TNF Superfamily Signalling and the Microbiome in Mouse Models of Psoriasis
Supported by Karen and Dale White Research Center of Excellence
Layman's Statement: Most current therapies for psoriasis treat the inflammatory response and not the cause of inflammation. We have shown that psoriasis like skin conditions can be triggered by the abnormal death of keratinocytes, the cells forming the outer layer of the skin. My research suggests that microbes living naturally on the skin might be an initiating cause of psoriasis, by priming keratinocytes to die when they should not. This death then leads to inflammation and skin disease.
In this project I will test whether my findings hold true in a clinically relevant, laboratory model of psoriasis. Taking advantage of my position in a worldleading laboratory with access to many genetically modified mice, I will test whether disruption of genes that help cause keratinocyte cell death can protect mice. By seeing which mice do not respond to the disease trigger I can identify what proteins are needed for psoriasis to occur. I will also test if mice that have been raised in an environment without bacteria can be primed to respond to a psoriasis trigger by exposure to individual bacterial species or products. This research will generate insights about how psoriasis is triggered and might lead to the development of new therapies.
Grant Abstract: This project builds on our work on the role of the TNF superfamily (TNFSF) in inflammation of the skin. Over the past 10 years, research conducted by us, and others, has indicated a role for cell death in the aetiology of inflammatory diseases such as psoriasis. Using three different genetic models and an innovative pharmacological model of Tumour Necrosis Factor (TNF) driven skin disease, we have investigated how signalling through TNFSF death and pattern recognition receptors can lead to cell death and inflammation in the skin. Our pharmacological model involves injection of a compound that induces death of keratinocytes, subcutaneously into adult mice, resulting in a local lesional response. We used this model to screen a panel of knock-out (KO) mice for resistance to cell death induced skin inflammation. One striking result from that screen showed that the microbiota plays a direct role in priming keratinocytes for TNF induced death that leads to exacerbation of inflammatory skin conditions. Our results suggest that, contrary to the current dogma; normal skin flora (not only pathogenic infection or dysbiosis) can contribute to skin inflammation.
In this project I will take the discoveries I have made and test them in a clinically relevant psoriasis model. I have access to a large collection of KO and mutant mouse strains, which I will screen for sensitivity/loss of sensitivity to imiquimod-induced psoriasis. Previous studies have found that when induced under germfree conditions severity of the disease is reduced. I will determine the impact of commensal microorganisms in psoriasis development by identifying if particular microbial products or species are responsible for the commensal contribution to psoriasis.
This work will improve our understanding of the molecular mechanisms involved in induction of psoriasis and determine the contribution of specific microbial species or products to disease initiation. Outcomes from this work would enable us to look for molecular biomarkers of disease in patient samples, which could aid in the clinical application of cell death inhibitory drugs that are currently being developed. Because commensal bacteria and their products can be targeted such work also has the potential for rapid therapeutic application.