Harming Thyself

Abstract

Psoriasis is an inflammatory autoimmune disorder of the skin characterized by excessive proliferation of keratinocytes and the presence of plasmacytoid dendritic cells (pDCs). Whereas pDCs normally sense microbial DNA in a Toll-like receptor 9 (TLR9)-dependent fashion, in psoriatic lesions pDCs respond to self-DNA and secrete interferon-α (IFN-α), which exacerbates the condition. Lande et al . investigated the mechanism involved and screened extracts of normal and psoriatic human skin (fractionated by reversed-phase high-performance liquid chromatography) for factors that could stimulate IFN-α production by cultured human pDCs. Extracts of normal skin did not induce a response; however, a fraction from psoriatic skin stimulated robust production of IFN-α as measured by enzyme-linked immunosorbent assay. Mass spectrometry identified the cathelicidin LL37, an antimicrobial peptide, as the stimulating factor. The addition of an antibody against LL37 blocked the stimulation by psoriatic skin extract of IFN-α secretion by pDCs. Western blotting and real-time reverse transcription polymerase chain reaction assays showed that LL37 protein and mRNA were more abundant in psoriatic skin than in healthy skin. LL37 is produced in the skin as an antibacterial defense after tissue damage, which often precedes psoriatic episodes. Treatment of pDC cultures with DNase, which removed DNA from dead pDCs, blocked the ability of LL37 to stimulate IFN-α secretion. Atomic force microscopy showed that LL37 formed aggregated complexes with DNA, and confocal microscopy and flow cytometry showed that these LL37-DNA complexes entered pDCs and were localized to early endosomes, where TLR9 is found. As Baumgarth and Bevins suggest, this study, which shows that LL37 can complex with self-DNA (released from dead keratinocytes) to activate pDCs in psoriasis and so disrupt tolerance (the nonresponsiveness to self) has implications for the treatment of autoimmunity. R. Lande, J. Gregorio, V. Facchinetti, B. Chatterjee, Y.-H. Wang, B. Homey, W. Cao, Y.-H. Wang, B. Su, F. O. Nestle, T. Zal, I. Mellman, J.-M. Schröder, Y.-J. Liu, M. Gilliet, Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449 , 564-569 (2007). [PubMed] N. Baumgarth, C. L. Bevins, Skin deep but complex. Nature , 449 , 551-553 (2007). [PubMed]