Circadian rhythm disruption promotes alcohol-induced liver and brain injury.

Abstract

Abstract Alcoholic liver disease (ALD) progression to cirrhosis and development of hepatic encephalopathy (HE) are characterized by hepatic and brain inflammation involving innate immune cells. Identifying the risk factors and immune mechanisms involved in susceptibility to liver and brain injury are significant unmet needs. Circadian rhythm disruption promotes alcohol-induced liver pathology. We aim to investigate whether circadian rhythm disruption also primes brain inflammation by impacting trafficking and inflammatory potential of recruited and resident mononuclear phagocytes (MP). Alcohol (EtOH) is delivered to C57BL/6 mice per a modified NIAAA model of alcoholic liver disease whereby chronic alcohol consumption (20% EtOH v/v in drinking water, 4 wks (Meadows-Cook diet)) is combined with three once daily binges of alcohol. Tissue was assessed via H&E and IHC for α-smooth muscle actin (αSMA) and collagen I (Col I) (liver) and allograft inflammatory factor 1 (Iba-1) (brain). All features associated with human alcoholic liver injury including steatosis, hepatic inflammation and early fibrogenesis were present. Brain mononuclear phagocytes analysed by flow cytometry revealed an increase in recruited and resident MP in response to the alcohol treatment. Moreover, in the steady-state, hepatic and brain MP populations demonstrate circadian oscillations. Thus, circadian rhythm disruption may modulate alcohol-induced alterations in mononuclear phagocyte trafficking and function similarly in brain and liver.