Characterization of temporal microglia and astrocyte immune responses in bile-duct ligated rat models of cirrhosis

Wright, G., Sharifi, Y., Newman, Tracey A., Davies, N.A., Vairappan, B., Perry, V.H. and Jalan, R. (2014) Characterization of temporal microglia and astrocyte immune responses in bile-duct ligated rat models of cirrhosis. Liver International, 34 (8), 1184-1191. (doi:10.1111/liv.12481). (PMID:24528887)

Abstract

Background & Aims: microglia and astrocyte related pro-inflammatory responses are thought to underpin cerebral sequelae of acute liver failure. Conversely, despite background pro-inflammatory responses in cirrhosis, overt brain swelling and coma associated with acute-on-chronic liver failure, is infrequent unless precipitated (e.g. sepsis). Moreover, in other chronic neurodegenerative disorders and sepsis the brain is protected from recurrent microbial insults by compensatory microglial-associated immune responses.

Aim: to characterize longitudinal cerebral immune responses in a bile duct-ligated (BDL) rat model of cirrhosis.

Method: rats underwent BDL or sham-operation before sacrifice at either 1-day, 1, 2 and 4-weeks post-surgery. We analysed consciousness, brain water, biochemistry, and immunohistochemistry to assess activation of microglia (ED-1, OX6 and Iba-1), astrocytes (Glial fibrillary acidic protein - GFAP), cellular stress (Heat shock protein - Hsp 25) and pro-inflammatory mediator expression (inducible nitric oxide synthase (iNOS), interleukin-1beta (IL-1β) and tumour growth factor-beta (TGF-β)).

Results: BDL significantly increased ammonia and bilirubin (p<0.01, respectively). The classical microglial markers OX6, ED1 and Iba-1 and pro-inflammatory IL-1β and iNOS were not significantly increased. However, the alternative microglial marker and regulatory cytokine TGF-β was elevated from day-1 to 4-weeks post BDL. GFAP expression was significantly increased in corpus callosum in all groups. In BDL rats, Hsp 25 was also increased in the corpus callosum, peaking at 2-weeks.

Conclusion: BDL triggers early alternative, but not classical, microglial activation. There was a correlation between astrocyte activation and cellular stress. These findings indicate early cerebral immune responses, which may be associated with immune tolerance to further challenge

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Contributors

Author: Tracey A. Newman

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