Abstract
BackgroundAcute-serum Amyloid A (A-SAA), one of the major acute-phase proteins, is mainly produced in the liver but extra-hepatic synthesis involving the skin has been reported. Its expression is regulated by the transcription factors NF-κB, C/EBPβ, STAT3 activated by proinflammatory cytokines.ObjectivesWe investigated A-SAA synthesis by resting and cytokine-activated Normal Human Epidermal Keratinocytes (NHEK), and their inflammatory response to A-SAA stimulation. A-SAA expression was also studied in mouse skin and liver in a model mimicking psoriasis and in the skin and sera of psoriatic and atopic dermatitis (AD) patients.MethodsNHEK were stimulated by A-SAA or the cytokines IL-1α, IL-17A, IL-22, OSM, TNF-α alone or in combination, previously reported to reproduce features of psoriasis. Murine skins were treated by imiquimod cream. Human skins and sera were obtained from patients with psoriasis and AD. A-SAA mRNA was quantified by RT qPCR. A-SAA proteins were dosed by ELISA or immunonephelemetry assay.ResultsIL-1α, TNF-α and mainly IL-17A induced A-SAA expression by NHEK. A-SAA induced its own production and the synthesis of hBD2 and CCL20, both ligands for CCR6, a chemokine receptor involved in the trafficking of Th17 lymphocytes. A-SAA expression was increased in skins and livers from imiquimod-treated mice and in patient skins with psoriasis, but not significantly in those with AD. Correlations between A-SAA and psoriasis severity and duration were observed.ConclusionKeratinocytes could contribute to psoriasis pathogenesis via A-SAA production, maintaining a cutaneous inflammatory environment, activating innate immunity and Th17 lymphocyte recruitment.
Highlights
Serum amyloid A (SAA) is the circulating precursor of amyloid fibril protein AA [1]
Keratinocytes could contribute to psoriasis pathogenesis via Acute-serum Amyloid A (A-SAA) production, maintaining a cutaneous inflammatory environment, activating innate immunity and Th17 lymphocyte recruitment
We previously shown that a combination of IL-1α, IL-17A, IL-22, oncostatine-M (OSM) and TNF-α target normal human epidermal keratinocytes (NHEK) in monolayer culture or in differentiated reconstituted human epidermis to generate a specific transcriptional profile and histological characteristics reproducing features of psoriasis [19, 20]
Summary
Serum amyloid A (SAA) is the circulating precursor of amyloid fibril protein AA [1]. The human SAA protein family contains different isoforms. SAA3, a pseudogene, is not transcribed whereas SAA4 is a constitutive, non-inducible protein (C-SAA). The production of SAA1 and SAA2, known as acute-phase protein-A (A-SAA) is inducible under inflammatory conditions. Because of their extensive homology (95%), neither SAA mRNA nor the protein isoforms 1 and 2 can be distinguished from each other. Acute-serum Amyloid A (A-SAA), one of the major acute-phase proteins, is mainly produced in the liver but extra-hepatic synthesis involving the skin has been reported. Its expression is regulated by the transcription factors NF-κB, C/EBPβ, STAT3 activated by proinflammatory cytokines
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