Keratinocytes have been recognized to actively participate in the skin immune response. It has been shown that keratinocytes express all components that are necessary to form the NLRP3 inflammasome complex including the adapter protein ASC and caspase-1. In this study, we investigated the presence and activity of the recently identified absent in melanoma 2 (AIM2) inflammasome in human keratinocytes. We were able to show that an AIM2 inflammasome is active in human keratinocytes. IL-1 production by keratinocytes plays a pivotal role in inflammatory processes in the skin. Activation of the AIM2 inflammasome in keratinocytes represents another potential trigger factor for the development and maintenance of inflammatory skin diseases.

Plasmacytoid dendritic cells (pDCs) were described to accumulate in the skin of patients with psoriasis and to be recruited into the dermis upon allergen challenge in atopic dermatitis. Activation of pDCs in the skin has been identified as an important initiator of psoriasis development. Ribonuclease (RNase) 7 is one of the major antimicrobial peptides secreted by keratinocytes and is expressed in significantly higher amounts in lesional skin of patients with atopic dermatitis or psoriasis than in healthy individuals. The skin-derived antimicrobial peptides human ß-defensin 2 and LL-37 indirectly stimulate the activity of skin pDCs, but to our knowledge, an immunomodulatory potential of RNase 7 has not yet been reported. We show here that RNase 7 enables human pDCs to recognize self-DNA and promotes their rapid sensing of bacterial DNA. This very fast innate immune response was sufficient to up-regulate the expression of several antiviral IFN-stimulated genes in human peripheral blood mononuclear cells and to inhibit an infection of primary human keratinocytes with herpes simplex virus 1. RNase 7 was a markedly stronger trigger for IFN-α expression in human pDCs than the other antimicrobial peptides. Our data indicate that RNase 7 exhibits potent immunomodulatory functions and supports the efficient recognition of microbial infections by human skin-infiltrating pDCs.

From the recent literature, there is considerable evidence that AMPs are induced in the skin in atopic dermatitis. However, some studies suggest that the induction, release or mobilization of some AMPs in atopic dermatitis may not reach sufficient levels to provide adequate control of cutaneous microbial colonization. Th2 cytokines appear to negatively influence the expression and induction of some AMPs. A number of immunoregulatory functions have been described for several AMPs. Most of them point to a proinflammatory function of AMPs in addition to their antimicrobial activities. Further studies are needed to clarify the role of AMPs in atopic dermatitis.

The human ribonuclease RNase 7 has been originally isolated from human skin and is a member of the human RNase A superfamily. RNase 7 is constantly released by keratinocytes and accumulates on the skin surface. The expression of RNase 7 in keratinocytes can be induced by diverse stimuli such as cytokines, growth factors, and microbial factors. RNase 7 exhibits a potent broad spectrum of antimicrobial activity against various microorganisms and contributes to control bacterial growth on the skin surface. The ribonuclease and antimicrobial activity of RNase 7 can be blocked by the endogenous ribonuclease inhibitor. There is also increasing evidence that RNase 7 exerts immunomodulatory activities and may participate in antiviral defense. In this review, we discuss how these characteristics of RNase 7 contribute to innate cutaneous defense and highlight its role in skin infection and inflammation. We also speculate how a potential dysregulation of RNase 7 promotes inflammatory skin diseases and if RNase 7 may have therapeutic potential.