Understanding the molecular elements of cathelicidin expression might lead to new treatments for inflammatory skin diseases (and help explain mechanisms of current therapies). As mentioned above, cathelicidin expression is regulated through the vitamin D3 pathway and involves epigenetic changes such as histone acetylation (52
). Targeting vitamin D3 metabolism and signalling might be beneficial in atopic dermatitis, in rosacea and in psoriasis. Several possible clinical applications are conceivable:
In the treatment of atopic dermatitis UVB therapy is frequently used. Currently, the effect of UVB irradiation is attributed to its effects on T cells and T-cell-mediated immune responses (63
). As outlined above, the underlying beneficial effect of UVB therapy could also be a result of the activation of cutaneous vitamin D3 synthesis (64
). Oral supplementation of 1,25D3 or vitamin D3 precursors might be beneficial in atopic dermatitis as well. 1,25D3 increases cathelicidin expression and antimicrobial activity in keratinocytes in vitro
). Increasing vitamin D3 metabolism or elevating vitamin D3 serum levels could contribute to the restoration of an effective barrier in atopic dermatitis. However, as topical 1,25D3 has been reported to induce skin irritation and an atopic-dermatitis mimicking pheno-type in mice further clinical and experimental studies have to be performed to prove its benefits (65
Alternatively, coactivators of the vitamin D3 pathway could be targeted: most of the known biological effects of 1,25D3 are mediated through the VDR, a member of the superfamily of nuclear hormone receptors (66
). After binding of 1,25D3, the VDR subsequently heterodimerizes with the retinoid X receptor (RXR). This complex binds to vita-min D receptor responsive elements (VDREs) within the promoter region of 1,25D3 responsive genes. After binding of the ligand-VDR-RXR complex to a VDRE, a number of nuclear receptor coactivator proteins are recruited inducing chromatin remodelling through intrinsic histone-modifying activities and direct recruitment of key components of a transcription initiation complex at the regulated promoter (67
). Targeting these coactivators or influencing epigenetic changes associated with VDR activity might help to increase transcriptional activity but limit 1,25D3 induced adverse effects (52
In rosacea, patients might benefit from therapies blocking cathelicidin expression and processing. Polymorphisms in the vitamin D receptor gene have been described in patients with severe rosacea indicating that vitamin D3 signalling is involved in pathogenesis (68
). Blocking cathelicidin expression by targeting the vitamin D3 pathway might represent a novel therapeutic approach in rosacea. As an example, vitamin D3 analogues without intrinsic activity at the vitamin D receptor have been shown to inhibit 1,25D3 induced cathelicidin in keratinocytes in vitro
Finally, in psoriasis, blocking cathelicidin peptide could break the vicious cycle of increased LL-37 expression, pDC activation and cutaneous inflammation. Again strategies to decrease cathelicidin in keratinocytes could target vitamin D3 signalling. Paradoxically, for a long time vitamin D3 analogues have been used in the therapy of psoriasis. Vitamin D3 analogues bind to and activate the vitamin D receptor and should therefore increase cathelicidin in keratinocytes presumably worsening inflammation in psoriasis. However, the opposite is true: vitamin D analogues resemble one of the pillars of topical psoriasis treatment. They ameliorate cutaneous inflammation and reverse morphological changes within lesional skin (69
). Understanding the molecular effects of vitamin D3 analogues on cutaneous innate immune function will eventually also lead to better treatment.
In summary, influencing cathelicidin expression via vita-min D3 signalling might offer a new treatment angle in the therapy of very common skin diseases. However, until the ‘sunshine vitamin’ can be targeted additional experimental work and clinical studies have to be performed to prove its safety and benefits. Overall, current data overwhelmingly support the importance of AMPs to healthy human skin but the key steps to put this information to therapeutic use remain to be done.