Neurochemical Mechanisms in Disease P38 ppsx

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Lawrence Abstract The first description of the inflammatory process appeared as early as the first century AD. Among the first things learned about inflammation is that vascular permeability is increased and leukocyte extravasation occurs. It is now realized that the central nervous system (CNS) is not as devoid of immune cell entrance as once believed and that neuroinflammation can occur. Even in the CNS absence of peripheral immune cells, cytokines from the periphery can influence glial activation in response to endogenous or exogenous stresses. Activated glial cells will secrete proinflammatory cytokines among other factors. The presence of relatively high concentrations of proinflammatory cytokines, such as IL-1, IL-6, and TNF-α,in the brain produces sickness behavior. Neuroinflammation is not only caused by viral or bacterial infection, but can also be the result of physical injury or neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and cerebral palsy. This chronic neuroinflammation is associated with a number of common factors; most notable among these is the increased concentration of proinflammatory cytokines. In addition to the ones listed above, others have been detected including, IL-18, IL-33, and HMGB1. Although TGF-β1 functions most often as an anti-inflammatory cytokine, under certain circumstances it, too, can have proinflammatory activity. Other common features of neuroinflammation include increased production of reactive oxygen species (ROS) and nitric oxide (NO), which function to increase apoptosis and promote neuronal damage. Activation of astrocytes is detected by elevated GFAP expression. Activated astrocytes promote chemokine expression causing permeability of the blood–brain barrier (BBB), thus allowing leukocytes to enter the brain tissue. The heavy metal Pb accumulates in glial cells and in doing so can potentiate cytokine and glutamate-mediated increases in the BBB permeability, as well as cause chronic glial cell activation. Pb’s ability to promote gliosis and deficiencies in chaperone protein function has prompted a com- parison of Pb toxicity to certain neurodegenerative disorders, such as Alzheimer’s D.A. Lawrence (B) New York State Department of Health, Wadsworth Center, Albany, NY 12201, USA e-mail: david.lawrence@wadsworth.org 359 J.P. Blass (ed.), Neurochemical Mechanisms in Disease, Advances in Neurobiology 1, DOI 10.1007/978-1-4419-7104-3_12, C  Springer Science+Business Media, LLC 2011 360 J. Kasten-Jolly and D.A. Lawrence and Parkinson’s diseases. Toxicity of other metals, such as, Al, Cu, Cd, Zn, and Hg was also found to share common features with Alzheimer’s disease. Keywords Alzheimer’s disease · Astrocytes · Blood–brain barrier (BBB) · Central nervous system (CNS) · Chaperone proteins · Chemokines · Cytokines · Heavy metals · Inflammation · Lead (Pb) · Map kinases · Microglia · Neurons · Nitric oxide (NO) · Reactive oxygen species (ROS) Contents 1 Introduction 360 1.1 Cytokines and Neuroinflammation 361 1.2 MAP Kinases and Stress Kinases 366 1.3 Microglia Cells 368 1.4 Astrocytes 369 1.5 Neuroinflammatory Aspects of Pb Toxicity 369 1.6 Neuroinflammatory Effects of Metals Other than Pb 372 2 Summary 374 References 375 1 Introduction The inflammatory process was first described by Cornelius Celsus in the first century AD when he listed the four signs of inflammation: rubor et tumor cum calore et dolore (redness and swelling with heat and pain). A fifth sign of inflammation has been annexed to the cardinal four, functio laesa (disruption of normal function); although its origin has been questioned (Rather, 1971), it is the disturbance of normal function that may lead to the potential pathological consequences of inflammation. The original four signs of inflammation were based mainly on peripheral skin observations. It wasn’t until the nineteenth and twentieth centuries that the cellular aspects of inflammation began to be understood. Julius Cohnheim observed that in the inflamed tissue there was increased vasodilation along with vascular permeability and leukocyte extravasation. Sir Thomas Lewis noted that the vascular changes were mediated by chemical substances present in serum (Cotran et al., 1994). It was not realized until much later that inflammation could occur in hid- den places, such as the central nervous system (CNS) and that inflammation could be initiated by endogenous or exogenous agents. With advancements in molecular and cellular methodology during the past few decades, much has been learned about the mediators of the inflammation process. Much of this knowledge has been obtained through the study of disease-related inflammation (Sheng et al., 1996; Akiyama et al., 2000; Combs et al., 2000; Cagnin et al., 2002; Rosales-Corral et al., 2004; Eikekenboom et al., 2006; Shepherd et al., 2006; Zipp and Aktas, 2006; Lassmann, 2007), injury, and animal models (Jafarian-Tehrani and Sternberg, 1999; CNS Cytokines 361 Kielian and Hickey, 2000). Although inflammation usually has positive influences in defense against pathogens, the processes can cause cellular damage and initiate or exacerbate various pathologies, especially autoimmune diseases and neurobehav- ioral diseases in susceptible humans and animals. Inflammation is closely associated with oxidative stress, and chronic inflammation along with its accompanying oxi- dant damage can lead to an acceleration of aging-related changes, which includes cytotoxicity (Norris et al., 2005). The present chapter is restricted to discussion of neuroinflammation, including information about the roles of cytokine, chemokines, MAP kinases, glia, and reactive oxygen species. Closing paragraphs present a discussion of metal neurotoxicity, with emphasis on the immune- and neurotoxicant lead (Pb), and the neuroinflammatory aspects of this toxicity. 1.1 Cytokines and Neuroinflammation 1.1.1 Interleukin (IL)-1, IL-6, and TNF-α The proinflammatory cytokines, IL-6, IL-1β, and TNF-α, are associated with sickness behavior and their levels increase in the CNS during viral or bacterial infections (Quan et al., 1999; Pollmacher et al., 2002; Anisman, 2004; Dantzer et al., 2007; 2008). The sickness behavior paradigm of lethargy (malaise and lack of mobility), loss of appetite and drinking, and altered body temperature (fever) is due to the signals of proinflammation cytokines delivered to the hypothalamus (Woiciechowsky et al., 1999). The brain monitors peripheral innate immune responses by several methods (Quan and Banks, 2007). One pathway involves activation of afferent nerves by locally produced cytokines and pathogen-associated molecular patterns (PAMPs), such as vagal nerve, during an abdominal infection. A second mechanism involves the humoral (antibody-mediated) pathway and Toll-like receptors (TLRs) located on macrophage-like cells residing in the circumventricular organs and the choroid plexus (Rao et al., 2005). These cells respond to immune complexes of antibody:antigen and PAMPs by producing proinflammatory cytokines. These cytokines then enter the brain by volume diffusion. Third, the overflow of cytokines in the systemic circulation can gain entry to the brain via cytokine transporters at the blood–brain barrier (Matyszak, 1998; Karman et al., 2006; Niederkorn, 2006). A fourth pathway involves activation of IL-1 receptors located on perivas- cular macrophages and endothelial cells of brain venules resulting in production of prostaglandin E2 by upregulation of cyclooxygenase (COX) enzyme synthesis (Pasinetti, 1998; Lacroix and Rivest, 1998;Lietal.,2001; Konsman et al., 2004; Sapirstein et al., 2005; Inoue et al., 2006). These prostaglandins will dif- fuse to the brain targets where they will alter the setpoint for various regulatory processes (Dantzer et al., 2007). However, it was noted that not all of the effects of prostaglandin E 2 were proinflammatory (Zhang and Rivest, 2001). Increased amounts of proinflammatory cytokines from the periphery lead to production of proinflammatory cytokines by microglia cells within the brain (Eikelenboom and Veerhuis., 1996; Hull et al., 1996; Becher et al., 2000; Calvo et al., 2005; Dantzer 362 J. Kasten-Jolly and D.A. Lawrence et al., 2007). The visible response to the increased proinflammatory cytokines in the brain is sickness behavior (Horai et al., 1998; Cartmell et al., 1999). Administration of LPS systemically to mice increases expression, both mRNA and protein, of IL-1β and other proinflammatory cytokines in the brain (Iwai et al., 2006). Also, administration of IL-1β or TNF-α to mice resulted in decreased motor activity, social withdrawal, reduced food and water intake, increased slow-wave sleep, and altered cognition (Campbell et al., 2007; Dantzer et al., 2008). IL-6 has been associated with fever and hippocampus associated cognitive impairment (Smith et al., 2007). Moreover, overexpression of IL-6 in a transgenic mouse model has demonstrated that increased IL-6 will cause astrocytosis and neurodegeneration (Campbell et al., 1993; Steffensen et al., 1994; Jafarian-Tehrani and Sternberg, 1999). IL-6 signals through the JAK1/STAT3 pathway, and it has been shown that LPS-induced plasma levels of IL-6 cause nuclear translocation of the transcription factor STAT3 in certain brain structures including the area postrema, the vascular organs of the lamina terminalis, and the subfornical organ, as well as the hypothalamic supraoptic nucleus (Rummel et al., 2004). The predominant CNS source of IL-6 is the activated astrocyte. IL-6 expression in astrocytes is regulated by proinflammatory factors (such as IL-1β and TNF-α), neurotransmitters, and second messengers (Van Wagoner and Benveniste, 1999). Expression of the proinflammatory cytokines is promoted through activation of NF-kB which is present in inactive form in the cytoplasm by its association with IκBα (Yabe et al., 2005). Proinflammatory cytokines may downregulate their own expression by increasing the expression of IκB or decreasing its proteolysis in certain cells of the brain (Laflamme and Rivest, 1999). Inhibition of NF-κB activation and inhibition of IκBα degradation occurs via a mechanism involving α-melanocyte stimulating hormone (αMSH), which is a pro-opiomelanocortin (POMC) derivative (Ichiyama et al., 1999). In the CNS, increases in proinflammatory cytokines lead to increased formation of reactive oxygen species (ROS) and upregulation of genes that produce toxic products, such as reactive nitrogen species (RNS) (Floyd, 1999; Patel et al., 2003). Synthesis of nitric oxide (NO), can be induced in the brain by mediators of inflammation present in the cerebrospinal fluid (Kong et al., 2000). Several reports have indicated that IL-1 can induce nitric oxide synthase (iNOS) gene expression and thus promote the formation of NO through regulation by interleukin-1 converting enzyme (ICE, caspase-1) (Jones et al., 2005; Juttler et al., 2007). In summary, activated glial cells release NO through increased expression of iNOS, upregulated by the presence of high concentrations of proinflammatory cytokines (Kifle et al., 1996; Stasiolek et al., 2000). Formation of ROS and NRS moieties can alter protein, DNA, RNA, lipid, and carbohydrate structures. Thus, unregulated inflammation can cul- minate in pathological impairment of normal functions; with disregulated oxidative stress, inhibition of mitochrondrial respiration can occur resulting in cytotoxicity (Brown and Bal-Price, 2003). It has been found that nitric oxide production can be inhibited by β- and γ-melanocortin in the mouse brain (Muceniece et al., 2004). CNS Cytokines 363 1.1.2 IL-18 Data from human and rodent studies have shown that IL-18 (previously referred to as interferon-gamma inducing factor, IGIF) expression can be associated with neuropathology in infection, autoimmune disease, ischemia, or closed head injury (Felderhoff-Mueser et al., 2005). IL-18 is a member of the IL-1 family of cytokines. Like IL-1β, it is synthesized as an inactive precursor protein (24 kDa) that is subsequently cleaved to the active18 kDa protein by caspase-1(ICE) (Nhan et al., 2006). The active form of IL-18 induces signal transduction by binding to its receptor, IL-18α/β receptor (IL1Rrp/IL1RAPL) expressed by diverse cell types, including neurons and glia cells. In adult brains of untreated BALB/c mice, IL-18 is constitutively the most highly expressed cytokine (Fig. 1). In the developing brain, IL-18 has been found in association with hypoxic-ischemic brain injury. Mice lacking IL-18 expression had smaller infarct size and a lesser extent of subcortical white matter injury (Felderhoff-Mueser et al., 2005). In a hypoxia model, IL-18 was associated with increased neuronal apoptosis. Therefore, IL-18 can exhibit neuropathology with respect to neuroinflammation and neurodegeneration. In experiments performed on the rat dentate gyrus, in vitro, IL-18 was found to Fig. 1 Constitutive expression of CNS cytokines. RNA from brains of male and female BALB/c mouse pups at 21 days of age was quantified by real-time RT-PCR. Whole-brain RNA was isolated using the Qiagen Lipid Tissue Midi RNA isolation kit. Brains were pooled by gender within each litter. Cytokine mRNA quantity was normalized to endogenous control GAPDH. Each bar repre- sents mean ± S.D. for N of 3 L. All of the cytokine levels significantly (p < 0.05) differed from each other except the following: IL-6:TNFα, IL-13:IFNγ,andTNFα:IFNγ; LT-β from IL-5, IL-6, IL-11, IL-13, TNFα,andIFNγ 364 J. Kasten-Jolly and D.A. Lawrence impair the induction of long-term-potentiation ( LTP) in NMDA receptor expressing neurons (Curran and O’Connor, 2001). Increased levels of IL-18 have now been reported to be present in the neurodegenerative disorder, Alzheimer’s disease (AD) (Bossu et al., 2008) and have been found associated with stress activation of brain microglia (Sugama et al., 2007). Human and mouse studies have shown that IL-1β and IL-18 are key players in fundamental inflammatory processes that increase during aging (Bodles and Barger, 2004; Joseph et al., 2005; Dinarello, 2006). Further evidence of the role of IL-18 in neuroinflammation is the finding that caspase-1 deficiency reduces inflammation- mediated transcription in the brain ( Mastronardi et al., 2007). In normal brain tissue caspase-1 is activated within molecular platforms called inflammasomes. Key proteins of inflammasomes are proteins containing caspase recruitment domains (CARDS), or pyrin domains (PYDS). CARD-only proteins are termed COPs and PYD-only proteins are termed POPs. These proteins modulate the inflammasome activity in response to pathogen infection and tissue destruction (Stehlik and Dorfleutner, 2007). For example, caspase-1 activation can be blocked by COPs, Iceberg, and COP1/Pseudo-ICE, with a CARD similar in sequence to caspase-1. Expression of Iceberg in monocytes abrogates the secretion of IL-1β in response to LPS stimulation. Because IL-18 is constitutively expressed at a high level in the adult mouse brain, it is possible that the noncleaved IL-18 proprotein may have a completely different function in the brain than the cleaved inflammation associated form. Such a precedent exists with IL-16. The uncleaved whole IL-16 molecule has neuronal activity (Kurschner and Yuzaki, 1999), whereas the truncated (cleaved by caspase-3) secreted IL-16 is a chemoattractant factor for CD4 + cells (Cruikshank et al., 2000). 1.1.3 Transforming Growth Factor-Beta (TGF-β) Reports on the activities of transforming growth factor-β1(TGFβ1) in the CNS have been conflicting in nature with some investigators describing anti-inflammatory effects and others indicating that TGFβ1 can have proinflammatory actions. Normal CNS concentrations of TGFβ1 are relatively high (Fig. 1), and it has been shown to be a potent neurotrophic cytokine with immunosuppressive properties. In the healthy adult brain, TGFβ1 inhibits proliferation of microglial and astrocyte cells. It has been suggested that the relatively high levels of TGFβ1 in the normal adult brain have some important function(s) in maintenance of neuronal growth and neuroim- mune function. Mice deficient in TGFβ1 displayed neuroinflammation throughout the brain, excessive astrogliosis, and proliferating microglia displaying a phagocytic, deramified, and abnormally activated phenotype (Makwana et al., 2007). Ultrastructural features of TGFβ1 deficiency showed focal blockade of axonal transport, perinodal damming of axonal organelles, focal demyelination, and myelin debris in granule-rich phagocytic microglia cells. In a ME7 model of a murine prion disease, removal of TGFβ1 resulted in severe cerebral inflammation, increased expression of iNOS, and acute neuronal death in diseased animals. The data indicate a critical role for TFGβ1 in regulation of microglia cells and minimization of brain inflammation in order to avoid further brain tissue damage (Boche et al., 2006). . called in ammasomes. Key proteins of in ammasomes are proteins containing caspase recruitment domains (CARDS), or pyrin domains (PYDS). CARD-only proteins are termed COPs and PYD-only proteins are. producing proinflammatory cytokines. These cytokines then enter the brain by volume diffusion. Third, the overflow of cytokines in the systemic circulation can gain entry to the brain via cytokine. mechanism involving α-melanocyte stimulating hormone (αMSH), which is a pro-opiomelanocortin (POMC) derivative (Ichiyama et al., 1999). In the CNS, increases in proinflammatory cytokines lead to increased

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