TNF‐α–secreting monocytes are recruited into the brain of cholestatic mice†‡

Abstract

Signaling occurs between the liver and brain in cholestatic liver disease, giving rise to sickness behaviors such as fatigue. However, the signaling pathways involved are poorly defined. Circulating inflammatory mediator levels are increased in cholestasis, leading to speculation that they may be capable of activating circulating immune cells that subsequently could gain access to the brain. Indeed, we have identified that at day 10 after bile duct resection-induced cholestasis, there is activation of circulating monocytes that express tumor necrosis factor ␣ (TNF-␣) in conjunction with increased expression of adhesion molecules by cerebral endothelium. Moreover, using intravital microscopy, we have identified markedly enhanced leukocytes rolling along cerebral endothelial cells, mediated by P-selectin, in bile duct-resected (BDR) but not control mice. In addition, we have identified increased infiltration of monocytes (but not lymphocytes) into the brains of BDR mice and found that these infiltrating monocytes produce TNF-␣. Furthermore, infiltration of TNF-␣-secreting monocytes into the brains of cholestatic mice is associated with a broad activation of resident brain macrophages to produce TNF-␣. In conclusion, cholestasis is associated with an activation of cerebral endothelium that recruits TNF-␣-producing monocytes into the brain. We hypothesize that enhanced TNF-␣ release within the brain may contribute to the development of cholestasis-associated sickness behaviors, including fatigue. (HEPATOLOGY 2006;43:154-162.)

Impact of primary biliary cirrhosis on perceived quality of life: The UK-PBC national study

“…The etiology of autonomic dysfunction in PBC is unclear; there may be both central and peripheral effects. In the central model brain injury, perhaps arising as a consequence of inflammatory processes occurring as a result of cholestasis inflammation (a model supported by animal modeling data for cholestasis 25 ), would affect autonomic regulating areas of the brain, leading to secondary peripheral autonomic effects. In the peripheral model vasomotor changes associated with liver disease and/or specific cardiac dysfunction associated with cardiac muscle abnormality in PBC 26,27 would give rise to processes mimicking central autonomic dysfunction peripherally.…”

Fatigue in primary biliary cirrhosis is associated with excessive daytime somnolence

“…Studies performed in animal models of cholestasis have suggested links between central nervous system changes resulting from cholestasis and fatigueassociated behavior patterns, 15,16 whereas magnetic resonance (MR) studies performed in human PBC have shown cholestasis-associated brain stem changes, the degree of which correlates strongly with fatigue severity. 17 A potential mechanism for the cholestasis-associated effects on both fatigue and sleep is suggested by the observation that, in cholestatic animal models, changes in brain inflammatory cytokine levels (possibly resulting from the recently demonstrated increase in central nervous system infiltrating cytokine releasing mononuclear seen in such animals 18 ) are strongly linked to fatigue-like behavior. Interleukin-6 is an inflammatory cytokine present at elevated levels in human liver with PBC 19,20 and is excessively released by both cultured biliary epithelial cells in response to hydrophobic bile acids of the type retained in the liver in cholestasis 21 and spontaneously by PBMC from patients with PBC.…”

Effects of Centrally Administered Etanercept on Behavior, Microglia, and Astrocytes in Mice Following a Peripheral Immune Challenge

“…However, etanercept indirectly reduces CNS inflammation by decreasing peripheral inflammation and preventing cross-talk (Kerfoot et al, 2006). This principal was evident in a 12 week treatment trial in psoriasis patients, where improved depressive symptoms were observed following subcutaneous etanercept injections (Tyring et al, 2006).…”

“…This association is likely related to extensive cross-talk occurring between immune cells within the central nervous system (CNS), such as microglia, and peripheral TNF-aproducing monocytes (Kerfoot et al, 2006). Peripheral lipopolysaccharide (LPS) inflammation activates Toll-like receptor 4 present on circumventricular organs and choroid plexus, resulting in NFkB activation and subsequent production of TNF-a.…”

“…Due to the link between peripheral cytokines and immune cells of the CNS (Kerfoot et al, 2006), we also sought to understand whether a single peripheral immune challenge would be sufficient to activate CNS immune cells. Our next aim was to investigate whether central blockage of TNF-a by etanercept would reverse the behavioral and neurobiological effects seen after LPS challenge.…”