title: TLR3/4 signaling is mediated via the NFκB-CXCR4/7 pathway in human alcoholic hepatitis and non-alcoholic steatohepatitis which formed Mallory-Denk bodies.
abstract: Activation of Toll-like receptor (TLR) signaling which stimulates inflammatory and proliferative pathways is the key element in the pathogenesis of Mallory-Denk bodies (MDBs) in mice fed DDC. However, little is known as to how TLR signaling is regulated in MDB formation during chronic liver disease development. The first systematic study of TLR signaling pathway transcript regulation in human archived formalin-fixed, paraffin-embedded (FFPE) liver biopsies with MDB formation is presented here. When compared to the activation of Toll-like signaling in alcoholic hepatitis (AH) and non-alcoholic steatohepatitis (NASH) patients, striking similarities and obvious differences were observed. Similar TLRs (TLR3 and TLR4, etc.), TLR downstream adaptors (MyD88 and TRIF, etc.) and transcript factors (NFκB and IRF7, etc.) were all upregulated in the patients' livers. MyD88, TLR3 and TLR4 were significantly induced in the livers of AH and NASH compared to normal subjects, while TRIF and IRF7 mRNA were only slightly upregulated in AH patients. This is a different pathway from the induction of the TLR4-MyD88-independent pathway in the AH and NASH patients with MDBs present. Importantly, chemokine receptor 4 and 7 (CXCR4/7) mRNAs were found to be induced in the patients livers in FAT10 positive hepatocytes. The CXCR7 pathway was significantly upregulated in patients with AH and the CXCR4 was markedly upregulated in patients with NASH, indicating that CXCR4/7 is crucial in liver MDB formation. This data constitutes the first demonstration of the upregulation of the MyD88-dependent TLR4/NFκB pathway in AH and NASH where MDBs formed, via the NFκB-CXCR4/7 pathway, and provides further insight into the mechanism of MDB formation in human liver diseases.
authors.affiliation: LA BioMed at Harbor UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: LA BioMed at Harbor UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: LA BioMed at Harbor UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA.
authors.forename: Brittany
authors.initials: B
authors.lastname: Tillman
authors.affiliation: VA Medical Center, Department of Medicine, Long Beach, CA, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Morgan
authors.affiliation: LA BioMed at Harbor UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: French
authors.affiliation: LA BioMed at Harbor UCLA Medical Center, Department of Pathology, Torrance, CA 90509, USA. Electronic address: sfrench@labiomed.org.
authors.forename: Samuel W
authors.initials: SW
authors.lastname: French
mesh_terms: D016022:Case-Control Studies; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D006519:Hepatitis, Alcoholic / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D059609:Mallory Bodies / Q000378:metabolism / Q000473:pathology*; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D054387:Receptors, CXCR / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C501896:ACKR3 protein, human; C527276:CXCR4 protein, human; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D012333:RNA, Messenger; D054387:Receptors, CXCR; D019718:Receptors, CXCR4; C495344:TLR3 protein, human; C495345:TLR4 protein, human; D051196:Toll-Like Receptor 3; D051197:Toll-Like Receptor 4
keywords: Chemokine receptor 4 and 7 (CXCR4/7); Liver disease development; Mallory–Denk bodies (MDBs); MyD88-dependent pathway; Toll-like receptor (TLR) signaling