## 4 Skin Biology, Vitamin D Synthesis, and Its Impacting Factors
### Synthesis and Metabolism of Vitamin D in Human Skin
Unlike most cells, which rely on the kidneys for circulating 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\), keratinocytes are able to operate this entire mechanism to perform this conversion. Higher quantities of CYP27B1 are expressed by keratinocytes than by kidney cells, further suggesting that the skin produces 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) primarily for local application rather than systemic circulation. Such local production enhances innate immunity, increasing the expression of antimicrobial peptides like cathelicidin, and modulates the adaptive immune system, promoting T cells and reducing inflammation activity. This local activation occurs even under conditions where circulating levels of 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) might be low due to impaired kidney function such as in CKD [30,103]. Via a different mechanism than the one in the kidney, the PTH promotes the creation of 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) in keratinocytes, since they do not respond to cycle adenosine monophosphate (cAMP) and do not own the PTH receptor. This makes keratinocyte-driven 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) generation independent of systemic PTH control, highlighting a local, rather than a systemic, role and a preventative effect against hyperproliferating conditions like psoriasis [129]. Additionally, 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) regulates its own levels within keratinocytes by inducing 25(OH)D\({}_{3}\)-24-hydroxylase (CYP24A), which breaks down 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) and prevents excess levels. This feedback mechanism ensures that little 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) enters the bloodstream from the skin. The activity of CYP27B1 in keratinocytes varies according to their differentiation and is the highest in undifferentiated cells and in the stratum basale of the epidermis. Elevations in factors like TNF-\(\alpha\) and interferon-gamma (IFN-\(\gamma\)), in conditions like eczema and psoriasis, enhance 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) production in response to UV light and skin barrier disruption, increasing CYP27B1 expression. This compensatory mechanism aids in restoring epidermal barrier function and reducing inflammation. Furthermore, 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) controls its own levels in keratinocytes by stimulating CYP24A, an enzyme capable of degrading 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) and preventing overabundance. This feedback system ensures that a very small amount of 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) can leave the skin and enter the bloodstream. Moreover, when keratinocytes differentiate, CYP27B1 activity changes. Accordingly, the highest activity is recorded in undifferentiated cells and the stratum basale of the epidermis. TNF-\(\alpha\) and IFN-\(\gamma\) are two pro-inflammatory factors that increase CYP27B1 expression, by mainly enhancing the generation of 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) in response to UV radiation and the disruption of the epidermal barrier [129]. As mentioned previously, via a hydroxylation in the 1\(\alpha\) (A ring) position, vitamin D\({}_{3}\) is first transformed into 25(OH)D\({}_{3}\) in the liver, and then is enzymatically converted to 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) in the kidney. 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) binds to the _VDR_s located both on the cell surface (membrane bound) and inside the immune cell's cytoplasm (intracellular), and thus, activates both innate and adaptive immune cells [30,137,138,139]. Concerning the innate immune cells and specifically dendritic cells (DCs), 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) is responsible for downregulating the major histocompatibility complex (MHC) class II's expression, and as a result, antigen recognition and DCs' activation are induced. When DCs are activated, the vast activity of T-lymphocytes (T cells) is triggered and vice versa, while 1\(\alpha\),25(OH)\({}_{2}\)D\({}_{3}\) suppresses pro-inflammatory cytokines' (i.e., IL-2) production and encourages anti-inflammatory cytokine generation [30].