Abstract
Psoriasis is a chronic inflammatory skin disease resulting from immune dysregulation. Regulatory T cells (Tregs) are important in the prevention of psoriasis. Traditionally, reactive oxygen species (ROS) are known to be implicated in the progression of inflammatory diseases, including psoriasis, but many recent studies suggested the protective role of ROS in immune-mediated diseases. In particular, severe cases of psoriasis vulgaris have been reported to be successfully treated by hyperbaric oxygen therapy (HBOT), which raises tissue level of ROS. Also it was reported that Treg function was closely associated with ROS level. However, it has been only investigated in lowered levels of ROS so far. Thus, in this study, to clarify the relationship between ROS level and Treg function, as well as their role in the pathogenesis of psoriasis, we investigated imiquimod-induced psoriatic dermatitis (PD) in association with Treg function both in elevated and lowered levels of ROS by using knockout mice, such as glutathione peroxidase-1−/− and neutrophil cytosolic factor-1−/− mice, as well as by using HBOT or chemicals, such as 2,3-dimethoxy-1,4-naphthoquinone and N-acetylcysteine. The results consistently showed Tregs were hyperfunctional in elevated levels of ROS, whereas hypofunctional in lowered levels of ROS. In addition, imiquimod-induced PD was attenuated in elevated levels of ROS, whereas aggravated in lowered levels of ROS. For the molecular mechanism that may link ROS level and Treg function, we investigated the expression of an immunoregulatory enzyme, indoleamine 2,3-dioxygenase (IDO) which is induced by ROS, in PD lesions. Taken together, it was implied that appropriately elevated levels of ROS might prevent psoriasis through enhancing IDO expression and Treg function.
Highlights
Psoriasis is a chronic, remitting and relapsing, inflammatory skin disease that is often associated with systemic manifestation, especially arthritis [1]
The results consistently showed that Tregs were hyperfunctional and psoriatic dermatitis (PD) was attenuated in elevated levels of reactive oxygen species (ROS), whereas Tregs were hypofunctional and PD was aggravated in lowered levels of ROS
The histology of the PD lesions was substantially distinguished between WT, Ncf12/2 and GPx12/2 mice; epidermal thickening and elongation of rete ridges were more prominent, hyperkeratosis and parakeratosis were exaggerated and parakeratotic microabscesses were often observed, vascular dilatation and inflammatory cell infiltration were more prominent in dermis of PD in Ncf12/2 mice; whereas all the pathological findings of PD were less prominent in GPx12/2 mice
Summary
Psoriasis is a chronic, remitting and relapsing, inflammatory skin disease that is often associated with systemic manifestation, especially arthritis [1]. Psoriasis is managed by topical treatment with steroids, immunosuppressants and several other agents. Psoralen and ultraviolet A (PUVA) photochemotherapy and other systemic therapies, such as using methotrexate, cyclosporine, oral retinoids and biological therapies, are in practice. Many psoriasis patients are still sufferring from frequent relapse, adverse drug effects, and other untoward reactions such as development of non-melanoma skin cancer [2]. Psoriasis is known to develop as a result of immune dysregulation, in particular hyperfunction of T helper 17 (Th17) cells [3,4]. Immune homeostasis is maintained by regulatory T cells (Tregs) that suppress immune effectors including
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