Reactive Oxygen Species Prevent Imiquimod-Induced Psoriatic Dermatitis through Enhancing Regulatory T Cell Function

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.

Mannan induces ROS-regulated, IL-17A–dependent psoriasis arthritis-like disease in mice

“…Although ROS has been suggested to be pathogenic in Ps and scleroderma (33,34), reduced neutrophil respiratory burst was observed in patients with scleroderma (34), suggesting a protective role for ROS. Recently, imiquimod-induced psoriatic dermatitis was shown to be prevented by ROS (35). Moreover, phagocyteproduced ROS affects rheumatoid arthritis development (36) and β1,3-glucan of Alcaligenes faecalis-induced ROS from monocytes suppressed innate inflammation (37).…”

Reactive Oxygen Species in Psoriasis and Psoriasis Arthritis: Relevance to Human Disease

“…Most importantly, macrophage-specific ROS production has been reported to suppress T cell responses and arthritis development [138]. It was previously suggested that Tregs under reduced ROS conditions are hypofunctional [139], and recently, Treg hyperfunctionality in elevated levels of ROS in an IMQ-induced Ps dermatitis model was observed [140]. Treg hyperfunctionality with high levels of ROS is suggested to operate as a compensatory mechanism to overcome the damaging effects of ROS and thereby decrease Ps disease activity [140].…”

“…It was previously suggested that Tregs under reduced ROS conditions are hypofunctional [139], and recently, Treg hyperfunctionality in elevated levels of ROS in an IMQ-induced Ps dermatitis model was observed [140]. Treg hyperfunctionality with high levels of ROS is suggested to operate as a compensatory mechanism to overcome the damaging effects of ROS and thereby decrease Ps disease activity [140]. Thus, the restoration of impaired Treg functions could be a possible therapeutic strategy for Ps patients.…”

Anti-Psoriasis Effects and Mechanisms of Α-(8-Quinolinoxy) Zinc Phthalocyanine-Mediated Photodynamic Therapy

“…Recent reports have proposed opposing views. Kim et al [41] investigated IMQ-induced psoriatic dermatitis in association with Treg function both in elevated and lowered levels of ROS and found that IQM-induced psoriasis was attenuated at elevated levels of ROS and was aggravated at reduced levels of ROS. Furuhashi et al [42] found that photo (chemo) therapy reduced circulating Th17 cells and restored circulating regulatory T cells in psoriasis.…”