title: 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.
authors.affiliation: Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Universidade Federal de Minas Gerais, Avenida Alfredo Balena 190, Santa Efigênia, Belo Horizonte, MG 30130-100, Brazil. Electronic address: brunoengler@gmail.com.
authors.forename: Bruno E
authors.initials: BE
authors.lastname: Faleiros
authors.affiliation: Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Universidade Federal de Minas Gerais, Avenida Alfredo Balena 190, Santa Efigênia, Belo Horizonte, MG 30130-100, Brazil.
authors.forename: Aline S
authors.initials: AS
authors.lastname: Miranda
authors.affiliation: Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Universidade Federal de Minas Gerais, Avenida Alfredo Balena 190, Santa Efigênia, Belo Horizonte, MG 30130-100, Brazil.
authors.forename: Alline C
authors.initials: AC
authors.lastname: Campos
authors.affiliation: Department of Morphology, Institute of Biological Sciences, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Lindisley F
authors.initials: LF
authors.lastname: Gomides
authors.affiliation: Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Lucas M
authors.initials: LM
authors.lastname: Kangussu
authors.affiliation: Department of Morphology, Institute of Biological Sciences, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Cristina
authors.initials: C
authors.lastname: Guatimosim
authors.affiliation: Department of Morphology, Institute of Biological Sciences, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Elizabeth R S
authors.initials: ER
authors.lastname: Camargos
authors.affiliation: Department of Morphology, Institute of Biological Sciences, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Menezes
authors.affiliation: Department of Pathology, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Avenida Antônio Carlos 6627, Pampulha, Belo Horizonte, MG 31270-901, Brazil.
authors.forename: Milene A
authors.initials: MA
authors.lastname: Rachid
authors.affiliation: Interdisciplinary Laboratory of Medical Investigation, School of Medicine, Universidade Federal de Minas Gerais, Avenida Alfredo Balena 190, Santa Efigênia, Belo Horizonte, MG 30130-100, Brazil. Electronic address: altexr@gmail.com.
authors.forename: Antônio L
authors.initials: AL
authors.lastname: Teixeira
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000648:ultrastructure; D002452:Cell Count; D018925:Chemokines / Q000097:blood / Q000378:metabolism*; D016207:Cytokines / Q000097:blood / Q000378:metabolism*; D005260:Female; D036904:Leukocyte Rolling; D008099:Liver / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D013853:Thioacetamide / Q000633:toxicity; D015854:Up-Regulation
chemical_list: D018925:Chemokines; D016207:Cytokines; D013853:Thioacetamide
keywords: Acute liver failure; Chemokine; Cytokine; Microglia; Neuroinflammation; Thioacetamide