Liver-brain inflammation axis

Liver-brain inflammation axis

Charlotte D’Mello and Mark G. SwainSnyder Institute of Infection, Immunity, and Inflammation, Liver Unit, Department of Medicine, University of Calgary,Calgary, Alberta, Canada

Submitted 10 May 2011; accepted in final form 24 August 2011

D’Mello C, Swain MG. Liver-brain inflammation axis. Am J Physiol Gastro-intest Liver Physiol 301: G749–G761, 2011. First published August 25, 2011;doi:10.1152/ajpgi.00184.2011.—It is becoming increasingly evident that peripheralorgan-centered inflammatory diseases, including chronic inflammatory liver dis-eases, are associated with changes in central neural transmission that result inalterations in behavior. These behavioral changes include sickness behaviors, suchas fatigue, cognitive dysfunction, mood disorders, and sleep disturbances. Whilesuch behaviors have a significant impact on quality of life, the changes within thebrain and the communication pathways between the liver and the brain that giverise to changes in central neural activity are not fully understood. Traditionally,neural and humoral communication pathways have been described, with the threecytokines TNF�, IL-1�, and IL-6 receiving the most attention in mediatingcommunication between the periphery and the brain, in the setting of peripheralinflammation. However, more recently, we described an immune-mediated com-munication pathway in experimentally induced liver inflammation whereby, inresponse to activation of resident immune cells in the brain (i.e., the microglia),peripheral circulating monocytes transmigrate into the brain, leading to develop-ment of sickness behaviors. These signaling pathways drive changes in behavior byaltering central neurotransmitter systems. Specifically, changes in serotonergic andcorticotropin-releasing hormone neurotransmission have been demonstrated andimplicated in liver inflammation-associated sickness behaviors. Understanding howthe liver communicates with the brain in the setting of chronic inflammatory liverdiseases will help delineate novel therapeutic targets that can reduce the burden ofsymptoms in patients with liver disease.

hepatic inflammation; cytokines; sickness behaviors; mood disorders

IT IS BECOMING INCREASINGLY evident that chronic liver diseasesare more than simply purely liver-centered diseases. Animalmodels and clinical observations have documented that chronicliver inflammation is associated with changes in the centralnervous system (CNS) that manifest as behavioral changes (23,72, 88, 91). Changes in behavior, such as fatigue, loss ofmotivation, malaise, and loss of social interest, are collectivelytermed sickness behaviors. While the presence of sicknessbehaviors can serve an adaptive purpose during acute systemicinfections, in the setting of chronic inflammation they cangreatly affect quality of life. Although sickness behaviors andaltered mood states are highly prevalent in patients withchronic inflammatory liver diseases, as well as nonliver sys-temic diseases (e.g., rheumatoid arthritis and inflammatorybowel disease), they have received little attention because of alimited understanding of how these changes within the CNSdevelop in the setting of peripheral organ-centered inflamma-tion (14, 45, 49, 88). Furthermore, hepatic encephalopathy,which is normally associated with advanced liver disease, isnot a requirement for the development of changes within theCNS in patients with chronic inflammatory liver disease (32,

34, 71). Changes in neurotransmission that give rise to behav-ioral alterations can occur in the absence of any pathologicalCNS tissue damage (32, 34, 78). Furthermore, changes incentral neural activity are often observed in patients withearly-stage liver disease as well (61, 71). This review focuseson how the inflamed liver can communicate with the brain andoutlines the associated changes in brain function that have beenobserved to occur as a result of this communication pathway.Although sickness behaviors and mood disorders have beendocumented in the setting of liver diseases of varied etiologies,including cholestatic liver diseases, autoimmune hepatitis, andviral hepatitis, their occurrence in the cholestatic liver diseaseprimary biliary cirrhosis (PBC) and in hepatitis C (Hep C) havereceived the most attention and are therefore mainly discussedin this review.

How Does the Liver Communicate With the Brain?

While changes within the brain have been largely over-looked in the setting of peripheral organ-centered inflammatorydiseases, much of what we know of the communication path-way between the periphery and the brain comes mainly fromexperimental studies examining central changes induced bysystemic administration of the gram-negative bacterial cellwall component LPS. LPS is a potent inducer of three cyto-kines that have received the most attention in mediating com-

Address for reprint requests and other correspondence: M. G. Swain, HealthResearch Innovation Centre, Univ. of Calgary, 3280 Hospital Dr. NW, Cal-gary, AB, Canada T2N 4N1 (e-mail: [email protected]).

Am J Physiol Gastrointest Liver Physiol 301: G749–G761, 2011.First published August 25, 2011; doi:10.1152/ajpgi.00184.2011. Review

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munication between the periphery and the CNS, namely,TNF�, IL-1�, and IL-6 (14, 24, 59, 100). Elevated plasmaendotoxin levels have been documented in patients withchronic liver disease (88, 108). Administration of endotoxin orcytokines to healthy volunteers or rodents results in the devel-opment of sickness behaviors and depressed mood (7, 29, 41,59). Furthermore, peripheral administration of cytokine antag-onists results in significant improvement in such behaviors,thereby highlighting the importance of peripheral cytokines incommunicating with the brain (47, 60, 99).

The liver is home to the largest resident macrophage popu-lation, the Kupffer cell. Liver inflammation is typically asso-ciated with activation of Kupffer cells and, thereby, the pro-duction of cytokines, including TNF�, IL-1�, and IL-6 (5). Inpatients with chronic inflammatory liver diseases, circulatinglevels of TNF�, IL-1�, and IL-6 are elevated (4, 61). Cytokinepolymorphisms are known to influence disease susceptibilityand severity, and, interestingly, genes involved in TNF� sig-naling and NF-�B activation have recently been implicated inthe pathogenesis of PBC (66). In addition, TNF� polymor-phisms have also been linked with sleep abnormalities, fatigue,and mood disorders (1, 20).

The CNS is protected by a blood-brain barrier, which con-sists of nonfenestrated endothelial cells with tight junctionsbetween them (83). Cytokines are large, hydrophilic moleculesthat cannot readily cross the blood-brain barrier. Four mainpotential peripheral communication pathways to the brain havebeen described in the setting of systemic inflammation (Fig. 1):1) the neural pathway, 2) signaling via cerebral endothelialcells (CECs), 3) signaling via the circumventricular organs(CVOs), and 4) immune cells.

The neural pathway. The liver is innervated by vagal affer-ents. Cytokines can directly activate vagal nerve afferents,since they have been described to express cytokine receptors,such as the IL-1 receptor (IL-1R) (30). In addition, macro-phages interspersed between vagal fibers within the nervecould also respond to cytokines (35). In LPS-induced perito-neal inflammation, vagal afferent signaling is activated, rapidlyrelaying information to the brain, as demonstrated by increasedFos (protein expressed by the immediate early gene c-fos, usedas an indicator of neuronal activation) expression in the pri-mary cerebral projection area, the nucleus tractus solitarius,and in the secondary cerebral projection areas, including theparabrachial and hypothalamic paraventricular nuclei (PVN)(Fig. 1) (35, 105). In rodents injected intraperitoneally withIL-1�, subdiaphragmatic vagotomy was associated with areduction in Fos expression in the nucleus tractus solitarius, aswell as a decrease in social exploratory behavior (see below)(9). However, in vagotomized rats, administration of IL-1� viaalternate routes (i.e., intravenously or centrally) did not have aninhibitory effect on social exploratory behavior (9). Observa-tions of communication of peripheral inflammation to the brainvia the neural route in rodents were also confirmed in humans,whereby increased activity in the insula cortex, where afferentvagus and spinal interoceptive neural pathways converge, wasobserved during performance of the Stroop Task during acuteperipheral inflammation induced by typhoid vaccination (39).Interestingly, subjective fatigue in subjects who received ty-phoid vaccination correlated with activity changes within theinsula and the anterior cingulate regions of the brain.

In chronic inflammatory diseases associated with prolongedincreases in circulating cytokines, it is likely that the neuralcommunication route plays a less important role in mediatingdevelopment of sickness behaviors. Patients with PBC whohave undergone a liver transplant report little change in theirfatigue in the absence of any clinical features indicative ofrecurrent PBC (65). Liver transplant patients reported nochange in fatigue severity even at a 2-yr follow-up (101).Furthermore, neurological dysfunction was still observed inPBC patients after liver transplantation, suggesting that thecentral neural changes in these patients could be long-lasting orpermanent (65).

Signaling via CECs: role of TNF�, IL-1� and IL-6. TNF� isproduced by macrophages, as well as T cells, natural killercells, and natural killer T cells. There are two known biologicalreceptors for TNF�: TNFR1 and TNFR2. TNF� signaling viaTNFRs leads to activation of the transcription factors NF-�Band activator protein-1 (75). IL-1� is produced primarily bymacrophages. Signaling by IL-1� is mainly through IL-1R1,whereas IL-1RII has no signaling capability (8). However,IL-1RII can still bind to IL-1� and, thereby, serves to decreaseIL-1� biological activity by preventing its interaction withIL-1R1. Receptors for TNF� and IL-1� have been documentedon CECs, as well as neuronal and glial cells (Fig. 2) (69, 85).NF-�B is normally found bound to its inhibitor I�B in the cellcytoplasm. In response to TNF� and IL-1� signaling, I�B is

Fig. 1. Potential communication pathways between the liver and the brain.1) The liver is innervated by vagal afferents that can respond to immunemediators such as TNF�, IL-1�, and IL-6. Vagal afferents project to the dorsalvagal complex, which includes the nucleus tractus solitarius (NTS), areapostrema, and dorsal motor nucleus; from here they then project to variedcerebral regions, including the paraventricular nucleus of the hypothalamus.2) TNF�, IL-1�, and IL-6 can interact with their receptors on cerebralendothelial cells (CECs) to induce their respective signaling pathways.3) Circulating TNF�, IL-1�, and IL-6 can access the brain via the circumven-tricular organs (CVOs) and the choroid plexus, regions of the brain that lacka blood-brain barrier. 4) Monocytes transmigrate into the brain in response toan initial activation of resident cerebral microglia to produce a potent mono-cyte chemoattractant (MCP-1). These liver-to-brain communication pathwayscan result in changes in central neural activity and, thereby, behavioralalterations.

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phosphorylated and degraded, allowing for NF-�B to translo-cate into the cell nucleus and promote transcription of targetgenes. After its degradation, I�B is rapidly resynthesized andserves as an endogenous inhibitor for NF-�B. The induction ofI�B mRNA has been extensively used as an indicator ofNF-�B activity (85). Systemic administration of LPS, TNF�,and IL-1� to rodents results in upregulation of I�B mRNA inCECs (58, 69). Since the TNF� and IL-1� genes have anNF-�B binding site in their promoter region, signaling cas-cades that lead to the activation of NF-�B (e.g., Toll-likereceptor signaling pathways) can promote increased expressionof these respective cytokines.

TNF� and IL-1� can interact with their receptors on CECsto induce the production of secondary messengers [e.g., PGs,nitric oxide (NO)], which can subsequently promote changes inneural activity within the brain (25, 78, 85). NO is produced byNO synthase (NOS). Constitutive NOS isoforms are present inendothelial cells (endothelial NOS) and neuronal cells (neuro-nal NOS). However, during inflammation, the inducible NOSisoform is upregulated in immune cells (e.g., macrophages), aswell as in CECs in response to proinflammatory cytokines suchas TNF� (53). PGs are lipophilic molecules produced by thecyclooxygenase (COX) enzymes. COX-1 is constitutivelypresent in CECs, while COX-2 is upregulated in response toinflammatory stimuli. Inducible NOS and COX-2 are targetgenes for NF-�B (75, 85). COX-2 mediates production of PGsfrom arachidonic acid. The PG subtype that has received themost attention for its ability to mediate central effects ofcirculating cytokines is PGE2. Consistent with COX-2 induc-tion by TNF� and IL-1�, PGE2 immunoreactivity in CECs isalso increased in response to systemic administration of thesecytokines in rodents (57, 69). Receptors for PGE2 are ex-pressed in areas of the brain implicated in emotional andbehavioral control, including the hypothalamus, amygdala, andCVOs, such as the area postrema (112). Central administration

of PGE2 causes rapid and transient expression of c-fos mRNAwithin multiple regions of the brain (56). Furthermore, inhibi-tion of PG synthesis with COX inhibitors, such as indometh-acin, can attenuate the reduction in locomotor activity and theincrease in time spent immobile in the forced swim test (FST)(see below) generally seen with peripheral LPS administrationin rodents (25).

In the liver, hepatocytes and leukocytes (including Kupffercells and neutrophils) express the IL-6R and also serve as asource of IL-6 (5). On activation, IL-6R can be shed from thesurface of cells. LPS stimulation upregulates the expression ofIL-6R in CECs and neuronal cells (100). IL-6 can bind to themembrane or soluble form of the IL-6R, and the IL-6-IL-6Rcomplex then interacts with the transmembrane componentglycoprotein (gp) 130, which is expressed on CECs, to induceits signaling cascade (85, 100). Conformational changes ingp130 result in activation of the associated enzymes Januskinases, which then mediate the phosphorylation and activationof the STAT family of transcription factors (Fig. 2). Targetgenes for the STAT transcription factors include acute-phaseproteins and adhesion molecules, such as ICAM-1 (85). UnlikeTNF� and IL-1�, systemic administration of IL-6 to rodentsdoes not lead to upregulation of I�B (58).

Signaling via the CVOs. The CVOs are regions of the brainthat lack an intact blood-brain barrier. These areas include thearea postrema, median eminence, and organum vascularis ofthe lamina terminalis. The capillaries in these regions arefenestrated, thereby allowing molecules within the circulationto have direct access to the CVO parenchyma (83). In responseto intravenous administration of IL-1� or TNF�, increasedmonocyte chemoattractant protein 1 (MCP-1) and TNFRmRNA expression, respectively, has been documented withinthe CVOs (69, 97). Induction of c-fos mRNA (suggestive ofneuronal activation) has also been observed in the CVOs withsystemic administration of TNF� to rodents (Fig. 1) (69).

Role of immune cells. The brain has traditionally beenconsidered an immune-privileged organ because of the pres-ence of a blood-brain barrier, which prevents the cerebral entryof immune cells (83). Microglia, the resident immune cells ofthe brain, are highly dynamic cells that are constantly survey-ing their environment (84). In CNS inflammatory diseases,activation of resident microglia and infiltration of immune cellsare cardinal pathological features (38, 52, 64). Much of ourunderstanding of the central changes that occur in the setting ofperipheral inflammation has come from studies that examinedthis in rodents that were treated systemically with LPS (41, 42).Such models of LPS-induced peripheral inflammation havedemonstrated that microglia can be activated in the setting ofsystemic inflammation. This can have significant implicationsfor promoting changes within the brain in the setting ofsystemic inflammation, since activated microglia can produce awide array of cytokines with neuromodulating effects, includ-ing TNF�, IL-1�, and IL-6 (75, 84). In models of CNSinflammatory diseases, such as experimental autoimmune en-cephalomyelitis (an animal model of multiple sclerosis), thatinvolve cerebral infiltration of T cells, microglia can also serveas antigen-presenting cells and can thereby mediate activationof T cells, which, in turn, can serve as a source of cytokineswithin the brain. Recently, in experimental cholestasis, micro-glia within the brain were found to be activated (23) (Fig. 3).Resting microglia have a “ramified” morphology with long

Fig. 2. Circulating cytokines can interact with receptors on CECs to mediateactivation of cells within the brain parenchyma. TNF� interacts with TNFreceptors (TNFR1 or TNFR2) on CECs and IL-1� signals via type 1 IL-1receptor (IL-1R1) to induce activation of the transcription factor NF-�B. Inresponse to TNF�- and IL-1�-mediated signaling, NF-�B separates from itsinhibitor I�B, translocates into the nucleus, and mediates transcription of targetgenes, which include cyclooxygenase 2 (COX-2) and inducible nitric oxide(NO) synthase (iNOS). COX-2 and iNOS activation leads to production ofPGE2 and NO, respectively, which can then activate microglia and other cellswithin the brain parenchyma. The IL-6-IL-6R complex interacts with glyco-protein 130 (gp130) on CECs to induce activation of the JAK/STAT pathway.

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extended processes, whereas microglia in cholestatic micewere generally more rounded with retracted processes, a mor-phology typical of activated microglia. Furthermore, activatedmicroglia in the brain were found predominantly in areasaround the ventricles and blood vessels, potential routes ofentry for infiltrating immune cells (23, 83).

Circulating monocytes in rodents are of two major subtypes:1) a noninflammatory subtype, which can give rise to tissueresident macrophages, and 2) an inflammatory subtype, whichexpresses high levels of chemokine (C-C motif) receptor 2(CCR2) and responds to MCP-1, a potent chemoattractant formonocytes. Similar monocyte subtypes have been character-ized in humans (37). Experimental cholestasis was accompa-nied by an increase in circulating inflammatory monocytes, anda large proportion of them were activated and expressed TNF�(23). Systemic inflammation is associated with activation ofcirculating immune cells and CECs, likely resulting in in-creased interactions between them. The leukocyte recruitmentparadigm has been well characterized in a number of tissues,whereby activated leukocytes first tether, then roll, and, onencountering an activating stimulus, firmly adhere to vascularendothelium (76). Rolling is primarily mediated by moleculescalled selectins, while adhesion is mediated by integrins. Allthree known selectins, P-, E-, and L-selectin, can bind toP-selectin glycoprotein ligand-1. Integrins are heterodimerscomprising an �- and a �-subunit and are categorized on thebasis of a common �-subunit (76). In cholestatic rodents,increased expression of VCAM-1 was documented on cerebralendothelium (51). VCAM-1, via its interaction with �4-integrinexpressed on monocytes, can mediate adhesion of monocytesto CECs. Intravital microscopy of the cerebral vasculaturedemonstrated increased rolling of leukocytes along cerebralendothelium in cholestatic mice (51). In addition, in responseto microglia activation and production of MCP-1, there was aneightfold increase in monocyte transmigration into the brains

of mice with experimental cholestasis (23, 51) (Fig. 3). TheMCP-1-CCR2 axis was important in mediating recruitment ofmonocytes into the brains of cholestatic mice, since cerebralmonocyte infiltration was inhibited in cholestatic mice thatwere deficient in MCP-1 or CCR2. Monocytes that infiltratedthe brains of cholestatic mice were located in the area aroundblood vessels and were also present in the brain parenchyma(23). Despite the redundancy in the chemokine system, theMCP-1-CCR2 axis plays a key role in mediating monocyterecruitment in other models of chronic inflammatory diseases,such as human immunodeficiency virus (HIV) encephalopathyand experimental autoimmune encephalomyelitis (38, 46).TNF� signaling via TNFR1 was important in mediating acti-vation of microglia to express MCP-1 and the subsequentcerebral recruitment of monocytes in cholestatic mice, sincethese events were prevented in cholestatic mice that weredeficient in TNFR1.

Endogenous production of cytokines within the brain. Whilecirculating cytokines can mediate their effects on central neuralactivity though the production of secondary mediators such asPGE2 and NO, they are also capable of inducing de novosynthesis of cytokines within the brain. For instance, peripheralTNF� administration in rodents upregulates IL-1� and TNF�expression within the brain (80). Glial cells and neurons arecapable of producing cytokines, and they also express func-tional cytokine receptors (75, 85). Peripheral LPS administra-tion in rodents results in increased TNF�, IL-1�, and IL-6expression in the brain (41, 42, 59, 80). Centrally producedcytokines appear to play an important role in mediating thebehavioral effects of acutely administered peripheral cyto-kines. IL-1� production within the brain was demonstrated tobe significant in mediating the effects of peripheral LPS, sincecentral administration of IL-1 receptor antagonist, an endoge-nous inhibitor of IL-1� signaling, reduced the expression ofIL-1�, IL-6, and TNF� in the hypothalamus and hippocampus

Fig. 3. Immune cell-mediated liver-to-brain commu-nication pathway. 1) Experimental cholestasis is as-sociated with activation of CECs to expressadhesion molecules such as P-selectin andVCAM-1. 2) Circulating chemokine (C-C motif)receptor 2 (CCR2)-expressing inflammatorymonocytes are increased in cholestatic rodents.3) Microglia are activated to express a potentmonocyte chemoattractant, MCP-1. 4) CCR2-expressing monocytes roll along CECs and thenadhere to and subsequently transmigrate intobrains of mice with experimental cholestasis.Monocyte infiltration into the brain can be in-hibited by peripheral administration of anti-P-selectin and anti-�4-integrin antibodies. 5) Infil-trating monocytes also express MCP-1 andcould further promote monocyte recruitmentinto the brain. 6) Microglia and cerebral infil-trating monocytes serve as a source of cytokinessuch as TNF�, a neuromodulator that has beenimplicated in the genesis of sickness behaviorsand mood disorders.

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of mice and decreased the food intake observed with systemicLPS administration (59).

Summary of potential peripheral signaling pathways to thebrain. In the setting of peripheral organ-centered inflammation,communication between the periphery and the brain can takeplace via neural, immune cell, or cytokine-driven routes. As aresult of these communication pathways, alterations in neu-rotransmission within the brain can manifest as sickness be-haviors (e.g., fatigue), altered mood, cognitive defects, or sleepdisturbances.

Fatigue and Liver Disease

Fatigue is a common complaint in patients with liver dis-eases of varied etiologies, including PBC, primary sclerosingcholangitis, autoimmune hepatitis, and chronic viral infection(88). In fact, in the cholestatic liver disease PBC, fatigue can bethe presenting symptom and is present in up to 50–80% ofpatients with PBC (43, 49, 70). Fatigue is a complex symptomthat has no association with markers of liver disease severityand can encompass a range of complaints, including lethargy,lack of motivation, malaise, and exhaustion. It has not receivedthe attention it warrants in the clinical setting, in part becauseof its subjective nature, which also makes it difficult to quan-titate in humans and in animal models. Furthermore, fatiguehas been associated with a poor prognosis, since in a 4-yrfollow-up study of fatigue in patients with PBC, fatigue sever-ity was found to be stable over the 4-yr period, and patientswith comparatively higher fatigue scores at the beginning ofthe study period had a significantly reduced survival rate (49).

Fatigue has been described as the “difficulty in initiation ofor sustaining voluntary activities” (19). Fatigue can be centralor peripheral in origin. Peripheral fatigue is a result of neuro-muscular dysfunction and is associated with physical, but notmental, fatigue. It results in a reduced ability to sustain phys-ical activity and can involve metabolic changes, such as in-creased peripheral muscle acidosis on exercise. Central fatigueis due to changes in central neurotransmitter systems, whichresult in a reduced ability to perform tasks that require self-motivation or the perception that a task requires more effort(18). Central fatigue can also be perceived as reduced neuraldrive to muscle, which can result in reduced ability to sustainphysical activity. While central and peripheral fatigue cancoexist, fatigue in chronic liver disease is generally believed tobe central in origin (88). Some of the studies that haveexamined fatigue in patients with PBC have used transcranialmagnetic stimulation during and after a standardized fatiguingexercise as a tool to study central fatigue. In healthy controls,transcranial magnetic stimulation-induced motor evoked po-tentials increase during a fatiguing exercise (as a result ofincreased excitability of the primary motor cortex) and, sub-sequently, decrease. In contrast, in PBC patients with highfatigue levels, the later decrease in motor evoked potentialsfails to occur (16). This finding further supports a centralmechanism of fatigue in patients with PBC. Furthermore,fatigue is often linked with other neuropsychiatric symptoms,such as anxiety and depression. Moreover, in the setting ofchronic inflammatory diseases, changes in neurotransmittersystems within the brain have been documented that likelycontribute to the pathogenesis of fatigue (14, 18, 88).

The basal ganglia comprise six nuclei that project to thelimbic system and frontal cortex. They are involved in motorcoordination, motivation, and emotional control (18). Altera-tions in neural activity in the basal ganglia have been linkedwith fatigue. Positron emission tomography scans in patientswith multiple sclerosis have demonstrated reduced glucosemetabolism in the frontal cortex and basal ganglia in fatiguedpatients compared with nonfatigued patients (86). Exposure totoxic levels of the heavy metal manganese results in develop-ment of severe fatigue. In patients with PBC, elevated plasmaconcentrations of manganese were associated with increasedfatigue levels. In addition, MRI studies conducted in the samegroup of patients demonstrated increased signal intensity in thebasal ganglia area in patients with high fatigue levels, possiblyassociated with increased manganese deposition (33).

In CNS pathologies, infiltrating immune cells are a signifi-cant source of cytokines, and inhibition of immune cell infil-tration has significant potential implications for associatedbehavioral alterations (38, 64). In cholestatic mice, monocytesthat infiltrate the brain were found predominantly in the motorcortex, hippocampus, and basal ganglia areas (Fig. 4) (23).Moreover, the infiltrating monocytes in cholestatic mice ex-pressed MCP-1, which could serve to further promote mono-cyte recruitment into the brain (23). The adhesion moleculesP-selectin and �4-integrin were important in mediating therolling and adhesion of leukocytes along the cerebral vascula-ture in cholestatic mice, since peripheral administration of acombination of anti-P-selectin and �4-integrin antibodies re-sulted in inhibition of these respective leukocyte interactionswith CECs, and this in turn prevented cerebral infiltration ofmonocytes in cholestatic mice (23). The time spent by an adultmouse in social investigative behavior toward a juvenile mouseintroduced into the home cage of the adult mouse has beenused as a behavior paradigm that examines the motivation,

Fig. 4. Region-specific cerebral infiltration of monocytes in cholestatic mice.Monocytes that infiltrate the brains of cholestatic mice were found predomi-nantly in the hippocampus, basal ganglia, and motor cortex areas. These areregions of the brain that have been implicated in the development of sicknessbehaviors, including fatigue. Inhibition of cerebral monocyte recruitment inexperimental cholestasis results in improvement in sickness behaviors. In-creased signal intensity (with magnetic resonance imaging) and alterations incerebral metabolites (as observed using proton magnetic resonance spectros-copy) in the basal ganglia area have been linked with fatigue and cognitiveimpairment, respectively.

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interest, and ability of the adult mouse to engage in socialbehaviors (7, 8, 23). Cholestatic mice spend less time in socialinvestigative behavior (i.e., interacting with the juvenilemouse) and more time in noninvestigative behaviors (e.g., timespent grooming and immobile). Inhibition of cerebral mono-cyte infiltration in cholestatic mice prevented this decrease insocial investigative behavior (23). Furthermore, a potential rolefor monocytes in mediating behavior alterations has beensuggested by observations made in two different studies. In astudy of rheumatoid arthritis patients, treatment with the anti-inflammatory agent methothrexate was associated with animprovement in disease severity, as well as a reduction inCCR2 expression on circulating peripheral blood monocytes(31). Babatin et al. (2), in a study of patients with PBC treatedwith methotrexate, showed an improvement in fatigue levels.

TNF� is important in relaying information about systemicinflammation to the brain. Administration of TNF� systemi-cally to rodents results in activation of CECs and cerebralmicroglia (23, 58). The development of sickness behaviors, aswell as cerebral inflammation, in response to peripheral LPS inrodents is markedly reduced in the absence of TNF� signaling(47, 80). Circulating monocytes in cholestatic mice are acti-vated and express TNF� (51). A role for peripheral TNF�signaling in mediating changes in central neural activity hasbeen highlighted in cholestatic mice, whereby the inhibition ofperipheral TNF� signaling in cholestatic mice was associatedwith a reduction in central microglial activation, as well as theprevention of monocyte infiltration into the brain (23). Loco-motor activity has been used as a surrogate marker of “fatigue-like” behavior in several experimental paradigms (11, 22, 25,47). Moreover, recording of locomotor activity by a motion-sensing device that was worn on the leg was found to correlateclosely with fatigue in patients with chronic fatigue syndrome,as well as in patients with PBC (70, 103). Cholestatic rodentsshow reduced locomotor activity when placed in an infraredbeam activity monitor. Cholestatic mice deficient in TNF� ortreated with an anti-TNF� serum peripherally demonstrate anincrease in locomotor activity and in social investigative be-havior (unpublished observations). Furthermore, cholestaticmice deficient in IL-6 also showed improvement in socialinvestigative behavior (Nguyen and Swain, unpublished obser-vations). In a study of rheumatoid arthritis patients, treatmentwith the anti-IL6R antagonist tocilizumab reduced fatiguelevels (12). In addition, reductions in locomotor activity andsocial investigative behavior in cholestatic mice have beendocumented at a time when microglia in the brain are activatedbut no monocyte infiltration in the brain could be detected(unpublished observations). Delineating the pathways that leadto microglial activation in the setting of peripheral inflamma-tory diseases can have broad implications for changes incentral neural activity. The tetracycline antibiotic minocyclinehas been used to inhibit microglial activation in animal modelsand in CNS pathologies (13, 41, 52). Administration of mino-cycline to rodents was associated with a reduction in LPS-induced microglial expression of proinflammatory cytokines,as well as an improvement in observed sickness behaviors (41).Furthermore, minocycline treatment, which was associatedwith reduced cerebral neuronal injury in a model of simianimmunodeficiency virus encephalitis, has also been linked witha reduction in CCR2-expressing circulating monocytes (13).

Serotonergic cell bodies are primarily located in the dorsalraphe nuclei in the midbrain and project to several regions inthe brain, including the hippocampus, hypothalamus, andamygdala. Serotonin [5-hydroxytryptamine (5-HT)] neu-rotransmission is involved in a wide variety of behaviors,including arousal, the sleep-wake cycle, locomotor activity,and mood (Fig. 5) (62, 68, 88). 5-HT can mediate its effects viaseveral receptor subtypes. The two 5-HT receptors that havereceived the most attention in relation to fatigue in liver diseaseare the 5-HT1A and 5-HT3 receptors. The 5-HT1A receptor ispresent on the cell bodies of serotonergic neurons (i.e., pre-synaptic 5-HT1A receptors) in the dorsal raphe nucleus, as wellas on postsynaptic neurons. Stimulation of the midbrain pre-synaptic 5-HT1A receptors results in reduced firing of seroto-nergic neurons and, thereby, reduced release of 5-HT into thesynapse. In cholestatic rodents, increased expression of the5-HT1A receptor in the midbrain has been observed (10).Repeated stimulation of the 5-HT1A receptor with a 5-HT1A

agonist (i.e., desensitizes the receptor), which would result inincreased 5-HT release into the synapse, was associated with areduction in the time spent immobile in the FST (see below)(93). The 5-HT3 receptor is structurally different from the5-HT1A receptor, since it is a ligand-gated ion channel. Inexperimental cholestasis, decreased hypothalamic 5-HT3 re-ceptors have been documented (72). Administration of the5-HT3 receptor antagonist tropisetron to cholestatic rodentsresults in improvement in fatigue-like behavior, as demon-strated by an increase in locomotor activity (72). In the clinicalsetting, serotonin receptor antagonists have been linked withimprovements in fatigue. Specifically, in patients with Hep Cthat were treated with the 5-HT3 receptor antagonist ondanse-tron, an improvement in fatigue was observed (77). In patientswith PBC, the effect of the 5-HT3 receptor antagonist ondan-setron on fatigue was controversial, in part due to patientunblinding during the study as a result of increased constipa-tion associated with the drug (96).

Fig. 5. Serotonergic neurotransmission within the brain. 5-HT neuronal cellbodies are located in the dorsal raphe nucleus in the midbrain. Stimulation ofpresynaptic 5-HT1A receptors reduces 5-HT release into the synapse. 5-HTneurons project to various brain regions and can modulate a wide spectrum ofbehaviors via their action on different receptor subtypes. 5-HT1A and 5-HT3

receptors have received the most attention in relation to fatigue in chronicinflammatory liver diseases. The presynaptic serotonin transporter 5-HTTfacilitates the reuptake of 5-HT released into the synapse. 5-HT neurotrans-mission has been linked to fatigue, mood disorders, cognitive impairment, andsleep disturbance.

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Hypothalamic-Pituitary-Adrenal Axis and Liver Disease

The hypothalamic-pituitary-adrenal (HPA) axis plays a ma-jor role in the stress response. External or internal stressorsresult in activation of the HPA axis (36, 98). Corticotropin-releasing hormone (CRH) is produced by neurons in the PVN.CRH stimulates the pituitary to release ACTH, which promotesglucocorticoid (cortisol in humans and corticosterone in ro-dents) release from the adrenal cortex. Glucocorticoids caninhibit the release of CRH at the level of the hypothalamus, andat the level of immune cells, glucocorticoids can inhibit therelease of proinflammatory cytokines (Fig. 6) (36, 98). Cyto-kines are capable of activating the HPA axis (28, 69, 89).Receptors for TNF� and PGs have also been found on neuronsin the PVN (69, 112). However, in the context of chronicinflammation, cytokine-HPA axis interactions are not com-pletely understood. Generally, in chronic inflammatory dis-eases that are associated with elevated proinflammatory cyto-kines (e.g., rheumatoid arthritis), hypoactivation of the HPAaxis has been observed (36, 98). Similar observations have alsobeen made in experimental cholestasis (91, 92, 94).

In addition to the PVN, CRH nerve fibers and receptors havebeen described in other regions of the brain and have beenimplicated in the modulation of a wide spectrum of behaviors,including anxiety, fatigue, and appetite control (3, 22, 36). Incholestatic rodents, decreased hypothalamic CRH levels havebeen documented, suggesting that CRH activation of the HPAaxis may be altered (11, 91). In addition, reduced Fos expres-sion in the hypothalamic PVN region in response to centraladministration of IL-1� has been demonstrated in cholestatic

rodents, further supporting reduced neuronal activation in thisregion (92). Consistent with this observation, the increase inACTH release typically observed in response to central IL-1�administration was markedly reduced in cholestatic rodents(94). CRH has been shown to have behavioral activatingeffects. Infusion of CRH centrally into cholestatic rats resultsin increased locomotor activity at a concentration withouteffect in control rats, suggesting that cholestasis is associatedwith increased sensitivity to central CRH (11). Alterations inthe HPA axis have also been observed in patients with PBCwho demonstrate increased ACTH secretion in response tointravenous CRH administration (95). This observation wouldbe consistent with an upregulation of pituitary CRH receptorsin these patients, possibly due to reduced central CRH release.Furthermore, it is likely that cytokines such as TNF� canstimulate corticosterone secretion from the adrenal cortex,findings supported by the observation that cholestatic rodentsthat were treated with an anti-TNF� serum peripherallyshowed a reduction in inflammation-induced circulating corti-costerone levels with no effect on plasma ACTH levels (89).

CRH can mediate its biological effects via CRH receptors(CRHR1 and CRHR2). CRHR1 has been implicated in thecontrol of locomotor activity, since mice deficient in CRHR1are resistant to the locomotor-inducing effects of central CRHinfusion (22). On the other hand, CRHR2 is associated withappetite control. In cholestatic rodents, increased expression ofCRHR1 within the hypothalamus has been documented (11).The increase in hypothalamic CRHR1 expression may be dueto decreased CRH levels in this region (11, 91). Furthermore,the behavioral activating effects of CRH in cholestatic rodentswere mediated by CRHR1, since pretreatment of cholestaticrats with a specific CRHR1 antagonist attenuated the increasein locomotor activity seen with central infusion of CRH (11).CRHR1 is also thought to be involved in mood disorders, sincemice deficient in CRHR2 spent more time immobile in the FST(see below), and this behavior was inhibited in the presence ofa CRHR1 antagonist (3).

Mood Disorders and Liver Disease

A role for cytokines in the pathogenesis of mood disordershas become increasingly evident (14, 24, 68). Elevations incirculating cytokines such as TNF� and IL-6 have been ob-served in patients with depression (61, 79, 109). Furthermore,administration of endotoxin or cytokines (including TNF� andIL-6) to healthy volunteers results in transient development ofdepressed mood and anxiety (29). Strong clinical support for arole for cytokines in depression also comes from patients withchronic inflammatory conditions that are commonly associatedwith elevations in inflammatory cytokines (e.g., rheumatoidarthritis, inflammatory bowel disease, and chronic liver dis-ease) or patients treated with cytokine therapy, such as cancerpatients and patients with Hep C, all of which are associatedwith a higher incidence of depression (40, 43, 74, 79). Severeneurological impairment is not necessary for the developmentof altered mood states, as was observed in the CNS inflamma-tory disease multiple sclerosis, where depression was notrelated to severity of neurological impairment and could occurin early stages of the disease (67). Furthermore, administrationof anti-cytokine therapies, such as anti-TNF� agents, in a

Fig. 6. Hypothalamic-pituitary-adrenal axis. Hypothalamic paraventricularnucleus neurons release corticotropin-releasing hormone (CRH), which is apotent stimulator of ACTH release from the pituitary. Hypothalamic CRHlevels are decreased in experimental cholestasis. ACTH stimulates release ofglucocorticoids from the adrenal cortex. Glucocorticoids can act on receptorsat the level of the hypothalamus and the pituitary to inhibit release of CRH andACTH, respectively, and can also act at the level of immune cells to inhibitrelease of proinflammatory cytokines such as TNF�, IL-1�, and IL-6. Inaddition to the hypothalamus, CRH nerve fibers and receptors have beendescribed in other regions of the brain and can thereby modulate a wide arrayof behavior.

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number of organ-centered inflammatory diseases is associatedwith an improvement in depressive symptoms (60, 99).

Anhedonia, defined as an inability to experience pleasure inthings once found enjoyable, is a feature of depression. As-sessment of anhedonia is a commonly used experimental par-adigm to examine “depressive-like” behavior in animals, andanhedonia is sensitive to antidepressants used to treat humandepression (24, 41, 90, 110). Such animal models have beenuseful in delineating the mechanisms that can lead to alteredmood states. Since rodents have a preference for saccharin-sweetened drinking water, a reduced consumption of sweet-ened drinking water would be reflective of anhedonia. Admin-istration of LPS to rodents results in development of anhedonia(24, 110). When cholestatic rodents were exposed to two waterbottles, one containing tap water and the other containing asaccharin solution, a reduced consumption of sweetened drink-ing water was documented (90). Another behavioral paradigmcommonly used to assess “depressive” behavior is the FST(24–26, 62). For the FST, rodents are placed in an inescapablecylinder of water, and the time spent in active swimming vs.time spent immobile is recorded. Immobility in the FST isbelieved to represent a failure to persist in survival behavior.The FST has been used to examine the effects of antidepres-sants, since the time spent immobile is markedly reduced inrodents treated with antidepressants (26). In cholestatic ro-dents, time spent immobile in the FST was increased and wassignificantly reduced by the repeated administration of a5-HT1A agonist (93).

Depression has been reported in patients with Hep C, evenbefore they undergo IFN-� therapy. Circulating TNF� waselevated in patients with Hep C prior to treatment with IFN-�,and the increase in plasma TNF�, as well as plasma IL-1�,levels was associated with higher depressive scores (61). HepC patients treated with IFN-� showed a higher prevalence ofmood disorders. In an examination of the effects of IFN-�therapy on plasma IL-6 levels and levels of depression inpatients with Hep C, Prather et al. (79) observed that IFN-�treatment resulted in increased circulating levels of IL-6, aswell as an increase in depressive scores. Furthermore, in astudy of changes within the plasma and the brain in response toIFN-� treatment, levels of IL-6 and MCP-1 were increased inthe cerebrospinal fluid of Hep C patients after 12 wk of IFN-�administration compared with control Hep C patients nottreated with IFN-� (81). Interestingly, a study that examinedassociations between gene polymorphisms and depression re-ported a higher risk of IFN-�-induced depression in patientswith Hep C with specific polymorphisms in the phospholipaseA2 and COX-2 genes (87).

The 5-HT neurotransmitter system has received the mostattention in relation to mood disorders (24, 68). Low 5-HTlevels have been commonly linked with depression. In patientswith Hep C, administration of therapies that increase cerebral5-HT levels, such as selective serotonin reuptake inhibitor-typedrugs (e.g., citalopram), has been demonstrated to improveIFN-�-induced depression (54). Tryptophan is an essentialamino acid that is required for the synthesis of 5-HT. Patientswith depression generally show low circulating levels of tryp-tophan (15, 24, 62). Indoleamine 2,3-dioxygenase (IDO) is anenzyme that is produced by macrophages and, on activation,can convert tryptophan to kynurenine. Cytokines such asTNF� and IFN-� can promote activation of IDO, which results

in less tryptophan being available for 5-HT synthesis (62, 68).Furthermore, administration of 1-methyltryptophan, a compet-itive inhibitor of IDO, can inhibit LPS-induced depressive-likebehavior in rodents (24). Cancer patients who were treatedwith IFN-� showed reduced levels of tryptophan within 1 moof therapy, and the decrease in serum tryptophan correlatedpositively with the severity of depressive symptoms (15). In astudy of Hep C patients treated with IFN-�, a decrease inplasma tryptophan and an increase in kynurenine plasma levelswere observed, and this in turn was associated with an increasein levels of depression in these patients (21). An alternate rolefor IDO in the pathogenesis of depression, independent of5-HT synthesis, has also been postulated. Tryptophan can beconverted by IDO to kynurenine, which can be further con-verted to kynurenic acid and quinolic acid. Quinolic acid couldalter central glutamatergic neurotransmission, which is alsolinked with the development of mood disorders (24, 68).Increased levels of kyneuric acid and quinolic acid have beenobserved in the cerebrospinal fluid of Hep C patients treatedwith IFN-� and could potentially contribute to the increasedincidence of depression in these patients (82). Limited studiesof this aspect of liver disease present a potentially interestingarea for future investigation.

There are several reports of comorbidity between depressionand sickness behaviors such as fatigue, and this is to beexpected, since the neurotransmitter systems that have beenimplicated in the pathogenesis of these behavioral disorders aresimilar. A strong correlation between fatigue and depressionhas been reported in patients with PBC and Hep C. Anassessment of fatigue and depression demonstrated that 44.8%of of 103 patients with PBC could be classified as havingdepression as assessed using the Beck Depression Inventory(BDI), and a significant correlation was found between theirlevels of fatigue and depression (43). A high incidence offatigue and depression was documented in patients withchronic viral hepatitis as well (50). It should also be mentionedthat more caution is needed in making the diagnosis of depres-sion or fatigue. Fatigue is often assumed to be caused bydepression, and the patient is then classified as being “de-pressed,” rather than “fatigued.” While the diagnosis of de-pression is generally made using questionnaires, there is astronger need for the diagnosis of depression by psychiatricevaluation. For instance, in a study of 92 PBC and primarysclerosing cholangitis patients, 42% were classified as having“depressive” symptoms according to the Beck DepressionInventory, whereas assessment by a psychiatric interview clas-sified only 3.7% as being “depressed” according to Diagnosticand Statistical Manual of Mental Disorders (DSM-IV) criteria(102). The need for a proper diagnosis of depression also stemsfrom the fact that mood disorders comprise a wide spectrum ofdepressive disorders. In patients with chronic inflammatorydiseases, a higher incidence of the “atypical” depression sub-type has been observed (36, 98). Typical depression is linkedwith features such as decreased appetite, insomnia, and in-creased anxiety, while atypical depression includes character-istics such as hyperphagia, hypersomnia, and increased sensi-tivity to social rejection. While the etiology of depression iscomplex, an important distinguishing factor between typicaland atypical depression from a biological perspective is thattypical depression is generally associated with increased CRHlevels and behavioral activation and, conversely, atypical de-

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pression is linked with reduced CRH levels and fatigue (36,98). Hence, this further strengthens the concern for a properdiagnosis of typical vs. atypical depression, since these diag-noses often require different therapeutic approaches.

Cognitive Impairment and Liver Disease

Administration of LPS or cytokines to healthy volunteersresults in mild impairments in memory and concentration andhas thereby highlighted a role for cytokines in cognitive dys-function (14, 24). While cognitive impairment has been typi-cally associated with advanced liver disease and often linkedwith the development of hepatic encephalopathy, it has beenobserved in patients with PBC or Hep C without evidence ofhepatic encephalopathy, and the levels of cognitive dysfunc-tion did not associate with biochemical markers of liver diseaseseverity. In addition, the cognitive impairments were mostlyrelated to problems with memory and concentration (34, 71).Cerebral proton magnetic resonance spectroscopy (MRS) canbe used to obtain information about cerebral biochemicalmetabolites. The most common metabolites measured are N-acetylaspartate, a neuronal marker, choline-containing com-pounds, which are components of the cell membrane, andmyo-inositol, which is an intracellular metabolite involved inthe synthesis of phosphoinositides and is mainly found in glialcells (1a, 6, 17a, 34). Elevations in myo-inositol are postulatedto be indicative of glial activation and proliferation, whileelevations in choline are thought to be indicative of cellularinfiltration or glial proliferation (6). Cerebral MRS studiesconducted in patients with PBC or in patients with Hep Cinfection have indicated elevations in myo-inositol and cholinelevels. In patients with Hep C infection or PBC, increasedcholine levels in the cerebral basal ganglia region were asso-ciated with cognitive dysfunction (71). In fact, patients withHep C who had an impairment in two or more tasks duringcognitive testing had a higher mean cerebral choline-to-crea-tine ratio than patients who scored better on these tasks (34).

While the Hep C virus was once considered strictly hepato-tropic in nature, Hep C viral RNA has been detected inperipheral blood mononuclear cells (106). In HIV patients,cerebral infiltrating monocytes serve as a route of entry into thebrain for the HIV virus (38). In postmortem brain tissue fromsix patients infected with Hep C, Hep C viral RNA, whileabsent in neurons and oligodendrocytes, was found primarilyin macrophages in the brain (107). Recently, observationssuggestive of cerebral macrophage activation in patients withHep C have been documented. Specifically, examination ofpostmortem brain tissue from seven patients with Hep Cdemonstrated an increased mRNA expression of proinflamma-tory cytokines such as TNF� and IL-1� in Hep C RNA-positive macrophages compared with Hep C RNA-negativemacrophages (106). In addition, cerebral MRS studies in 25patients with Hep C with mild liver inflammation showed anincreased myo-inositol-to-creatine ratio in all 25 patients. Inthe patients with Hep C who underwent cognitive testing, theincrease in the cerebral myo-inositol-to-creatine ratio was as-sociated with prolonged working memory reaction times (32).These findings suggest that glial activation could take place inthe setting of viral liver inflammation and has significantimplications for mediating alterations in central neural activity.

Sleep Disturbances and Liver Disease

Sleep abnormality, specifically, increased daytime sleepi-ness, is a complaint documented in many liver disease patients.In a study of 48 patients with PBC, daytime sleepiness asmeasured by the Epworth Sleepiness Scale, was increased inpatients with PBC compared with healthy controls, with �50%of patients with PBC having a score �10 (established thresholdindicative of significant daytime hypersomnolence). In thepatients with PBC, the amount of daytime sleepiness had noassociation with biochemical markers of liver disease severity(70). In Hep C patients treated with IFN-� and followed overa 4-mo period, reduced quality of sleep over the study periodwas reported (79).

TNF�, IL-1�, and IL-6 play a role in physiological controlof the sleep-wake cycle and likely contribute to the daytimesleepiness observed in patients with liver disease (44). Admin-istration of these cytokines to rodents results in increased timespent asleep, and, conversely, cytokine antagonists have theopposite effects (44, 73). Elevated levels of TNF� and IL-6have also been reported in patients with sleep disorders such asnarcolepsy and sleep apnea, which are commonly associatedwith increased daytime sleepiness (104). In addition, in Hep Cpatients treated with IFN-�, elevated levels of plasma IL-6were associated with poor sleep quality, as observed over a4-mo treatment period (79). The CRH and 5-HT neurotrans-mitter systems have been linked with sleep abnormalities.Central infusion of CRH into rodents results in increased timein wakefulness (less time sleeping), and administration of aCRH receptor antagonist, astressin, reduces the time in wake-fulness (17). The role of the serotonergic neurotransmittersystem in sleep abnormality is complex, and it has beenimplicated in promoting wakefulness, as well as increasedsleep times (44). Furthermore, a strong association between thedegree of daytime sleepiness and fatigue has been reported,suggesting the existence of overlap in the neurotransmittersystems and mechanisms that give rise to these respectivesymptoms (70). Modafinil, a therapeutic agent associated withamelioration of daytime sleepiness, was also found to reducefatigue severity in a small cohort of patients with PBC (48).

Conclusions and Future Directions

Although there are caveats in extrapolating animal data tohumans, findings from animal models and clinical studies havecontributed significantly to furthering our understanding ofsome of the mechanisms that can contribute to the symptom-ology seen in patients with chronic inflammatory liver dis-eases. While the predominance of these symptoms may varyacross liver diseases of varying etiologies, the alterations inunderlying neurotransmitter systems that have been implicatedin their pathogenesis appear to be quite similar. It is evidentthat TNF�, IL-1�, and IL-6, the three cytokines that havereceived the most attention in mediating changes in centralneural activity in the setting of peripheral inflammation, arelikely key promoters of central neural changes in chronic liverdiseases. Moreover, although TNF�, IL-1�, and IL-6 areredundant in some of their effects, the benefit from antagoniz-ing only one of them (e.g., inhibiting TNF� or IL-6) suggeststhat some cytokines may be more predominant in mediatingbehavioral changes in the setting of different inflammatorydiseases (12, 60, 99). Targeting the 5-HT neurotransmitter

Review



system has also proven to be advantageous in relation tofatigue and/or depression in patients with liver disease (54, 77).

Recently, cerebral microglial activation was found in post-mortem brain tissue from patients with Hep C infection andpatients with cirrhosis and hepatic encephalopathy (106, 111).However, evidence for microglial activation in the setting ofother chronic liver diseases is still lacking. In patients withchronic inflammatory liver diseases, this could be investigatedusing noninvasive methods such as cerebral proton MRS (seeabove). In experimental cholestasis, microglia are activatedand subsequently lead to cerebral monocyte infiltration (23,51). Importantly, inhibition of both of these events is associ-ated with a significant improvement in sickness behaviors (23).CNS inflammatory diseases that are associated with microglialactivation show a marked reduction in neuroinflammation withadministration of minocycline (52). In addition, anti-adhesiontherapies that have targeted P-selectin and �4-integrin havealso been effective in improving sickness behaviors in exper-imental cholestasis, as well as in reducing cerebral inflamma-tion in CNS pathologies (23, 64). Such therapeutic interven-tions have not been explored in the setting of chronic inflam-matory liver diseases and may be beneficial in improvingsickness behaviors in patients with chronic liver diseases.Furthermore, MRI studies in patients in which circulatingmonocytes have been labeled with small paramagnetic ironoxide particles have been used to track the infiltration ofmonocytes into the brains of patients with CNS inflammatorydiseases, including multiple sclerosis, in which monocyte re-cruitment into the brain is a pathological feature (27). Similarstudies in patients with chronic inflammatory liver diseaseswould be very useful in demonstrating whether monocytesinfiltrate the brains of these patients, thereby presenting a noveltherapeutic target in relation to amelioration of sickness be-haviors in patients.

While the 5-HT neurotransmitter system has received themost attention in the setting of liver disease, other neurotrans-mitter systems, such as the GABA, dopamine, and norepineph-rine neurotransmitter systems, have been implicated in medi-ating behavioral alterations (14, 18, 62). These behavioralchanges include cognitive dysfunction and fatigue, and, there-fore, alterations in these neurotransmitter systems may play arole in promoting behavioral changes in the setting of inflam-matory liver diseases. In addition, changes in the CRH neu-rotransmitter system have been described in the cholestaticliver disease PBC and warrant investigation in other chronicliver inflammatory diseases as well (11, 91, 92, 95). It hasbecome increasingly evident that peripheral organ-centeredinflammatory diseases, including chronic liver diseases, are notpurely organ-limited diseases but are associated with changesin central neural activity. Continuing to delineate how thediseased liver communicates with the brain to subsequentlymediate the changes that occur within the brain will enable usto identify novel therapeutic targets that can serve to decreasethe burden of debilitating symptoms such as fatigue in patientswith chronic inflammatory liver disease.

GRANTS

C. D’Mello is funded by a Canadian Institutes of Health Research FrederickBanting doctoral scholarship. M. G. Swain holds the Cal Wenzel FamilyFoundation Chair in Hepatology. This work was supported by an operatinggrant from the Canadian Institutes of Health Research to M. G. Swain.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

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Liver-brain inflammation axis

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