The Role of the Neutrophilic Network in the Pathogenesis of Psoriasis

Abstract

One role of neutrophils, the most abundant innate immune sentinels, is neutrophil extracellular trap (NET) formation, which plays a significant role in immune surveillance. However, NET operation is bidirectional. Recent studies report that NETs may contribute to the development of autoimmune diseases such as psoriasis. The participation of neutrophils in the pathogenesis of that disease is dependent on an autoinflammatory feedback loop between neutrophils, lymphocytes, dendritic cells and keratinocytes. Our aim was to clarify the field of NET research in psoriasis and highlight the main factors required for NET generation, which may be a target of new therapies. This article presents a comphrehensive review concerning studies addressing the participation of neutrophils in the pathogenesis of psoriasis. Based on the available English-language literature, we discuss original papers presenting significant research findings which may help to understand and interpret the NET formation process in psoriasis, as well as the newest systematic reviews on PubMed. Next, the comparison, synthesis and summary of reported results were performed to clearly indicate the specific component of the NET which participates in the development of psoriasis.

The Role of Neutrophils in Spondyloarthritis: A Journey across the Spectrum of Disease Manifestations

“…PsO is an inflammatory skin disease rather prevalent (1–5%) worldwide [ 76 ] and in approximately 10 to 30% is associated with or may precede PsA occurrence [ 77 ]. The crosstalk between innate and adaptive immune systems leads to a self-perpetuating inflammatory loop played by T cells (mainly Th1, Th17, and Th23 driven), dendritic cells, keratinocytes, and neutrophils [ 78 ].…”

“…The activity of NADPH oxidase (NOX2) and MPO, two key enzymes responsible for the respiratory burst, is increased both in the skin and serum of PsO patients and correlates with PASI severity [ 86 , 87 ]. Enzymes stored and then released by neutrophils granules are implicated into the pathogenesis of psoriasis: (i) proteinase 3 is involved in the proteolytical activation of inflammatory mediators (such as IL-36 and Tumor Necrosis Factor (TNFα)) [ 78 , 88 ] and in the formation of autoantigens in psoriasis (LL37) [ 89 ], contributing both to local and systemic inflammation; (ii) neutrophil elastase (NE) enhances keratinocyte proliferation via proteolytic activation of epidermal growth factor receptor (EGFR) signaling [ 90 ] and together with (iii) cathepsin G contribute to IL-36 activation and subsequent skin inflammation [ 88 ]; (iv) the relevance of MPO, already mentioned for its role in the respiratory burst, is also evinced by genetic and functional studies where the gene encoding for MPO resulted as a genetic determinant of generalized pustular psoriasis and neutrophil abundance [ 91 ]; (v) finally lipocalin 2 (LCN2) is an antimicrobial protein which seems to enhance Th17-mediated inflammation, and whose serum level is elevated in psoriatic patients and correlate with the severity of itching [ 92 ].…”

Interleukins 20 and 8 – less widely known cytokines in psoriasis

“…Additionally there was a positive correlation between NET formation and psoriasis severity. These data suggest that NETs may therefore play a role in the pathogenesis of psoriasis [101,102]. IL-8 is mainly produced by monocytes/macrophages, T lymphocytes, neutrophils, fibroblasts, endothelial cells and keratinocytes [91,103,104], but this cytokine is released by neutrophils under certain activation conditions [105][106][107][108].…”

Editorial: The role of neutrophils and its NETosis in autoimmunity and autoinflammation

“…Neutrophils, the most abundant innate immune sentinels, are equipped with a plethora of antimicrobial molecules and are the first cells to migrate toward sites of inflammation to eradicate a wide array of microbial pathogens and clear necrotic cellular debris. The antimicrobial factors used by neutrophils to kill pathogens include antimicrobial peptides (e.g., lactoferrin, human α-defensins, also known as human neutrophil peptides (HNPs), and cathelicidin LL-37), proteolytic enzymes, and reactive oxygen species (ROS) ( 1 , 2 ). Neutrophils kill and prevent the dissemination of invading pathogens via phagocytosis; the release of toxic proteins from azurophilic (or primary) granules, specific (or secondary) granules, and gelatinase (or tertiary) granules; and the ensnarement of pathogens through the release of DNA in the form of neutrophil extracellular traps (NETs) ( 3 ).…”