Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D–dependent mechanism

Abstract

An essential element of the innate immune response to injury is the capacity to recognize microbial invasion and stimulate production of antimicrobial peptides. We investigated how this process is controlled in the epidermis. Keratinocytes surrounding a wound increased expression of the genes coding for the microbial pattern recognition receptors CD14 and TLR2, complementing an increase in cathelicidin antimicrobial peptide expression. These genes were induced by 1,25(OH) 2 vitamin D 3 (1,25D3; its active form), suggesting a role for vitamin D 3 in this process. How 1,25D3 could participate in the injury response was explained by findings that the levels of CYP27B1, which converts 25OH vitamin D 3 (25D3) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-β 1 . Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-β 1 from inducing cathelicidin, CD14, or TLR2 in human keratinocytes, while CYP27B1-deficient mice failed to increase CD14 expression following wounding. The functional consequence of these observations was confirmed by demonstrating that 1,25D3 enabled keratinocytes to recognize microbial components through TLR2 and respond by cathelicidin production. Thus, we demonstrate what we believe to be a previously unexpected role for vitamin D 3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.

Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity

“…23 The broader applicability of this mechanism for injury-induced enhancement of 1,25 (OH) 2 D production with respect to barrier sites other than the skin remains unclear, and it is interesting to note that cells from the colon do not seem to induce cathelicidin in response to 1,25(OH) 2 D. 24 The basis for regulation of vitamin-D-induced innate immunity in keratinocytes also requires clarification, particularly in view of the 'feed-forward' induction of TLR expression by 1,25(OH) 2 D. One possible explanation for this regulation in keratinocytes is that (unlike macrophages), they show suppression of CP27B activity and induction of CP24A activity in response to 1,25(OH) 2 …”

Vitamin D and Human Pregnancy

“…These include granulocytic cells such as neutrophils which provide a rapid response to infection and inflammation, and which also show 1,25(OH) 2 Dinduced antibacterial activity 138 . Other studies have demonstrated the induction of CYP27B1 in keratinocytes as part of a mechanism to support 1,25(OH) 2 D-induced epidermal antimicrobial responses following wounding of the skin 139 . In a similar fashion, CYP27B1 expression has been reported in the gastrointestinal (GI) tract 25 , and this may play a role in mediating immune responses and protection against inflammation within the GI tract 140,141 .…”

Innate barriers against skin infection and associated disorders

“…For example, several recent studies have demonstrated that Vitamin D influences the expression and function of microbial recognition elements such as Toll Like Receptor-2 (TLR2) [6,7]. Furthermore, the innate antimicrobial recognition system provides an excellent example of the interplay between primary innate antimicrobial responses and adaptive responses dependent on antigen presentation.…”

“…PRRs such as TLR2 and CD14, together with the AMP cathelicidin, are all increased by 1,25D3 . Upon injury of normal skin the enzyme responsible for 1-hydroxylation of 25D3 is induced and this induction leads to a local increase in 1,25 D3 [6]. The consequences of this system in human disease is still unfolding, but intriguing correlations between vitamin D nutritional status and inflammatory diseases and cancer are unfolding [58].…”

“…Another approach is the development of compounds that induce an increase in AMP production. Vitamin D and its analogs are one example of this, and their application to human skin or cells in culture increases their capacity to kill pathogens such as S. aureus and Group A Streptococcus [6]. Another novel therapeutic approach involves targeting the transcriptional regulator hypoxia-inducible factor-1α (HIF-1α).…”