Vitamin K-dependent Genes in the Control of Skin Immunity

On the outermost edge of the body a dense network of dendritic cells (DCs), the so called Langerhans cells (LCs), represent the first immune barrier. The establishment and maintenance of this epidermal network is dependent on the cytokine transforming growth factor-b1 (TGF-b1) expressed by keratinocytes (KC) and LCs. We could recently identify a crucial downstream effector of TGF-b1, the receptor tyrosine kinase Axl. Axl belongs to the TAM receptor family, with the additional members Tyro3 and Mer, and gets activated through the vitamin K-dependent ligands Gas6 and Protein S. Axl mediates parts of the TGF-b1 effects on LC differentiation, enhancement of phagocytosis and inhibition of pro-inflammatory cytokine signalling. Moreover, the activity of the TAM receptors was crucial for resolving antigen-specific T-cell mediated skin inflammation in mice. In line with this, constitutive Axl is activated and Mer is neo-induced in human skin LCs in response to allergens and both of these genes are controlled by TGF-b1. Therefore, these receptors might secure immunologic tolerance at body surfaces. Vice versa, dysfunction of these receptors in LCs might lead to autoimmune/ inflammatory skin diseases such as lupus erythematosus, psoriasis or atopic dermatitis. Consequently we here aim to better characterize downstream effectors of TAM receptors during LC differentiation/ activation and to study potential involvement of these receptors in human skin disorders. In preliminary experiments, we added vitamin K to serum- free LC generation cultures in order to activate the endogenous ligands Gas6 and Protein S. Vitamin K exhibited Axl-dependent positive effects on LC differentiation and LC-associated gene expression including the induction of several anti-inflammatory signature genes. Additionally, we identified for the first time a second vitamin K-dependent receptor-ligand system downstream of TGF-b1 in LCs, the Protein C receptor system, which is implicated in wound healing and anti-inflammatory actions. We will study the role of these receptors during LC differentiation /function and during skin inflammation.

The basic principle of conventional cancer therapy, like chemotherapy and radiotherapy, is the direct killing of fast dividing tumor cells. Yet, as these nonselective cytotoxic strategies also affect healthy, actively proliferating cells, patients suffer from stigmatizing adverse effects (e.g. complete hair loss, anemia, and diarrhea). Because of recent progress in the field of precision medicine, tumor specific alterations can now be selectively addressed by targeted cancer therapies. Today, targeted cancer drugs are used as first- and second-line therapy with a high level of clinical efficacy. Interestingly, whereas with these drugs "classical" adverse effects of cancer therapy are not observed, patients treated with targeted cancer drugs frequently develop "novel" adverse effects that compromise the patient's quality of life and may even lead to therapy discontinuation. Tyrosine kinase inhibitors are, together with immunotherapy, among the most promising approaches for modern efficient cancer therapy. In particular inhibitors for the epidermal growth factor receptor (EGFR-I), which are widely used to treat solid tumors such as colorectal and lung cancer, are associated with a high frequency of stigmatizing cutaneous side effects, including an acneiform rash, dry skin, pruritus, paronychia, alopecia or aberrant hair growth. Importantly, there is a direct correlation between cancer therapy response and rash severity, indicating that the rash severity correlates with EGFR blockade efficiency. It has been established that cutaneous side effects are caused by the direct inhibition of EGFR signaling in the skin. During a FWF funded project it could now be established that barrier defects and the skin microbiota play a fundamental role during the development of these side effects. Specifically, the blockade of the EGFR disrupts the controlled eruption of hair through the outer skin layer (epidermis). This leads to a skin barrier break, which induces an allergic immune-response similar to atopic dermatitis. At the same instance, the opening of the hair canal leads to the entry of the commensal skin microbiota, which aggravates the inflammation. This is followed by a microbial shift to pathogenic bacteria like Staphylococcus aureus and leads to a dramatic exaggeration and expansion of the inflammatory skin reaction. Furthermore, the signaling pathway downstream of EGFR could be identified as the ERK cascade. This information was key to the development of a novel therapy approach: the researchers succeeded in compensating for the lack of EGFR through application of another grow factor (the keratinocyte growth factor), which also activates the ERK pathway, thereby securing the skin barrier during hair eruption. These findings can now be implicated into current cancer treatment regimen to improve the patients quality of life and increase targeted cancer therapy efficacy.