HPV16 activates the AIM2 inflammasome in keratinocytes.

Human papillomaviruses (HPV) are double-stranded DNA viruses, which selectively infect keratinocytes in stratified epithelia. After an initial infection, many patients clear HPV. In some patients, however, HPV persist, and dysfunctional innate immune responses to HPV infection could be involved in the ineffective clearing of these viruses. In this study, the mechanisms of HPV-induced immune responses in keratinocytes were investigated. Binding of viral DNA leads to AIM2 inflammasome activation and IL-1ß release, while IFI16 activation results in IFN-ß release. Using immunohistochemistry, AIM2 and IFI16-two recently identified sensors for cytosolic DNA-were also detected in HPV positive skin lesions. CISH stainings further confirmed the presence of cytosolic HPV16 DNA in biopsy samples. Moreover, active IL-1ß and cleaved caspase-1 were detected in HPV infected skin, suggesting inflammasome activation by viral DNA. In subsequent functional studies, HPV16 DNA triggered IL-1ß and IL-18 release via the AIM2 inflammasome in normal human keratinocytes. Although HPV DNA did not induce IFN-ß in keratinocytes, IFN-ß secretion was observed when AIM2 was blocked. Meanwhile, blocking of IFI16 increased HPV16 DNA-induced IL-1ß, but not IL-18, secretion. These findings suggest crosstalk between IFI16 and AIM2 in the immune response to HPV DNA. In sum, novel aspects concerning HPV-induced innate immune responses were identified. Eventually, understanding the mechanisms of HPV-induced inflammasome activation could lead to the development of novel strategies for the prevention and treatment of HPV infections.

Honey bee (Apis mellifera) venom induces AIM2 inflammasome activation in human keratinocytes.

BACKGROUND: Following allergen exposure, cytokines and other pro-inflammatory signals play an important role in the immunological cascade leading to allergic sensitization. Inflammasomes sense exogenous and endogenous danger signals and trigger IL-1ß and IL-18 activation which in turn shape Th2 responses. Honey bee venom (BV) allergies are very common; however, the local inflammatory cascade leading to the initiation of allergic sensitization is poorly understood. In this study, the local inflammatory cascades in skin after exposure to BV were investigated. METHODS: The mechanisms of inflammasome activation in human skin and in cultured keratinocytes upon BV exposure were analyzed by ELISA, Western blot, flow cytometry, siRNA techniques, and immunofluorescence. RESULTS: In an ex vivo bee sting model, BV induced IL-1ß release suggesting the activation of inflammasomes. Indeed, in cultured keratinocytes, the BV component melittin triggered IL-1ß and IL-18 release via the AIM2 inflammasome. AIM2 is a cytosolic DNA receptor, and mitochondrial as well as genomic DNA was detected in the cytosol of melittin-treated keratinocytes as triggers of inflammasome activation. As a mechanism, melittin mediated destruction of mitochondrial membranes leading to the leakage of mitochondrial DNA into the cytosolic compartment. CONCLUSION: These data suggest that upon BV exposure, keratinocytes are involved in an innate immune response by the activation of the AIM2 inflammasome and subsequent IL-1ß and IL-18 release triggered by endogenous DNA. As IL-1ß and IL-18 are involved in Th2- and IgE-mediated immune reactions, these results could add to the understanding of the role of the tissue microenvironment to subsequent allergic responses.

[Cathelicidins: multifunctional defense molecules of the skin]. / Cathelicidine: multifunktionelle Abwehrmoleküle der Haut.

The human skin is constantly exposed to microbial pathogens but infections only rarely occur. Innate cutaneous immunity is a primary system for protection against infection, and antimicrobial peptides (AMPs) expressed in skin are essential defence molecules. The AMPs include molecules such as the defensins that were first characterized for their antimicrobial properties as well as other peptides and proteins first known for their activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins are unique AMPs that act as defensive and signalling molecules. Two different pathways are involved in this function: cathelicidins have direct antimicrobial activity and they also initiate a host of cellular responses in cytokine release, inflammation and angiogenesis. Several skin diseases are associated with cathelicidin dysfunction. In atopic eczema, for example, cathelicidin expression is suppressed, whereas in rosacea cathelicidin peptides are abnormally processed to forms that induce cutaneous inflammation and a vascular response. In psoriasis cathelicidin peptide converts self-DNA to a potent stimulus in an autoinflammatory cascade. Current studies have unexpectedly identified vitamin D3 as a major factor for the regulation of cathelicidin expression. This finding may provide new strategies in the management of infectious and inflammatory diseases of the skin by targeting control of the expression and function of cathelicidin and other AMPs.

[Infants and young children with fever of unknown origin. Systematic procedure based on a diagnosis-therapy diagram]. / Säuglinge und Kleinkinder mit unklarem Fieber. Systematisches Vorgehen anhand eines Diagnose-Therapie-Diagramms.

Febrile children comprise a substantial proportion of ambulatory pediatric visits. The management of febrile children needs to be structured to minimize the likelihood of unfavorable outcomes as well as the unnecessary use of antibiotics. The guidelines for the management of febrile children in this review are based on recently published data and are aimed to be recommendations until bacterial foci and pathogens are identified.