RESUMEN
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.
Asunto(s)
Anticuerpos/uso terapéutico , Enfermedades Inflamatorias del Intestino/inmunología , Interferón gamma/inmunología , Interleucina-12/inmunología , Interleucina-17/inmunología , Interleucina-23/inmunología , Interleucinas/inmunología , Psoriasis/inmunología , Células TH1/fisiología , Factor de Necrosis Tumoral alfa/inmunología , Adulto , Anticuerpos/inmunología , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/fisiopatología , Interferón gamma/fisiología , Interleucina-12/fisiología , Interleucina-17/fisiología , Interleucina-23/fisiología , Interleucinas/fisiología , Masculino , Estudios Prospectivos , Psoriasis/etiología , Psoriasis/fisiopatología , Piel/inmunología , Piel/patología , Piel/fisiopatología , Células TH1/inmunología , Factor de Necrosis Tumoral alfa/fisiología , Ustekinumab , Interleucina-22RESUMEN
Cathelicidin is strongly expressed in lesional skin in psoriasis and may play an important role as both an antimicrobial peptide and as an autoinflammatory mediator in this chronic skin disease. The mechanism of increased cathelicidin in psoriatic keratinocytes is not known, but recent observations have found that psoriasis has abundant Th17 cells that produce IL-17A and IL-22. We found that human keratinocytes stimulated with supernatants from T cells isolated from lesional psoriatic skin increased expression of cathelicidin when stimulated in the presence of 1,25-dihydroxyvitamin D(3) (1,25D(3)). This increase was signaled through the IL-17RA. In vitro, IL-17A, but not IL-22, enhanced cathelicidin mRNA and peptide expression in keratinocytes dependent on the presence of 1,25D(3). At the same time, coincubation with 1,25D(3) blocked induction of human beta-defensin 2 (HBD2), IL-6, and IL-8, which are other target genes of IL-17A. Act1, an adaptor associated with IL-17RA and essential for IL-17A signaling, mediated cathelicidin induction, as its suppression by small interfering RNA inhibited HBD2 and cathelicidin. Both, 1,25D(3) and IL-17A signaled cathelicidin induction through MEK-ERK. These results suggest that increased IL-17A in psoriatic skin increases cathelicidin through a vitamin D(3)-, Act1-, and MEK-ERK-dependent mechanism. Therapy targeting this cathelicidin-regulating system might be beneficial in patients suffering from psoriasis.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/biosíntesis , Colecalciferol/farmacología , Interleucina-17/fisiología , Queratinocitos/inmunología , Queratinocitos/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Antibacterianos/biosíntesis , Péptidos Catiónicos Antimicrobianos/genética , Catelicidinas , Línea Celular , Células Cultivadas , Humanos , Mediadores de Inflamación/fisiología , Queratinocitos/enzimología , Sistema de Señalización de MAP Quinasas/inmunología , Psoriasis/enzimología , Psoriasis/inmunología , Psoriasis/patología , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/metabolismo , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/fisiología , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/inmunologíaAsunto(s)
Péptidos Catiónicos Antimicrobianos/efectos de la radiación , Colecalciferol/efectos de la radiación , Regulación de la Expresión Génica/efectos de la radiación , Queratinocitos/efectos de la radiación , Rayos Ultravioleta , Péptidos Catiónicos Antimicrobianos/biosíntesis , Péptidos Catiónicos Antimicrobianos/genética , Calcitriol/biosíntesis , Colecalciferol/metabolismo , Cromatografía Líquida de Alta Presión , Deshidrocolesteroles/metabolismo , Expresión Génica , Humanos , Queratinocitos/metabolismo , Radioinmunoensayo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND: In patients with rosacea, environmental stressors, especially UVB radiation, trigger disease flares that are characterized by inflammation and vascular hyperactivity. An altered innate immune detection and response system, modulated to a large extent by the aberrant production and processing of human cathelicidin LL-37, is thought to play a central role in disease pathogenesis. OBJECTIVE: To investigate whether the proinflammatory and proangiogenic effects of UV radiation are enhanced in the presence of cathelicidin LL-37. METHODS: Human skin ex vivo and epidermal keratinocytes in vitro were exposed to UVB irradiation. The proinflammatory effects of UVB exposure in the presence and absence of LL-37 were characterized using immunoblot, transfection, qPCR, and a cell-based second messenger assay. ELISA was used to assess cytokine release and the angiogenic potential of endothelial cells was evaluated using an in vitro angiogenesis assay. RESULTS: UVB irradiation triggered the inflammasome-mediated processing and release of IL-1ß. LL-37 augmented this UV-induced IL-1ß secretion by acting on the P2X7 receptor on keratinocytes. P2X7 receptor activation by UVB and LL-37 resulted in an increase in intracellular calcium concentrations, which enhances inflammasome activation and subsequent IL-1ß release. Furthermore, IL-1ß and LL-37 worked synergistically to increase the angiogenic potential of endothelial cells. CONCLUSION: Cathelicidin LL-37 modulates the proinflammatory and proangiogenic effects of UV radiation and thereby contributes to enhanced sensitivity to sun exposure in rosacea.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/metabolismo , Inflamasomas/metabolismo , Inflamasomas/efectos de la radiación , Rosácea/etiología , Rosácea/metabolismo , Rayos Ultravioleta/efectos adversos , Calcio/metabolismo , Células Cultivadas , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-1beta/metabolismo , Queratinocitos/metabolismo , Queratinocitos/efectos de la radiación , Neovascularización Patológica/etiología , Tolerancia a Radiación/fisiología , Receptores Purinérgicos P2X7/metabolismo , CatelicidinasRESUMEN
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.
Asunto(s)
Calcitriol/análogos & derivados , Fármacos Dermatológicos/farmacología , Psoriasis/inmunología , Proteínas S100/metabolismo , Células Th17/metabolismo , Péptidos Catiónicos Antimicrobianos/metabolismo , Calcitriol/farmacología , Células Cultivadas , Humanos , Inflamación/metabolismo , Interleucina-17/metabolismo , Interleucinas/metabolismo , Queratinocitos/metabolismo , Psoriasis/metabolismo , Proteína A7 de Unión a Calcio de la Familia S100 , Proteínas S100/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Interleucina-22RESUMEN
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.
RESUMEN
The proinflammatory cytokine interleukin-1ß (IL-1ß) plays a central role in the pathogenesis and the course of inflammatory skin diseases, including psoriasis. Posttranscriptional activation of IL-1ß is mediated by inflammasomes; however, the mechanisms triggering IL-1ß processing remain unknown. Recently, cytosolic DNA has been identified as a danger signal that activates inflammasomes containing the DNA sensor AIM2. In this study, we detected abundant cytosolic DNA and increased AIM2 expression in keratinocytes in psoriatic lesions but not in healthy skin. In cultured keratinocytes, interferon-γ induced AIM2, and cytosolic DNA triggered the release of IL-1ß via the AIM2 inflammasome. Moreover, the antimicrobial cathelicidin peptide LL-37, which can interact with DNA in psoriatic skin, neutralized cytosolic DNA in keratinocytes and blocked AIM2 inflammasome activation. Together, these data suggest that cytosolic DNA is an important disease-associated molecular pattern that can trigger AIM2 inflammasome and IL-1ß activation in psoriasis. Furthermore, cathelicidin LL-37 interfered with DNA-sensing inflammasomes, which thereby suggests an anti-inflammatory function for this peptide. Thus, our data reveal a link between the AIM2 inflammasome, cathelicidin LL-37, and autoinflammation in psoriasis, providing new potential targets for the treatment of this chronic skin disease.
Asunto(s)
Citosol/metabolismo , ADN/metabolismo , Inflamasomas/metabolismo , Queratinocitos/metabolismo , Queratinocitos/patología , Psoriasis/metabolismo , Psoriasis/patología , Péptidos Catiónicos Antimicrobianos , Catelicidinas/metabolismo , Citosol/patología , Proteínas de Unión al ADN , Humanos , Interleucina-1beta/biosíntesis , Proteínas Nucleares/metabolismo , Unión ProteicaRESUMEN
Constant exposure to a wide variety of microbial pathogens represents a major challenge for our skin. Antimicrobial peptides (AMPs) are mediators of cutaneous innate immunity and protect primarily against microbial infections. Cathelicidins were among the first AMPs identified in human skin and recent evidence suggests that they exert a dual role in innate immune defense: At first, due to their antimicrobial activity they kill pathogens directly. In addition, these peptides initiate a potent host response to infection resulting in cytokine release, inflammation and a cellular response. Disturbed cathelicidin expression and function was observed in several common inflammatory skin diseases, such as psoriasis where cathelicidin peptide converts inert self-DNA and self-RNA into an autoimmune stimulus. In atopic dermatitis decreased levels of cathelicidin facilitating microbial superinfections have been discussed. Furthermore, abnormally processed cathelicidin peptides induce inflammation and a vascular response in rosacea. Until recently, the molecular mechanisms underlying cathelicidin regulation were unknown. Recently, the vitamin D3 pathway was identified as the major regulator of cathelicidin expression. Consequently, vitamin D3 entered the spotlight as an immune modulator with impact on both innate and adaptive immunity. Therapies targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Infecciones Bacterianas/inmunología , Catelicidinas/metabolismo , Colecalciferol/inmunología , Piel/metabolismo , Presentación de Antígeno , Enfermedades Autoinmunes/complicaciones , Infecciones Bacterianas/complicaciones , Actividad Bactericida de la Sangre , Catelicidinas/inmunología , Regulación de la Expresión Génica/inmunología , Humanos , Inmunomodulación , Inflamación , Transducción de Señal , Piel/inmunologíaRESUMEN
Cathelicidin is an antimicrobial peptide (AMP) and signaling molecule in innate immunity and a direct target of 1,25-dihydroxyvitamin D3 (1,25D3) in primary human keratinocytes (NHEK). The expression of cathelicidin is dysregulated in various skin diseases and its regulation differs depending on the epithelial cell type. The secondary bile acid lithocholic acid (LCA) is a ligand of the vitamin D receptor (VDR) and can carry out in vivo functions of vitamin D3. Therefore we analyzed cathelicidin mRNA- and peptide expression levels in NHEK and colonic epithelial cells (Caco-2) after stimulation with LCA. We found increased expression of cathelicidin mRNA and peptide in NHEK, in Caco-2 colon cells no effect was observed after LCA stimulation. The VDR as well as MEK-ERK signaled the upregulation of cathelicidin in NHEK induced by LCA. Collectively, our data indicate that cathelicidin induction upon LCA treatment differs in keratinocytes and colonic epithelial cells. Based on these observations LCA-like molecules targeting cathelicidin could be designed for the treatment of cutaneous diseases that are characterized by disturbed cathelicidin expression.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/biosíntesis , Calcitriol/farmacología , Detergentes/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Queratinocitos/metabolismo , Ácido Litocólico/farmacología , Quinasas Quinasa Quinasa PAM/metabolismo , Vitaminas/farmacología , Péptidos Catiónicos Antimicrobianos/inmunología , Células CACO-2 , Calcitriol/uso terapéutico , Detergentes/uso terapéutico , Activación Enzimática/efectos de los fármacos , Activación Enzimática/inmunología , Regulación de la Expresión Génica/inmunología , Humanos , Queratinocitos/inmunología , Ácido Litocólico/uso terapéutico , Quinasas Quinasa Quinasa PAM/inmunología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/inmunología , ARN Mensajero/biosíntesis , ARN Mensajero/inmunología , ARN Mensajero/aislamiento & purificación , Enfermedades de la Piel/tratamiento farmacológico , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/metabolismo , Vitaminas/uso terapéutico , CatelicidinasRESUMEN
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.