RIPK1 downregulation enhances neutrophil extracellular traps in psoriasis

Introduction: Psoriasis is an immune-mediated systemic disease. Neutrophils are enriched in psoriasis lesions and can form neutrophil extracellular traps (NETs) to activate keratinocytes. Receptor-interacting protein kinase RIPIK1 and RIPIK3 are involved in necroptosis and NET formation. Aim: To elucidate whether RIPIK1 regulates circulating neutrophils to form NETs and inflammation in psoriasis. Material and methods: Blood samples of psoriasis patients (n = 20) and healthy controls (n = 20) were detected by flow cytometry. The expression level of RIPK1/3 in isolated circulating neutrophils from psoriasis patients (n = 17) and healthy controls (n = 17) was examined by quantitative real-time PCR. SYTOX Green dye and PicoGreen reagent were used to detect NET formation and DNA release in neutrophils under the stimulation of phorbol 12-myristate 13-acetate (PMA) and necrostain-1 (Nec-1). Correlation analysis was performed between RIPK1/3 expression and Psoriasis Area Severity Index (PASI), neutrophil-to-lymphocyte ratio (NLR). Results: RIPIK1 and RIPIK3 expression in protein levels were decreased in monocytes and neutrophils from peripheral blood of psoriasis patients. In isolated psoriasis neutrophils, RIPIK1 and Caspase8 mRNA were downregulated while RIPIK3 and MLIKL mRNA were elevated, leading to the necroptosis pathway. In addition, RIPK1-inhitor-necrostatin-1 (Nec-1) enhanced NETosis in psoriasis neutrophils in vitro. More importantly, there is a negative correlation between RIPIK1 and psoriasis disease severity. Conclusions: Our data demonstrated that downregulated RIPIK1 expression in psoriasis neutrophils may enhance NET generation. RIPIK1 may be identified as a novel therapeutic target in psoriasis.