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 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/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.

The Pivotal Role of CXCR7 in Stabilization of the Pulmonary Epithelial Barrier in Acute Pulmonary Inflammation

“…CXCR7 inhibition decreased the phosphorylation and therefore activation of NF-kB, confirming our findings on tight junction formation and chemokine concentrations. This is in accordance with the literature, where NF-kB was linked with CXCR7 signaling in choroid endothelial cells after LPS stimulation (28) and also in human alcoholic hepatitis (40).…”

Different roles of FAT10, FOXO1, and ADRA2A in hepatocellular carcinoma tumorigenesis in patients with alcoholic steatohepatitis (ASH) vs non-alcoholic steatohepatitis (NASH)

“…It is well accepted that the rates of those progressing to cirrhosis or HCC annually are lower in the NASH if compared with those in ASH. Our published data support that different molecules or pathways may be involved in ASH compared with NASH during the tumorigenesis [Nguyen et al, 2018][Lu et al, 2018] Our work also showed that the TLR/NFKB/CXCR4/7 [Liu et al, 2014][French et al, 2012] [Nan et al, 2010], PI3K/AKT/mTORC1 signaling pathways [Afifiyan et al, 2017], and Tec kinase signaling pathway connected each other during MDB formation both in ASH and NASH [Afifiyan et al, 2017]. …”

“…In our previous studies, we showed that in addition to the TLR/NFKB/CXCR4/7 [Liu et al, 2014][French et al, 2012][Nan et al, 2005][French et al, 2010] and PI3K/AKT/mTORC1 signaling pathways [Afifiyan et al, 2017], Tec kinase signaling pathway connects these two systems together in Mallory-Denk Bodies (MDB) formation both in ASH and NASH [Afifiyan et al, 2017]. During these studies we found that HLA-F-adjacent transcript 10 (FAT10), a ubiquitin-like modifier protein which functions as a proteasomal degradation signal [Schmidtke et al, 2009][Rani et al, 2012][Hipp et al, 2005], plays an important role in MDB formation and tumorigenesis [Oliva et al, 2010][Oliva et al, 2008][French et al, 2012] and we proved that MDB forming cells express preneoplastic phenotypic features [Nan et al, 2006].…”

The therapeutic detoxification of chlorogenic acid against acetaminophen-induced liver injury by ameliorating hepatic inflammation

“…MyD88 is reported to play important roles in transiting signals from various TLRs to its downstream NFjB signaling pathway [31,37]. Reports showed that TLRs/NFjB signaling pathway was involved in the progression of alcoholic hepatitis and non-alcoholic steatohepatitis [38,39]. NFjB is inactivated through binding with its inhibitor IjB, and when extracellular stimuli activate IKK, which in turn leads to the phosphorylation of the N-terminal signal response domain of NFjB-bound IjB, leading to the proteasomal degradation of IjB and activation of NFjB [40,41].…”