Cationic antimicrobial peptides in psoriatic skin cooperate to break innate tolerance to self‐DNA

Abstract

Psoriasis is a T-cell-mediated skin autoimmune disease characterized by the aberrant activation of dermal dendritic cells (DCs) and the sustained epidermal expression of antimicrobial peptides. We have previously identified a link between these two events by showing that the cathelicidin antimicrobial peptide LL37 has the ability to trigger selfnucleic acid mediated activation of plasmacytoid DCs (pDCs) in psoriatic skin. Whether other cationic antimicrobial peptides exert similar activities is unknown. By analyzing heparin-binding HPLC fractions of psoriatic scales, we found that human beta-defensin (hBD)2, hBD3, and lysozyme are additional triggers of pDC activation in psoriatic skin lesions. Like LL37, hBD2, hBD3, and lysozyme are able to condense self-DNA into particles that are endocytosed by pDCs, leading to activation of TLR9. In contrast, other antimicrobial peptides expressed in psoriatic skin including elafin, hBD1, and psoriasin (S100A7) did not show similar activities. hBD2, hBD3, and lysozyme were detected in psoriatic skin lesions in the vicinity of pDCs and found to cooperate with LL37 to induce high levels of IFN production by pDCs, suggesting their concerted role in the pathogenesis of psoriasis.Keywords: Antimicrobial peptides r Plasmacytoid DC r Psoriasis r Skin r Toll-like receptor Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPsoriasis is a common T-cell-mediated inflammatory disease of the skin, which, in its most prevalent form, is characterized by the appearance of scaly erythematous plaques that may cover large Correspondence: Dr. Michel Gilliet e-mail: Michel.gilliet@chuv.ch areas of the patient's body [1][2][3]. A key feature of psoriasis is the abnormal activation of dendritic cell (DC) subsets in the dermal compartment leading to the downstream T-cell-mediated autoimmune cascade [4]. A role for plasmacytoid DCs (pDCs) producing type I IFNs appears to be central in this process. pDC-derived * These authors contributed equally to this work.www.eji-journal.eu 204Roberto Lande et al. Eur. J. Immunol. 2015. 45: 203-213 IFNs activate conventional DCs that stimulate autoimmune T cells to migrate into the epidermis [5]. Here, these T cells produce Th17 cytokines 7], which directly initiate keratinocyte proliferation and an abnormal epidermal differentiation pattern [8,9]. Another key feature of psoriasis is the excessive production of antimicrobial peptides (AMPs) and proteins by keratinocytes [10][11][12]. These AMPs are best known for their role in killing pathogenic microorganisms such as Gram-positive and Gramnegative bacteria, protozoa, fungi, as well as some viruses [13]. The antimicrobial activity of AMPs has been ascribed to their unique cationic and amphiphatic structure, which allows interaction with and disruption of microbial membranes containing a high degree of negative charges. Three major antimicrobial peptide classes found in psoriatic skin are the cathelicidin, β-defensins, or S100 proteins. ...

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“…17,37,38 It can also form pores in membranes, enable endosomal access, and has been reported to signal to the immune system via TLR9. 39 …”

The multifaceted biology of plasmacytoid dendritic cells

“…In psoriasis, self nucleic acids form complexes with antimicrobial peptides which activate pDCs through TLR7 and TLR9 193–195 . Interestingly, the Vitamin D analogue calcipotriol, which is used to treat psoriatic skin lesions, triggers tolerogenic responses in cDCs and was recently shown to impair the capacity of both human and mouse pDCs to induce T cell proliferation and effector T cell differentiation 196 .…”

Human dendritic cell subsets and function in health and disease

“…Anti-microbial peptides including LL37, human beta defensin and lysozyme produced by keratinocytes of psoriatic patients all act as carriers to deliver self nucleic acids to endosomal compartments of pDC to induce high IFN-a levels in the skin [125].…”