Summary Neutrophils make up an essential part of the innate immune system, and are involved both in the initial responses to pathogens, and in orchestrating later immune responses. Neutrophils recognize pathogens through pattern‐recognition receptors (PRRs), which are activated by microbial motifs. The Nod‐like receptors (nucleotide‐binding domain leucine‐rich repeat containing family; NLRs) constitute a recently discovered group of PRRs whose role in the neutrophil immune responses is not yet characterized. The present study aimed to investigate the expression and function of NLRs in neutrophils. Neutrophils were isolated from human peripheral blood, and the presence of nucleotide‐binding oligomerization domain 1 (NOD1), NOD2 and NACHT‐LRR‐PYD‐containing protein 3 (NLRP3) was evaluated with flow cytometry and immunohistochemistry. The expression of NOD1, NOD2 and NLRP3 messenger RNA was determined using real‐time reverse transcription–polymerase chain reaction. Changes in neutrophil cytokine secretion, phenotype and migration following agonist‐induced activation were studied using enzyme‐linked immunosorbent assay, flow cytometry and a chemotaxis assay, respectively. No expression of NOD1 was found in isolated neutrophils and stimulation with the NOD1 ligand γ‐d‐glutamyl‐meso‐diaminopimelic acid induced no signs of activity. In contrast, a marked expression of NOD2 and NLRP3 was found. NOD2 activation with MurNAc‐l‐Ala‐d‐isoGln (MDP) resulted in interleukin‐8 secretion, CD62 ligand down‐regulation, CD11b up‐regulation and increased migration towards an inflammatory stimulus. NLRP3 activation with alum caused interleukin‐1β secretion and facilitated migration. Altogether, this suggests that NLRs may be a previously unknown pathway for neutrophil activation.

Background: NACHT-leucine-rich repeat-and PYD-containing (NLRP)3 protein controls the

Our data support the involvement of NLRP1 and the NLRP1 inflammasome in psoriasis susceptibility and further support the role of innate immunity in psoriasis.

Psoriasis is an inflammatory skin disorder characterized by the hyperproliferation of basal epidermal cells. It is regarded as T-cell mediated, but the role of keratinocytes (KCs) in the disease pathogenesis has reemerged, with genetic studies identifying KC-associated genes. We applied flow cytometry on KCs from lesional and nonlesional epidermis to characterize the phenotype in the germinative compartment in psoriasis, and we observed an overall increase in the stemness markers CD29 (2.4-fold), CD44 (2.9-fold), CD49f (2.8-fold), and p63 (1.4-fold). We found a reduced percentage of cells positive for the early differentiation marker cytokeratin 10 and a greater fraction of CD29 þ and involucrin þ cells in the psoriasis KCs than in nonlesional KCs. The upregulation of stemness markers was more pronounced in the K10 þ cells. Furthermore, the psoriasis cells were smaller, indicating increased proliferation. Treatment with IL-17 and IL-22 induced a similar expression pattern of an up-regulation of p63, CD44, and CD29 in normal KCs and increased the colony-forming efficiency and long-term proliferative capacity, reflecting increased stem cell-like characteristics in the KC population. These data suggest that IL-17 and IL-22 link the inflammatory response to the immature differentiation and epithelial regeneration by acting directly on KCs to promote cell stemness.

Chemokines may contribute to the systemic inflammation that is linked to the increased risk of co-morbidities in patients with psoriasis. The aim of this study was to investigate circulating chemokines in patients with psoriasis and their relationship to disease severity. Analysis of plasma levels of chemokines in patients with psoriasis before narrowband ultraviolet B (UVB) therapy revealed increased expression of Th1-associated CXCL9 and -10, Th2-associated CCL17 and CCL22, and Th17-associated CCL20. CCL20 correlated with disease severity. UVB therapy reduced skin symptoms, but did not affect the chemokine levels in plasma. Anti-CD3 and anti-CD28-mediated activation of peripheral blood mononuclear cells (PBMCs) caused a higher secretion of Th2 cytokine interleukin (IL)-13 by PBMCs from patients with psoriasis than from healthy controls. The sustained high expression of inflammatory chemokines is a potential link to systemic inflammation in psoriasis. UVB therapy may be a more effective treatment of local rather than systemic inflammation.

Background: Psoriasis is associated with a systemic inflammation and an increased frequency of

Psoriasis is a chronic inflammatory skin disease with both local and systemic components. Genome-wide approaches have identified more than 60 psoriasis-susceptibility loci, but genes are estimated to explain only one-third of the heritability in psoriasis, suggesting additional, yet unidentified, sources of heritability. Epigenetic modifications have been linked to psoriasis and altered DNA methylation patterns in psoriatic versus healthy skin have been reported in whole-skin biopsies. In this study, focusing on epigenetic modifications in the psoriatic uninvolved skin, we compared the lesional and non-lesional epidermis from psoriasis patients with epidermis from healthy controls. We performed an exhaustive genome-wide DNA methylation profiling using reduced representation bisulfite sequencing, which interrogates the methylation status of approximately 3-4 million CpG sites. More than 2,000 strongly differentially methylated sites were identified and a striking overrepresentation of the Wnt and cadherin pathways among the differentially methylated sites was found. In particular, we observe a strong differential methylation in several psoriasis candidate genes. A substantial number of differentially methylated sites present in the uninvolved versus healthy epidermis suggests the presence of a pre-psoriatic state in the clinically healthy skin type. Our exploratory study represents a starting point for identifying biomarkers for psoriasis-prone skin before disease onset.

SummaryBackground Vascular modifications occur early in the development of psoriasis, and angiogenesis is one of the key features in the pathogenesis of the disease. Objectives To identify the role of the S100 protein psoriasin in psoriasis-associated angiogenesis. Methods The role of psoriasin in mediating angiogenesis was investigated by silencing psoriasin with small interfering RNA (siRNA) and measuring psoriasisassociated angiogenic factors in human epidermal keratinocytes. The secretion of psoriasin and the effect of psoriasin on general regulators of angiogenesis in keratinocytes, and on endothelial cell migration, proliferation, tube formation and production of angiogenic mediators, was evaluated. Results Reactive oxygen species (ROS) and hypoxia induced the expression of psoriasin. Downregulation of psoriasin in keratinocytes using siRNA altered the ROSinduced expression of the psoriasis-associated angiogenic factors vascular endothelial growth factor (VEGF), heparin-binding epidermal growth factor-like growth factor, matrix metalloproteinase 1 and thrombospondin 1. Overexpression of psoriasin altered several regulators of angiogenesis and led to the secretion of psoriasin. Treatment with extracellular psoriasin induced proliferation, migration and tube formation in dermal-derived endothelial cells to a similar extent as VEGF and interleukin-17, and induced the expression and release of proangiogenic mediators. These effects were suggested to be mediated by the PI3K and nuclear factor kappa B pathways. Conclusions These findings suggest that psoriasin expression is promoted by oxidative stress in keratinocytes and amplifies the ROS-induced expression of angiogenic factors relevant to psoriasis. Moreover, extracellularly secreted psoriasin may act on dermal endothelial cells to contribute to key features angiogenesis.