*TNF-mediated chronic liver injury:
Our group is interested in the interplay between IKKγ/Nemo and TNFR-mediated cell death of hepatocytes during chronic liver injury. The nuclear factor (NF)-κB signaling pathway mediates a variety of important cellular functions by regulating immune and inflammatory responses. NF-κB transcription factors are kept inactive in the cytoplasm through binding to members of the IκB family of inhibitory proteins. Upon stimulation, NF-κB translocates into the nucleus, where it activates pro-inflammatory target genes. IKKγ/Nemo is the essential regulatory unit of the IKK complex. Deletion of IKKγ/Nemo is lethal during embryonic development, as mice die from hepatocyte apoptosis. Futhermore, hepatocyte-specific IKKγ/Nemo knockout mice (NemoΔhepa) are highly susceptible to TNF-mediated spontaneous cell death. NemoΔhepa mice develop a spontaneous phenotype characterized by apoptosis, compensatory proliferation, hepatitis and end-stage hepatocellular carcinoma. All of the above renders this animal model ideal for investigating human NASH and HCC. At present, we are very interested in the role of death receptors, the MAPKs, oxidative stress and the immune system during the Nemo-mediated hepatitis.
*Innate immune signaling and gut-liver interactions in different models of liver injury
Hepatic inflammation is a common trigger of liver disease, and is considered the main driver of hepatic tissue damage leading to fibrogenesis and hepatocellular carcinoma (HCC) development. The inflammatory phenotype during CLD can be attributed to the innate immune system, which is the first line of defence against invading pathogens and is crucial for the overall survival of the host. Recognition of immunogenic signals by the innate immune system is orchestrated via pathogen recognition receptors (PRR), such as Toll-like receptors (TLR) and NOD-like receptors (NLR). PRRs recognize pathogen-associated molecular patterns (PAMPS) and endogenous damage-associated molecular patterns (DAMPS) that are increased in the circulation due to increased bacterial translocation and tissue damage, respectively. The activation of these PRRs induces the transcription of genes involved in the innate immune responses, such as pro-inflammatory cytokines (e.g. IL-1b, IL-6), Type-1 interferons, anti-microbial proteins and many others. Therefore, PRR signalling can play a crucial role during hepatic injury. The focus of our group is to unravel the hepatic inflammatory response, mechanisms by which immune cells are activated and recruited into the liver, how these cells cause injury and stress, and the interactions with the gut microbiome.