The Immunoregulatory Role Of 2’fucosyllactose In Psoriasis-like Skin Inflammation

Psoriasis is a chronic immune-mediated inflammatory erythematosquamous dermatosis disorder,characterized by uncontrolled keratinocyte proliferation,recruitment of T cells to the skin and release of pro-inflammatory cytokines.Although the molecular mechanisms governing psoriasis pathogenesis are unclear,many studies have indicated that T helper 17(Th17)cells and Th17 related cytokines play an important role in the development of psoriasis lesions.Th17 cells were reported to infiltrate into psoriasis lesions,and levels of circulating Th17 cells in psoriatic patients’ peripheral blood are elevated and positively correlate with psoriasis Area and Severity Index(PASI).Expansion and survival of these T cells depends on myeloid cell produced interleukin 23,which drives the differentiation of Th17 cells.In addition,Th17 cells produce several mediators such as interleukin(IL)-17A,IL-17F,and IL-22,which induce keratinocyte proliferation and other hallmark features of psoriasis.2’fucosyllactose(2-FL)is part of acidic and neutral fucosylated human milk oligosaccharides(HMOs)which constitutes nearly 30%of all HMOs.2-FL has been reported to offer a protective effect against infectious diseases and support aspects of immune development and regulation.Despite the immunomodulatory function of 2-FL has been revealed in recent years,few researches paid attention to the effect of 2-FL on regulating immune-mediated diseases.In this study,we sought to investigate the effect of 2-FL in the development of psoriasis on a mouse model.We established imiquimod(IMQ)-induced psoriasis-like skin lesions in mice,and found that 2-FL significantly ameliorated IMQ-induced symptoms of erythema,thickening and the psoriatic histological changes like epidermal hyperplasia,elongated rete-like ridges,acanthosis in the epidermis and perivascular infiltration of the inflammatory cells in the upper dermis.And data showed that the PASI score was significantly decreased in mice with 2-FL administration compared to model mice.The ameliorates skin inflammation in 2-FL administration mice was associated with the reduced proportion of Th17 lymphocytes,infiltration of pro-inflammatory cytokines and Th17 related inflammatory cytokines.Furthermore,we have determined that 2-FL reduced the phosphorylation of signal transducer and activator of transcription 3(STAT3)and mRNA expression of RORyt upon IMQ stimulation,which might be the reason for the decreasing recruitment of Th17 cells.In vitro,2-FL inhibited differentiation of Th17 cells,phosphorylation of STAT3 and RORyt mRNA levels in spleen cells under Th17 polarizing conditions.In summary,our results suggest that 2-FL inhibits IMQ-induced psoriasis by regulating Th17 cell response and cytokine secretion via phosphorylation of STAT3.