Psoriatic keratinocytes prime neutrophils for an overproduction of superoxide anions

Abstract

Psoriatic plaques result from an abnormal proliferation of keratinocytes associated with the local presence of T lymphocytes and neutrophils. The exact role of neutrophils in psoriatic lesions remains unclear. The present investigation was aimed at deciphering the capacity of psoriatic keratinocytes to alter in vitro functions of neutrophils. Blood neutrophils from healthy donors were incubated with psoriatic (PK) or healthy keratinocytes (HK) with and without IL-2-activated healthy T lymphocytes. The study was focussed on neutrophil capacity of adherence, viability and superoxide anion production. PK or HK with or without T lymphocytes similarly augmented neutrophil viability after 48 h of co-incubation. PK or HK did not directly activate the superoxide production by neutrophils. However, they both primed neutrophils for an increased fMLF-induced production of superoxide, an effect enhanced by the presence of T lymphocytes. PK were 1.5-fold more efficient than HK to augment this superoxide production. PK cultured with T lymphocytes induced the adhesion of neutrophils 4.7 times more efficiently than HK. The adherence of neutrophils was mediated through ICAM-1, LFA-1 and Mac-1, independently of bioactive lipids. The effects of PK and HK on neutrophil viability and priming were independent of direct cellular contact. In conclusion, keratinocytes can impact neutrophils by increasing their lifespan, and by priming them to overproduce superoxide. PK are more efficient than HK in priming neutrophils, an effect enhanced by T lymphocytes. These results indicate that neutrophils could contribute to psoriasis pathogenesis partly through their pathological interactions with PK.

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

“…The analysis of gene expression alone is not sufficient to resolve this issue, but quantitative analyses of gene expression can at least provide objective insights [7]. Our analysis of genes near susceptibility loci from psoriasis GWAS studies lends support to multiple cell types, including T-cells, but above all our findings bolster support for neutrophils as participants in pathogenetic disease mechanisms [24,49,54,55,60]. We expect that this conclusion can be sharpened by future work, based upon the identification of new psoriasis susceptibility loci, new experimental evidence, generation of new datasets for evaluating cell type-specific expression, and continued development of bioinformatic analysis protocols.…”

“…Neutrophils also represent a source of cytokines demonstrated to drive lesion development, such as IL-17A, and indeed one study indicated that IL-17A(+) neutrophils are more abundant in lesions than IL-17A(+) T-cells [54]. Such epidermal neutrophils generate reactive oxygen species such as superoxide anion, leading to tissue damage and possible hyper-activation of innate defense mechanisms [55]. Neutrophils also interact with other cell types, such as KCs, T-cells and dendritic cells.…”

Aquaporin-3-mediated hydrogen peroxide transport is required for NF-κB signalling in keratinocytes and development of psoriasis

“…Regarding the redox state in psoriasis, there are increasing studies that showed higher levels of oxidative stress markers in psoriatic subjects, such as nitric oxide 63 , superoxide dismutase, catalase 64 , superoxide anions 65 and peroxiredoxin 2 (refs 66,67). A recent report also showed significantly higher H 2 O 2 and Nox activity in white blood cells of psoriatic patients compared with controls 68 .…”

Contribution of myeloperoxidase and inducible nitric oxide synthase to pathogenesis of psoriasis

“…In addition, recently conducted studies showed that the blood neutrophil counts are increasing in patients with psoriasis and amount of superoxide anions are increased in these neutrophils [16, 17]. …”