RNase 7 Strongly Promotes TLR9-Mediated DNA Sensing by Human Plasmacytoid Dendritic Cells

Abstract

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.

Differential Inflammatory-Response Kinetics of Human Keratinocytes upon Cytosolic RNA- and DNA-Fragment Induction

“…During normal cornification, keratinocytes express deoxyribonucleases (DNases) [ 12 ]; however, it was recently shown that reduced keratinocyte DNase activity in psoriasis results in suppressed DNA degradation and, as a consequence, parakeratosis [ 13 ] and the presence of excess DNA fragments in the cytosol. Similarly, disturbed ribonuclease activities were described in psoriatic skin [ 14 , 15 ], which might result in excess RNA fragments.…”

Immune Modulation by Human Secreted RNases at the Extracellular Space

“…Finally, expression of the protein was recently reported to be induced in basal cells of damaged airway epithelia, reinforcing the idea of a protective role for this protein following tissue injury (Table 1 ) ( 70 ). A very recent study showed that this protein directly stimulated plasmocytoid DCs following tissue damage and infection, and the authors of the report proposed to classify hRNase7 as an alarmin ( 54 ). Interestingly, the immuno-modulatory activity of the RNase correlates with binding to self-DNA and activation of TLR9 receptors.…”

Expression and Function of Host Defense Peptides at Inflammation Sites

“…In line with this, a novel mechanism of nucleic acid recognition by LL-37 utilizing cell surface RNA scavenger receptors (SRs) has been described [122], which results is enhanced clathrin-dependent endocytosis, facilitating the overproduction of inflammatory cytokines and chemokines. Recently also RNase7 was found to utilize plasmacytoid dendritic cell (pDC) TLR-9 signaling mode of IFN-α activation even more strongly than LL-37, emphasizing its crucial role in autoimmune inflammatory skin diseases [123]. Interestingly, other antimicrobial peptides expressed in the skin, such as psoriasin, elafin, or hBD-1, lack the ability of interacting with the host nucleic acids, which may be related to their lower net charge ( Figure 2) [120].…”