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Interleukin-17A-induced production of acute serum amyloid A by keratinocytes contributes to psoriasis pathogenesis.

ABSTRACT: 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.We 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.NHEK 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.IL-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.Keratinocytes could contribute to psoriasis pathogenesis via A-SAA production, maintaining a cutaneous inflammatory environment, activating innate immunity and Th17 lymphocyte recruitment.

SUBMITTER: Couderc E

PROVIDER: S-EPMC5510841 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Project description:Psoriasis is an auto-inflammatory skin disease characterized by abnormal activation of epidermal keratinocytes, aberrant neovascularization, and dysregulation of immune cells. MicroRNAs are small non-coding RNAs that mainly function in the post-transcriptional regulation of gene expression. Recently, accumulating evidence has demonstrated that expression of microRNAs is dysregulated in psoriasis patients and microRNAs play key roles in psoriasis pathogenesis. Downregulation of miR-193b-3p has been identified to be associated with psoriasis development. However, the precise functions and action mechanisms of miR-193b-3p in psoriasis pathogenesis remain unclear. In this study, we confirmed the downregulation of miR-193b-3p in psoriasis patients, psoriasis-like inflammatory cellular models, and an imiquimod (IMQ) -induced mouse model. A negative correlation was found between miR-193b-3p level and patient Psoriasis Area and Severity Index (PASI) score. Furthermore, miR-193b-3p suppressed proliferation, inflammatory-factor secretion, and the STAT3 and NF-κB signaling pathways in keratinocytes. Importantly, intradermal injection of agomiR-193b-3p blocked, whereas antagomiR-193b-3p augmented, the psoriasis-like inflammation in the IMQ-induced mouse model. Bioinformatics analysis and the dual-luciferase reporter assay showed that miR-193b-3p targets ERBB4 3' untranslated region (UTR). In addition, ERBB4 induced proliferation, inflammatory-factor production, and the STAT3 and NF-κB pathways in keratinocytes. Most importantly, forced expression of ERBB4 could attenuate the effects of miR-193b-3p in keratinocytes, indicating that miR-193b-3p inhibits keratinocyte activation by directly targeting ERBB4. In conclusion, our findings demonstrated that the miR-193b-3p-ERBB4 axis underlies the hyperproliferation and aberrant inflammatory-factor secretion of psoriatic keratinocytes, providing a novel, microRNA-related causal mechanism and a potential therapeutic target in psoriasis.

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Interleukin-17A-induced production of acute serum amyloid A by keratinocytes contributes to psoriasis pathogenesis.

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