unre- that establish feed-forward loops may overwhelm normal resolu- solved question is whether inhibition of these responses will be tion mechanisms. Although some inflammatory stimuli induce a safe and effective means of reversing or slowing the course beneficial effects (e.g., phagocytosis of debris and apoptotic of disease. To effectively address this question, it will be neces- cells), and inflammation is linked to tissue repair processes, sary to learn more about how inflammatory responses are uncontrolled inflammation may result in production of neurotoxic induced within the central nervous system and the mechanisms factors that amplify underlying disease states. As a starting point by which these responses ultimately contribute to pathology. for comparing and contrasting roles of inflammation in the path- Here, we review studies of the roles of inflammation mediated ogenesis of AD, PD, ALS, and MS, we will first briefly consider by the innate and adaptive immune systems in the pathogenesis general features of inflammation in the context of innate and of AD, PD, ALS, and MS and highlight some of the important adaptive immunity. areas for future investigation. Inducers and Sensors of Infection and Injury The inflammatory response represents a highly regulated biolog- Inflammation, Immunity, and Repair ical program that, on the one hand, must enable the innate and The immune system plays essential roles in the maintenance of adaptive immune systems to effectively deal with rapidly dividing tissue homeostasis and the response to infection and injury. microbial pathogens but, on the other hand, involves the produc- Microglia are the major resident immune cells in the brain, where tion of factors that are themselves capable of inducing significant they constantly survey the microenvironment and produce tissue pathology. As a consequence, genes that play key roles factors that influence surrounding astrocytes (another type of in amplification or effector functions of inflammatory responses 918 Cell 140, 918–934, March 19, 2010 ª2010 Elsevier Inc. are actively repressed under normal conditions and are only influence substrate metabolism, protein synthesis, cell motility, induced when cells sense evidence of infection or injury. Inflam- phagocytosis, intracellular killing, and antigen presentation. matory responses to infectious agents are typically initiated by The generation of reactive oxygen species (ROS), e.g., through pattern recognition receptors that bind to so-called pathogen- the NADPH oxidase system, is an important antimicrobial mech- associated molecular patterns (stranger signals). One class of anism but also exemplifies a system that can result in collateral pattern recognition receptor is exemplified by the Toll-like recep- damage to tissue, e.g., the parenchymal cells in the brain. tors (TLRs), which recognize a diverse set of pathogen-associ- Cellular and Tissue Context ated molecules that are not present in the host (see Review Inflammatory responses are typically localized and involve by O. Takeuchi and S. Akira on page 805 of this issue). For communication between immune, vascular, and parenchymal example, TLR4 recognizes lipopolysaccharide (LPS) associated cells. Resident populations of tissue macrophages play key roles with gram-negative bacteria, whereas TLR3 recognizes viral as sentinels of infection and injury but are also increasingly double-stranded RNA. These receptors are expressed on many recognized as having an influence on normal tissue homeo- cell types but are highly expressed on cells that play central roles stasis. Macrophage phenotypes can be considered in the in innate immune responses, including macrophages and micro- context of ‘‘activation’’ status, with M1 or ‘‘classical activation’’ glia. Pattern recognition receptors have more recently been describing the proinflammatory phenotypic response to IFN-g found to also be capable of responding to endogenously derived produced by Th1 T lymphocytes or signaling through TLRs. molecules, such as components released from necrotic cells M2 or ‘‘alternative activation’’ describes distinct phenotypic (danger signals) and by molecules that may be formed as responses to cytokines, such as IL-4 and IL-13, produced by a consequence of pathogenic mechanisms. Roles of TLR2 and Th2 lymphocytes and other cell types (see Review by C. Nathan TLR4 have recently been established in the pathogenesis of and A. Ding on page 871 of this issue). The term ‘‘deactivated’’ several chronic inflammatory diseases in animal models, and macrophage has been used to describe phenotypic responses specific TLR4 polymorphisms are associated with several to anti-inflammatory cytokines, such as IL-10. Transition of human age-related diseases, including atherosclerosis, type 2 tissue-resident macrophages from the M2 to the M1 phenotype diabetes, and rheumatoid arthritis, raising the question of generally is associated with inflammation-induced pathologies, whether these receptors also contribute to inflammatory pro- such as diet-induced insulin resistance (Lumeng et al., 2007). grams associated with neurodegenerative disease (Balistreri As noted above, microglia exhibit a deactivated phenotype in et al., 2009). In addition to pattern recognition receptors, puriner- the healthy brain and may play important roles in maintenance gic receptors are expressed on microglia and astrocytes and are of tissue homeostasis through communication with astrocytes capable of responding to ATP released from cells following cell and neurons, analogous to homeostatic roles of ‘‘alternatively death, traumatic injury, or ischemia (Di Virgilio et al., 2009). activated’’ macrophages in other tissues. The central nervous Microglia and astrocytes also express a number of so-called system (CNS) is an immunologically privileged site and circu- ‘‘scavenger receptors’’ that have been demonstrated to be lating immune cells normally do not have access to it in the involved in the uptake of a number of substrates, including absence of inflammation or injury. Dendritic cells with special- oxidized proteins, lipids, and apoptotic cells, and that may also ized antigen-presenting capabilities do not appear to be present contribute to cell signaling (Husemann et al., 2002). under normal conditions. Microglia appear to be the major initial Transduction Systems sensors of danger or stranger signals recognized

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