Neutrophil extracellular trap formation is increased in psoriasis and induces human β-defensin-2 production in epidermal keratinocytes

Abstract

Neutrophil extracellular traps (NETs) have been implicated in the development of certain immune-mediated diseases, but their role in psoriasis has not been clearly defined. Human β-defensin-2 (HBD-2) is an important antimicrobial peptide overexpressed in psoriasis epidermis. We evaluated whether the amount of NETs is increased in psoriasis and determined the effect of NETs on HBD-2 production in epidermal keratinocytes. Using fluorescent microscopy, we found that patients with psoriasis (n = 48) had higher amount of NETotic cells in their peripheral blood compared to healthy controls (n = 48) and patients with eczema (n = 35). Psoriasis sera showed increased ability to induce NET formation in control neutrophils but normal NET degradation ability. The amount of NETs in the peripheral blood correlated with psoriasis disease severity. NETosis was also observed in the majority (18 of 20) of psoriasis skin specimens. Furthermore, NETs induced HBD-2 mRNA and protein production in keratinocytes, and immunohistochemical analysis confirmed strong expression of HBD-2 in psoriasis lesional skin. In summary, NET formation is increased in peripheral blood and lesional skin of psoriasis patients and correlates with disease severity. Additionally, NET-induced HBD-2 production may provide a novel mechanism for the decreased susceptibility of psoriasis plaques to microbial infections.

Cleaved N-terminal histone tails distinguish between NADPH oxidase (NOX)-dependent and NOX-independent pathways of neutrophil extracellular trap formation

“…Being able to discriminate between NETs derived through NOX-dependent or NOX-independent pathways, we next assessed whether we could detect NOX-dependent or NOX-independent NETs in blood plasma obtained from patients with prototype NET-associated diseases; that is, septic shock,28 RA,13 psoriatic arthritis (PsA)29 and SLE 30. We first measured circulating MPO–DNA complexes and then evaluated whether positivity in the MPO–DNA ELISA coincided with positivity in additional ELISAs employing anti-histone antibodies directed against N-terminal tails (H2B-K12Ac and/or H4-K8,12,16Ac).…”

Cancer and inflammation

“…They also contain granules and can release anti-microbial molecules similar to the resident granulocytes and can create “neutrophil extracellular traps” (NETs). NETs are networks of DNA-rich fibers embedded with histones and granule proteins including neutrophil elastase, cathepsin G and myeloperoxidase that can trap and kill bacteria and fungi extracellularly, without phagocytosis (40, 45, 93, 107). The monocytes can differentiate into macrophages when they enter the tissue and also phagocytose cells and debris.…”

Mechanisms and disease relevance of neutrophil extracellular trap formation

“…Despite these findings, murine RA models using PAD4 (enzyme driving protein citrullination in neutrophils) knock-out mice to interrogate NET contribution in vivo, revealed discrepant results depending on the arthritis model used and relative contributions of different PADs in the microenvironmental RA context. 7,51,84 Among dermatologic indications, neutrophilic inflammation and NETosis have attracted particular attention for psoriasis 85,86 where neutrophils are found as major infiltrating immune cell in skin histologies, yet their functional relevance in disease initiation or progression remains largely elusive. A previous publication showed that the nucleic acid sensor AIM2 is involved in the uptake of DNA into keratinocytes if the DNA is complexed with LL-37.…”