TLR3/4 Signaling is Mediated via the NF?B-CXCR4/7 Pathway in Human Alcoholic Hepatitis and Non Alcoholic Steatohepatitis Which Formed Mallory-Denk Bodies.

Experimental and molecular pathology

PubMedID: 24997224

Liu H, Li J, Tillman B, Morgan T, French BA, French SW. TLR3/4 Signaling is Mediated via the NF?B-CXCR4/7 Pathway in Human Alcoholic Hepatitis and Non Alcoholic Steatohepatitis Which Formed Mallory-Denk Bodies. Exp Mol Pathol. 2014;.
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 (NF?B and IRF7, etc.) were all up regulated 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 up regulated 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 up regulated in patients with AH and the CXCR4 was markedly up regulated in patients with NASH, indicating that CXCR4/7 is crucial in liver MDB formation. This data constitutes the first demonstration of the up regulation of the MyD88-dependent TLR4/ NF?B pathway in AH and NASH where MDBs formed, via the NF?B-CXCR4/7 pathway, and provides further insight into the mechanism of MDB formation in human liver diseases.