Secretory Leukocyte Proteinase Inhibitor-Competent DNA Deposits Are Potent Stimulators of Plasmacytoid Dendritic Cells: Implication for Psoriasis

Abstract

Secretory leukocyte proteinase inhibitor (SLPI) is a well-established inhibitor of serine proteases such as human neutrophil elastase (HNE) and a NF-κB regulatory agent in immune cells. In this paper, we report that SLPI plays a previously uncharacterized role in regulating activation of plasmacytoid dendritic cells (pDCs). As the main source of IFN type I (IFNI), pDCs are crucial contributors to inflammatory and likely wound-healing responses associated with psoriasis. The mechanisms responsible for activation of pDCs in psoriatic skin are therefore of substantial interest. We demonstrate that in lesional skin of psoriasis patients, SLPI together with its enzymatic target HNE and DNA, is a component of neutrophil extracellular traps (NETs). Whereas SLPI+ neutrophils and NETs were found to colocalize with pDCs in psoriatic skin, a mixture of SLPI with neutrophil DNA and HNE induced a marked production of IFNI by pDCs. IFNI synthesis by stimulated pDCs was dependent on intracellular DNA receptor TLR9. Thus, SLPI may contribute to psoriasis by enabling pDCs to sense extracellular DNA and produce IFNI.

Cellular dissection of psoriasis for transcriptome analyses and the post-GWAS era

“…Under certain conditions, moreover, neutrophils express MHC class II molecules such as HLA-DR, which may allow neutrophils to interact directly with T-cells and participate in antigen presentation and T-cell activation [24,57-59]. Post-apoptotic neutrophils within the epidermis may also provide a source of autoantigens by the formation of neutrophil extracellular traps (NETs) consisting of a web-like chromatin structure, human neutrophil elastase (HNE), cathelicidin (LL37), and secretory leukocyte proteinase inhibitor (SLPI) [60-62]. These NET components provide DNA complexes that can enhance pDC activation and production of cytokines such as IFN-α [60].…”

“…Post-apoptotic neutrophils within the epidermis may also provide a source of autoantigens by the formation of neutrophil extracellular traps (NETs) consisting of a web-like chromatin structure, human neutrophil elastase (HNE), cathelicidin (LL37), and secretory leukocyte proteinase inhibitor (SLPI) [60-62]. These NET components provide DNA complexes that can enhance pDC activation and production of cytokines such as IFN-α [60]. …”

IgA Enhances NETosis and Release of Neutrophil Extracellular Traps by Polymorphonuclear Cells via Fcα Receptor I

“…Thus, a role for NETs in early innate immunity is strongly supported. However, NET formation may also play a role in adaptive immune responses, as it was demonstrated that NETs stimulate plasmacytoid dendritic cells (36). Additionally, NETs were shown to prime T cells by reducing their threshold for activation (37).…”

Social networking of human neutrophils within the immune system

“…3 EVs are cell-derived membrane vesicles of heterogeneous size, containing hundreds of distinct proteins, lipids, and microRNAs, 41 that have been shown to mainly down-modulate the inflammatory responses in activated DCs (Table 1). In this context, recent publications have reported that NETs can also mediate cross-talk between neutrophils and several DC subsets and suggested that they represent a novel mechanism involved in the pathogenesis of SLE 42,43 and psoriasis in humans, 44,45 or type 1 diabetes (T1D) 46 and autoimmune vasculitis 47 in mice. Interestingly, inhibitory effects of NETs on lipopolysaccharide (LPS)-induced DC maturation and cytokine production have also been observed, given that NET-treated DCs inhibit T-lymphocyte proliferation and skew T-cell differentiation toward a T-helper type 2 (Th2) phenotype (L. S. Barrientos, V. Marin-Esteban, and S. Chollet-Martin, unpublished data, 2014).…”