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In innate immune responses, activation of Toll-like receptors (TLRs) triggers direct antimicrobial activity against intracellular bacteria, which in murine, but not human, monocytes and macrophages is mediated principally by nitric oxide. We report here that TLR activation of human macrophages up-regulated expression of the vitamin D receptor and the vitamin D-1-hydroxylase genes, leading to induction of the antimicrobial peptide cathelicidin and killing of intracellular Mycobacterium tuberculosis. We also observed that sera from African-American individuals, known to have increased susceptibility to tuberculosis, had low 25-hydroxyvitamin D and were inefficient in supporting cathelicidin messenger RNA induction. These data support a link between TLRs and vitamin D-mediated innate immunity and suggest that differences in ability of human populations to produce vitamin D may contribute to susceptibility to microbial infection.

Mammalian and fish skin share protective activities against environments that are rich in infectious agents. Fish epidermis is endowed with an extrinsic barrier consisting of a mucus layer and antimicrobial peptides (AMPs). These operate together as a protective chemical shield. As these AMPs are evolutionarily well preserved and also found in higher vertebrate skin (including human epidermis), fish skin offers a unique opportunity to study the origins of innate antimicrobial defense systems. Furthermore, the broad spectrum of fish mucus antimicrobial activities renders piscine AMPs interesting to investigative dermatology, as these may become exploitable for various indications in clinical dermatology. Therefore, this article aims at casting light on fish mucus, the evolutionary relationship between human and fish AMPs, and the latter’s antibacterial, antifungal, and even antiviral activities. Moreover, we develop dermatological lessons from, and sketch potential future clinical applications of, fish mucus and piscine AMPs.

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 D3 (1,25D3; its active form), suggesting a role for vitamin D3 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 D3 (25D3) to active 1,25D3, were increased in wounds and induced in keratinocytes in response to TGF-beta1. Blocking the vitamin D receptor, inhibiting CYP27B1, or limiting 25D3 availability prevented TGF-beta1 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 D3 in innate immunity, enabling keratinocytes to recognize and respond to microbes and to protect wounds against infection.

The antimicrobial peptides (AMP) psoriasin (S100A7) and koebnerisin (S100A15) are differently induced in psoriatic skin. They act synergistically as chemoattractants and “alarmins” to amplify inflammation in psoriasis. Th17 cytokines are key players in psoriasis pathogenesis and vitamin D analogs feature anti-psoriatic effects; both of these activities could be mediated through epidermal AMP regulation. We show that supernatants of cultured psoriatic T cells induce and release psoriasin and koebnerisin from keratinocytes and the Th17 cytokines IL-17A, tumor necrosis factor-α, and IL-22 differently regulate psoriasin and koebnerisin reflecting their distinct expression pattern in normal and psoriatic skin. IL-17A is the principal inducer of both S100 and their expression is further amplified by cooperating Th17 cytokines in the micromilieu of psoriatic skin. Increased extracellular psoriasin and koebnerisin also synergize as “alarmins” to prime epidermal keratinocytes for production of immunotropic cytokines that further amplify the inflammatory response. Treatment of psoriatic plaques with the vitamin D analog calcipotriol interferes with the S100-mediated positive feedback loop by suppressing the increased production of psoriasin and koebnerisin in psoriatic skin and their Th17-mediated regulation in epidermal keratinocytes. Thus, targeting the S100-amplification loop could be a beneficial anti-inflammatory approach in psoriasis and other inflammatory skin diseases.

Antimicrobial peptides are gene-encoded molecules first discovered for their microbicidal properties but recently shown to have pro- or anti-inflammatory functions. Their role as immune regulators is being expanded with evidence that some antimicrobial peptides stimulate keratinocyte migration, proliferation and cytokine or chemokine production. Poorly named, antimicrobial peptides are multifunctional pillars around which the innate and adaptive immune response has evolved.

Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory \"alarmins\" in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs beta-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IkappaB-alpha protein and inhibition of NF-kappaB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP \"alarmin\" expression might be a novel goal in treatment of chronic inflammatory skin diseases.

Hormonally active vitamin D3—1,25-dihydroxyvitamin D3 (1,25D3)—acts as a signaling molecule in cutaneous immunity by increasing pattern recognition through Toll-like receptor-2 (TLR2), and increasing the expression and function of antimicrobial peptides. Here we show that the actions of 1,25D3 on keratinocyte innate immune responses are influenced by histone acetylation and require the steroid receptor coactivator 3 (SRC3), which mediates inherent histone acetyltransferase (HAT) activity. SRC3 was detected in the suprabasal and granular layer of the skin, similar to cathelicidin expression. HAT activity was important to keratinocyte cathelicidin expression as the combination of histone deacetylase inhibitors (HDACi) (butyrate or trichostatin A) and 1,25D3 increased cathelicidin and CD14 expression and enhanced the antimicrobial function of keratinocytes against Staphylococcus aureus. This treatment, or activation of TLR2, also directly increased acetylation of histone 4. Small interfering RNA silencing of the vitamin D receptor or SRC3 blocked the induction of cathelicidin and CD14 by 1,25D3. HDACi could not reverse this effect or influence cathelicidin in the absence of 1,25D3, suggesting that both are necessary for function. These studies demonstrate that the epigenetic control of gene transcription by histone acetylation is important for 1,25D3-regulated antimicrobial and TLR function of keratinocytes, essential elements of the innate immune response of the skin.

Anti-tumor necrosis factor (TNF) therapy-induced psoriasiform skin lesions are a recently described side effect in patients with inflammatory bowel disease. Interleukin (IL)-12/IL-23 neutralization is an effective therapy for these lesions. As Th17 cytokines, such as IL-17A, and IL-1 family members, such as IL-36, play a significant role in plaque psoriasis, we analyzed the involvement of IL-17C and IL-36γ in anti-TNF–induced skin lesions of patients with Crohn's disease.MethodsIL-36γ and IL-17C levels in biopsies of anti-TNF–induced psoriasiform skin lesions of patients with Crohn's disease were assessed by immunohistochemical analysis and correlated to additional immunohistochemical data. IL-36γ and IL-17C messenger RNA, protein, and induced gene expression in human primary keratinocytes were analyzed using quantitative real-time polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay.ResultsIL-36γ and IL-17C are increased in anti-TNF–induced psoriasiform skin lesions of patients with Crohn's disease, compared with healthy controls. Epidermal IL-36γ and IL-17C levels strongly correlate with each other (r = 0.748, P = 0.003). In contrast to IL-12 and IL-23, IL-36γ increases the expression of proinflammatory signals and effector molecules of innate immunity in keratinocytes. However, IL-17C affects keratinocyte defensin gene expression only in combination with TNF-α. IL-36γ induces TNF-α expression in keratinocytes and sustains a self-amplifying proinflammatory loop with IL-17C by inducing its own expression and that of IL-17C.ConclusionsOur study demonstrates a unique role of the previously unknown self-amplifying, proinflammatory IL-36γ/IL-17C loop in the pathogenesis of anti-TNF–induced psoriasiform skin lesions. These findings suggest a beneficial effect of IL-36γ/IL-17C inhibition during anti-TNF–induced psoriasiform lesions in patients with inflammatory bowel disease.

Antimicrobial peptides (AMPs) are effectors of cutaneous innate immunity and protect primarily against microbial infections. An array of AMPs can be found in and on the skin. Those include peptides that were first discovered for their antimicrobial properties but also proteins with antimicrobial activity first characterized for their activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins were among the first families of AMPs discovered in skin. They are now known to exert a dual role in innate immune defense: they have direct antimicrobial activity and will also initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis. Altered cathelicidin expression and function was observed in several common inflammatory skin diseases such as atopic dermatitis, rosacea and psoriasis. Until recently the molecular mechanisms underlying cathelicidin regulation were not known. Lately, vitamin D3 was identified as the major regulator of cathelicidin expression and entered the spotlight as an immune modulator with impact on both, innate and adaptive immunity. Therapies targeting vitamin D3 signalling may provide novel approaches for the treatment of infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions through AMP regulation.

Background We analysed incidence, predictors, histological features and specific treatment options of anti-tumour necrosis factor α (TNF-α) antibody-induced psoriasiform skin lesions in patients with inflammatory bowel diseases (IBD). Design Patients with IBD were prospectively screened for anti-TNF-induced psoriasiform skin lesions. Patients were genotyped for IL23R and IL12B variants. Skin lesions were examined for infiltrating Th1 and Th17 cells. Patients with severe lesions were treated with the anti-interleukin (IL)-12/IL-23 p40 antibody ustekinumab. Results Among 434 anti-TNF-treated patients with IBD, 21 (4.8%) developed psoriasiform skin lesions. Multiple logistic regression revealed smoking (p=0.007; OR 4.24, 95% CI 1.55 to 13.60) and an increased body mass index (p=0.029; OR 1.12, 95% CI 1.01 to 1.24) as main predictors for these lesions. Nine patients with Crohn's disease and with severe psoriasiform lesions and/or anti-TNF antibody-induced alopecia were successfully treated with the anti-p40-IL-12/IL-23 antibody ustekinumab (response rate 100%). Skin lesions were histologically characterised by infiltrates of IL-17A/IL-22-secreting T helper 17 (Th17) cells and interferon (IFN)-γ-secreting Th1 cells and IFN-α-expressing cells. IL-17A expression was significantly stronger in patients requiring ustekinumab than in patients responding to topical therapy (p=0.001). IL23R genotyping suggests disease-modifying effects of rs11209026 (p.Arg381Gln) and rs7530511 (p.Leu310Pro) in patients requiring ustekinumab. Conclusions New onset psoriasiform skin lesions develop in nearly 5% of anti-TNF-treated patients with IBD. We identified smoking as a main risk factor for developing these lesions. Anti-TNF-induced psoriasiform skin lesions are characterised by Th17 and Th1 cell infiltrates. The number of IL-17A-expressing T cells correlates with the severity of skin lesions. Anti-IL-12/IL-23 antibody therapy is a highly effective therapy for these lesions.