Up-regulation of brain cytokines and chemokines mediates neurotoxicity in early acute liver failure by a mechanism independent of microglial activation

Abstract

The neurological involvement in acute liver failure (ALF) is characterized by arousal impairment with progression to coma. There is a growing body of evidence that neuroinflammatory mechanisms play a role in this process, including production of inflammatory cytokines and microglial activation. However, it is still uncertain whether brain-derived cytokines and glial cells are crucial to the pathophysiology of ALF at the early stage, before coma development. Here, we investigated the influence of cytokines and microglia in ALF-induced encephalopathy in mice as soon as neurological symptoms were identifiable. Behavior was assessed at 12, 24, 36 and 48 h post-injection of thioacetamide, a hepatotoxic drug, through locomotor activity by an open field test. Brain concentration of cytokines (TNF-α and IL-1β) and chemokines (CXCL1, CCL2, CCL3 and CCL5) were assessed by ELISA. Microglial activation in brain sections was investigated through immunohistochemistry, and cellular ultrastructural changes were observed by transmission electron microscopy. We found that ALF-induced animals presented a significant decrease in locomotor activity at 24 h, which was accompanied by an increase in IL-1β, CXCL1, CCL2, CCL3 and CCL5 in the brain. TNF-α level was significantly increased only at 36 h. Despite marked morphological changes in astrocytes and brain endothelial cells, no microglial activation was observed. These findings suggest an involvement of brain-derived chemokines and IL-1β in early pathophysiology of ALF by a mechanism independent of microglial activation.

The role of PPAR activation during the systemic response to brain injury

“…Mechanistically, neutrophil-mediated oxidative stress and subsequent cellular dysfunction or necrosis may contribute to the hepatic derangement seen in patients who have suffered acute CNS injury [ 50 ]. Early acute hepatic failure has been shown to upregulate central cyto/chemokines, including CXCL1, which mediate neurotoxic effects independently of microglial activation [ 51 ]. It is therefore easy to postulate the development of a feedforward cycle of ongoing peripheral inflammation and organ dysfunction following ischaemic brain injury that results in ongoing central inflammation, impeding the response to stroke and worsening functional outcomes.…”

Acute liver failure enhances oral plasma exposure of zidovudine in rats by downregulation of hepatic UGT2B7 and intestinal P-gp

“…The TAA-induced ALF rat model was used in this study. This model has been widely used and is well established for liver function assessments, because it resembles several pathophysiological and clinical features of ALF in humans [44] . As expected, TAA treatment was accompanied by liver failure, as indicated by increased serum levels of liver enzymes (AST and ALT), AKP, TNF-α and total bilirubin, though serum ammonia levels were not changed by ALF.…”

Neuroinflammatory Signals during Acute and Chronic Liver Diseases

“…This HE-associated microgliosis could be atenuated with anti-inlammatory treatment modalities [5][6][7], which also atenuated or delayed various neurocognitive deicits [8]. While mice injected with TAA displayed a signiicant reduction in locomotor activity, which was accompanied by increased expression of certain proinlammatory cytokines and chemokines, no microglia activation was observed [8]. However, it is conceivable that this observation may be an anomaly of this model rather than evidence of a lack of microglia involvement.…”

“…Furthermore, increased number of microglia [5][6][7] and increased reactive phenotype [6] has been demonstrated in the cerebral cortex of AOMinjected mice. This HE-associated microgliosis could be atenuated with anti-inlammatory treatment modalities [5][6][7], which also atenuated or delayed various neurocognitive deicits [8]. While mice injected with TAA displayed a signiicant reduction in locomotor activity, which was accompanied by increased expression of certain proinlammatory cytokines and chemokines, no microglia activation was observed [8].…”