We developed a powerful technology for switchable, reversible and tissue-specific ectopic gene expression of AP-1 monomers/dimers in the skin, liver and bone, complemented by several tissue/cell specific loss-of-function mouse models. We use mouse and human tissue samples for large-scale studies, such as deep sequencing (RNA-Seq, ChIP-Seq) and mass spectrometry analyses. We evaluate possible biomarkers and therapeutic approaches in small-scale preclinical studies based on these screens. A major focus of the lab is to study the function of AP-1 proteins in skin development but also in organ and whole body metabolism using loss-(LOF) and gain-of-function (GOF) mouse models (GEMM).
At the origins of skin inflammation
Using mice with inducible epidermal deletion of JunB and cJun (DKO*) that develop skin inflammation and a psoriatic-arthritis-like (PsA) disease, we aim to elucidate potential therapeutic targets to alleviate skin and joint inflammation.
Using lineage tracing in the DKO* psoriasis-like mouse model as well as a novel GEMM with epidermal stem cells (ESCs) deletion of JunB and cJun, we found that mutant ESCs initiate epidermal hyperplasia and skin inflammation by priming neighbouring non-mutant epidermal cells to acquire a psoriasis-like phenotype. Mechanistically, TSLP neutralisation reduces non-mutant keratinocytes proliferation and VEGFα expression, an important pro-inflammatory mediator in psoriasis. These findings unravel specific roles of epidermal populations in psoriasis-like disease and provide novel mechanistic insights into epidermal cell interactions under inflammatory conditions.
Skin inflammation, arthritis and bone loss
Rheumatoid, Psoriatic and Osteoarthritis (OA) are destructive joint pathologies linked to chronic inflammation. Using cell type-specific and inducible AP-1 LOF mouse models, combined with experimental arthritis models, we found that c-Fos is a key regulator of surgery- and age-induced OA.
We previously identified the S100A8/A9 complex as highly elevated in our DKO*-GEMM as well as in human psoriatic skin samples. We have now generated a new DKO*-GEMM with epidermal and global deletion of S100A9 to determine the specific role of keratinocyte-derived and neutrophil-derived S100A9 in skin or joint inflammation. Psoriatic patient samples with and without arthritis are also being examined in collaboration with Goerg Schett, Erlangen.
Characterisation of the systemic inflammatory disease in epidermal-deficient JunB GEMMs indicated a skin inflammation to bone cross-talk by Il-17A-mediated inhibition of Wnt signalling in osteoblasts. These mice also suffer from dysbiosis and chronic S. aureus colonisation, which is exacerbated in the absence of adaptive immunity. We have also generated several GEMMs to define the role of autophagy and antimicrobial proteins (AMPs), such as S100A8/A9 and Lipocalin-2, and in the systemic effects of inflammatory skin diseases.
Skin inflammation and Cancer
It has been suggested that psoriatic patients have decreased skin cancer risk. Using our psoriasis-like mouse model and the well-established DMBA/TPA chemical carcinogenesis protocol, we observed that psoriasis-like mice with severe phenotype have a significant decrease in chemically induced skin papillomas compared to controls. Detailed characterisation suggests that in the context of chronic skin inflammation, elevated expression of senescence markers, chemokines and antimicrobial proteins may modulate papilloma formation. We are now expanding our studies to additional skin inflammation models and patient samples.
Liver disease - metabolism, fibrosis, inflammation and cancer
AP-1 proteins are important modulators of hepatic lipid metabolism as specific AP-1 dimers can either activate or repress PPARγ transcription. Therefore, fatty liver disease and obesity most likely depend on AP-1 dimer composition. In addition, ectopic expression of specific Fos or Fra-2, but not Fra-1-containing AP-1 dimers in hepatocytes, leads to liver dysplasia, inflammation, fibrosis and tumours with HCC signatures. Mechanistically, molecular analyses point to the involvement of pathways connected to human hepatocellular carcinoma (HCC), such as the Wnt/b-catenin and Myc pathways and/or to altered cholesterol and bile acids metabolism. A robust connection between c-Fos expression and the activity of the LXR/RXR pathway, an important regulator of cholesterol homeostasis, was unravelled and most likely contributes to the oncogenic function of c-Fos in hepatocytes. We are currently testing whether any of the pathways we discovered can be exploited therapeutically to treat liver cancer in preclinical models.
Cancer-associated cachexia (CAC)
CAC is a complex wasting syndrome characterised by loss of muscle and fat along with ‘browning’, a switch from white to brown fat, as previously described. Our aim is to understand the systemic events taking place in CAC and to identify novel biomarkers and therapeutic targets. Systemic inflammation is a consistent event in CAC with innate immune cells, such as neutrophils, as a major cell type. Interestingly, Lipocalin-2, an adipokine important in innate immunity is highly upregulated in CAC and may be a potential new biomarker. We found that CAC is not prevented in a neutropenic situation suggesting that increased neutrophils may not be a key determinant for CAC. Ongoing studies show that the Renin-Angiotensin-Aldosterone System (RAAS) is dysregulated in CAC in humans and mice, potentially leading to cardiac dysfunction. We are now dissecting, in mice and in human CAC samples, the involvement of the central and peripheral nervous system, the RAAS as well as the tissue-specific role of Ucp-1; in collaboration with R. Señarís, La Compostella, Spain; M. Petruzzelli, Cambridge, UK; H. Watzke MUW Vienna; M. Poglitsch, Attoquant Inc, Vienna; P. Benedikt and R. Zechner, Graz, Austria.