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Increased cortical CCL3 expression is associated with microglia activation and can be ablated by reducing circulating TGFβ1 during hepatic encephalopathy
Author(s) -
McMillin Matthew,
DeMorrow Sharon
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.691.4
Subject(s) - ccl3 , microglia , chemokine , neuroprotection , downregulation and upregulation , ccr1 , chemokine receptor , transforming growth factor , endocrinology , medicine , receptor , chemistry , inflammation , ccl2 , biochemistry , gene
Hepatic encephalopathy (HE) is a neuroinflammatory complication associated with liver failure. Other neuroinflammatory disorders show involvement of chemokine ligand 3 (CCL3) and its receptor chemokine receptor 1 (CCR1). Transforming growth factor beta 1 (TGFβ1) modulates these proteins and is elevated in the serum during HE. Our aims were to examine CCL3 and CCR1 expression in the cortex and their interactions with TGFβ1 signaling during HE. Male C57Bl/6 mice were injected with azoxymethane (AOM) to induce HE. Neutralizing antibodies against TGFβ or clodronate liposomes were injected prior to AOM. Cognitive impairment was monitored and at coma brains and livers were dissected. CCR1, CCL3 and IBA1 expression was assessed by immunofluorescence and immunoblotting. Microglia activation occurred following AOM treatment and microglia depletion with clodronate liposomes delayed neurological decline in AOM mice. Cortical CCL3 protein, but not CCR1, was significantly elevated in AOM mice. Treatment with neutralizing antibodies against TGFβ delayed neurological decline and decreased CCL3 protein with no effects on CCR1. Our data suggest that microglia activation following AOM could be due to upregulation of CCL3 and that neutralizing antibodies against TGFβ are neuroprotective possibly through the suppression of CCL3 protein in AOM mice. Research support is provided from NIDDK via 7R01DK082435–03.