Liver-induced inflammation hurts the brain
Authors: Rita Garcia-Martinez, Juan Cordoba
Journal: Journal of Hepatology (2011)

Regulatory T cells suppress sickness behaviour development without altering liver injury in cholestatic miceJournal of HepatologyVol. 56Issue 3PreviewCholestatic liver diseases are commonly accompanied by debilitating symptoms, collectively termed sickness behaviours. Regulatory T cells (Tregs) can suppress inflammation; however, a role for Tregs in modulating sickness behaviours has not been evaluated. Full-Text PDF The immune system is activated following injury or infection. The local response can be accompanied by a systemic response, which includes the synthesis and release of different mediators by innate immune cells. The liver is not an exception and when exposed to an acute or chronic insult generates an inflammatory response that may affect other organs. Liver-induced inflammation is able to cause disturbances in the central nervous system (CNS) including metabolic (hyperthermia, somnolence, loss of body weight) and behavioural manifestations (lethargy, anhedonia, decreased social interaction). These manifestations are collectively termed "sickness behaviour" [[1]Konsman J.P. Parnet P. Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications.Trends Neurosci. 2002; 25: 154-159Abstract Full Text Full Text PDF PubMed Scopus (759) Google Scholar], and are attributed to dysfunction of the CNS. The underlying mechanisms responsible for this periphery-to-brain inflammatory communication are not fully understood, but include both neural and humoral pathways that act in parallel (Fig. 1) [[2]Dantzer R. O'Connor J.C. Freund G.G. Johnson R.W. Kelley K.W. From inflammation to sickness and depression: when the immune system subjugates the brain.Nat Rev Neurosci. 2008; 9: 46-56Crossref PubMed Scopus (4899) Google Scholar]. The neural pathway involves afferent nerves (vagal and trigeminal nerves) that can be locally activated by cytokines present at the site of injury and project to different areas of the brain. The humoral route involves cytokines that interact with the brain diffusing freely from the blood in areas lacking the blood–brain-barrier (the circumventricular organs), or communicate with the brain by activating the endothelium and transmitting signals to brain parenchyma. A key component of this signalling process is the activation of the immune cells resident in the brain parenchyma (microglia), which are usually in a quiescent state. The activation of microglia is considered essential in the innate immune response of the brain and leads to the release of molecules, such as neurosteroids and/or prostaglandins that affect neurons. Neuroinflammation is a process that has gained increased attention in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, and has also been described in hepatic encephalopathy [[3]Butterworth R.F. Hepatic encephalopathy: a central neuroinflammatory disorder?.Hepatology. 2011; 53: 1372-1376Crossref PubMed Scopus (172) Google Scholar]. According to the data published in this issue of the Journal of Hepatology, neuroinflammation may also participate in more subtle neurological manifestations of liver disease. The article by Nguyen et al. investigates the underlying mechanisms of sickness behaviour in a murine model of cholestasic liver injury (bile duct ligation, BDL). In agreement with other studies [[4]Burton M.D. Sparkman N.L. Johnson R.W. Inhibition of interleukin-6 trans-signaling in the brain facilitates recovery from lipopolysaccharide-induced sickness behavior.J Neuroinflammation. 2011; 8: 54Crossref PubMed Scopus (97) Google Scholar], sickness behaviour is related to an increase in serum interleukin-6 (IL-6). In the current model, the generation of IL-6 was clearly shown to originate in the cholestasic liver and induced IL-6 signalling in the brain via endothelial activation, as suggested by an increase in the expression of p-STAT3 in endothelial cells of the hippocampus. These observations support the notion that systemic symptoms such as fatigue, frequently present in chronic cholestasic diseases, may originate from the effects of liver-induced inflammation on the brain. This is an interesting concept that may initiate a new approach for treating the symptoms associated with chronic liver disorders. The authors were able to modify the IL-6 immune response by manipulating regulatory T cells (Treg). Sickness behaviour in BDL mice was enhanced by depletion of Treg and diminished following Treg infusion. Treg manipulation did not alter liver injury, but was associated with changes in hepatic levels of IL-6 mRNA, plasma levels of IL-6 and peripheral blood mononuclear cell expression of IL-6. No remarkable changes were found in TNFα or IL-1β levels. The potential role of IL-6 in sickness behaviour development was further investigated in IL-6 knockout BDL mice. These animals showed similar baseline behaviours and a resistance to developing neurological sickness behaviour after BDL. However, they exhibited typical sickness behaviours when injected with IL-6. Previously, there have been attempts to modify the course of primary biliary cirrhosis (PBC) using immunomodulatory therapies [[5]Kaplan M.M. DeLellis R.A. Wolfe H.J. Sustained biochemical and histologic remission of primary biliary cirrhosis in response to medical treatment.Ann Intern Med. 1997; 126: 682-688Crossref PubMed Scopus (126) Google Scholar] that may yet be shown to be beneficial. Infusion of Treg's has been used to hasten immune reconstitution in bone marrow transplantation [[6]Di I.M. Falzetti F. Carotti A. Terenzi A. Castellino F. Bonifacio E. et al.Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation.Blood. 2011; 117: 3921-3928Crossref PubMed Scopus (829) Google Scholar]. However, Treg therapy is not currently understood as a treatment to be applied to PBC patients, but rather as a paradigm to investigate its pathogenesis. The current study validates the BDL mice to investigate the systemic manifestations of cholestasis and supports the neurological origin of sickness behaviour. This interpretation is in accordance with data from PBC patients, in whom an increased plasma concentration of neurosteroids, which activate the GABA-A receptor and result in neuroinhibition, has been found [[7]Ahboucha S. Butterworth R.F. Pomier-Layrargues G. Vincent C. Hassoun Z. Baker G.B. Neuroactive steroids and fatigue severity in patients with primary biliary cirrhosis and hepatitis C.Neurogastroenterol Motil. 2008; 20: 671-679Crossref PubMed Scopus (17) Google Scholar]. Similarly, abnormalities in central activation and cortical inhibitory and excitatory circuits have been recently described in fatigued PBC patients in a neurophysiology study [[8]McDonald C. Newton J. Lai H.M. Baker S.N. Jones D.E. Central nervous system dysfunction in primary biliary cirrhosis and its relationship to symptoms.J Hepatol. 2010; 53: 1095-1100Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar]. Recently, inflammation has been identified as a factor with important systemic repercussions on liver diseases [[9]Wong F. Bernardi M. Balk R. Christman B. Moreau R. Garcia-Tsao G. et al.Sepsis in cirrhosis: report on the 7th meeting of the International Ascites Club.Gut. 2005; 54: 718-725Crossref PubMed Scopus (310) Google Scholar]. Cirrhotic patients are particularly susceptible to bacterial infections which may be followed by systemic complications [[10]Arvaniti V. D'Amico G. Fede G. Manousou P. Tsochatzis E. Pleguezuelo M. et al.Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.Gastroenterology. 2010; 139: 1246-1256Abstract Full Text Full Text PDF PubMed Scopus (798) Google Scholar] that can be responsible for patient's demise, in spite of apparent control of the bacterial infection. The systemic inflammatory response appears to be an important mediator that leads to vasodilatation of splanchnic arterial vessels, circulatory impairment, and hepatorenal syndrome [[11]Gines P. Schrier R.W. Renal failure in cirrhosis.N Engl J Med. 2009; 361: 1279-1290Crossref PubMed Scopus (636) Google Scholar]. The brain has long been considered an immune-privileged organ protected from systemic inflammation by the blood–brain-barrier, a concept that has recently changed. Systemic infection can induce delirium without direct bacterial infestation of the CNS and without signs of systemic sepsis [[12]van Gool W.A. van de Beek D. Eikelenboom P. Systemic infection and delirium: when cytokines and acetylcholine collide.Lancet. 2010; 375: 773-775Abstract Full Text Full Text PDF PubMed Scopus (394) Google Scholar]. Activation of the peripheral immune system has strong effect on the brain through pro-inflammatory cytokines, which can induce delirium in susceptible subjects. Older people appear to be more sensitive due to a more permeable blood–brain-barrier, over-activation of microglia or insufficient cholinergic inhibition in the CNS. Similarly, systemic inflammation can precipitate hepatic encephalopathy in predisposed patients, due to previous small-vessel cerebrovascular disease [[13]Rovira A. Minguez B. Aymerich F.X. Jacas C. Huerga E. Córdoba J. et al.Decreased white matter lesion volume and improved cognitive function after liver transplantation.Hepatology. 2007; 46: 1485-1490Crossref PubMed Scopus (76) Google Scholar], activated microglia [[14]Cagnin A. Taylor-Robinson S.D. Forton D.M. Banati R.B. In vivo imaging of cerebral "peripheral benzodiazepine binding sites" in patients with hepatic encephalopathy.Gut. 2006; 55: 547-553Crossref PubMed Scopus (86) Google Scholar] or brain atrophy [[15]Garcia M.R. Rovira A. Alonso J. Aymerich F.X. Huerga E. Jacas C. et al.A long-term study of changes in the volume of brain ventricles and white matter lesions after successful liver transplantation.Transplantation. 2010; 89: 589-594Crossref PubMed Scopus (33) Google Scholar]. Continuous activation of peripheral inflammation can have long-lasting consequences on the brain, as it has been proposed for chronic hepatitis C [[16]Bokemeyer M. Ding X.Q. Goldbecker A. Raab P. Heeren M. Arvanitis D. et al.Evidence for neuroinflammation and neuroprotection in HCV infection-associated encephalopathy.Gut. 2011; 60: 370-377Crossref PubMed Scopus (89) Google Scholar]. The occurrence of infections does increase the risk of Alzheimer's disease or accelerate the progression of established dementia [[17]Holmes C. Cunningham C. Zotova E. Culliford D. Perry V.H. Proinflammatory cytokines, sickness behavior, and Alzheimer disease.Neurology. 2011; 77: 212-218Crossref PubMed Scopus (165) Google Scholar], probably because peripheral inflammation causes a continuous activation of microglia. The administration of non-steroidal anti-inflammatory drugs (NSAID) may become a new strategy to prevent dementia; in rheumatoid arthritis NSAID protect against the subsequent development of Alzheimer's disease [[18]Aisen P.S. The potential of anti-inflammatory drugs for the treatment of Alzheimer's disease.Lancet Neurol. 2002; 1: 279-284Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar]. In experimental models of liver failure, NSAID ameliorate cognitive disturbances [[19]Cauli O. Rodrigo R. Piedrafita B. Boix J. Felipo V. Inflammation and hepatic encephalopathy: ibuprofen restores learning ability in rats with portacaval shunts.Hepatology. 2007; 46: 514-519Crossref PubMed Scopus (176) Google Scholar]. However, NSAID use is not promoted in cirrhosis, because they may be dangerous due to their effects on renal function and enhanced bleeding risk. The explanation for the beneficial effects of NSAID on cognitive function is that they interfere with mediators that can cause persistent damage through bystander injury to neighbouring neurons. Activation of microglia (the "macrophages" of the brain) appears to play a pivotal role in this process. In patients with cirrhosis, infection, and inflammation are frequent precipitating factors for hepatic encephalopathy that may activate microglia [[20]Haussinger D. Schliess F. Pathogenetic mechanisms of hepatic encephalopathy.Gut. 2008; 57: 1156-1165Crossref PubMed Scopus (257) Google Scholar]. Cognitive decline has been documented following an episode of encephalopathy [[21]Bajaj J.S. Schubert C.M. Heuman D.M. Wade J.B. Gibson D.P. Topaz A. et al.Persistence of cognitive impairment after resolution of overt hepatic encephalopathy.Gastroenterology. 2010; 138: 2332-2340Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar], even after complete recovery of liver function following liver transplant [[22]Sotil E.U. Gottstein J. Ayala E. Randolph C. Blei A.T. Impact of preoperative overt hepatic encephalopathy on neurocognitive function after liver transplantation.Liver Transpl. 2009; 15: 184-192Crossref PubMed Scopus (118) Google Scholar]. In addition, patients with history of hepatic encephalopathy that have undergone liver transplant show permanent cognitive impairment and smaller normalised brain volume with reduced N-acetyl aspartate (an indication of neurone loss) [[23]Garcia-Martinez R. Rovira A. Alonso J. Jacas C. Simón-Talero M. Chavarria L. et al.Hepatic encephalopathy is associated with posttransplant cognitive function and brain volume.Liver Transpl. 2011; 17: 38-46Crossref PubMed Scopus (111) Google Scholar]. There are multiple data that show that activation of peripheral inflammation may cause injury to the brain in patients with liver disease. The extent and consequences of the CNS damage depends on multiple factors, including the characteristics of the inflammatory response. The work by Nguyen et al. shows that this inflammatory process can be initiated in the liver and can cause sickness behaviour associated with cholestasic diseases. Although many questions remain unclear and further investigations are required, this study supports the notion that liver-induced inflammation hurts the brain and justifies the evaluation of new immunomodulatory therapies in liver diseases. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Rita Garcia-Martinez is the recipient of grants from Spanish Association for the Study of the Liver (AEEH) and from European Association for the Study of the Liver (Sheila Sherlock EASL Fellowship). We are indebted to Dr. Nathan Davies for critical review of the manuscript and helpful discussions.