Recently, a growing number of studies have shown that natural compounds extracted from plants have satisfying effects for the treatment of human diseases. For example, artemisinin, which is extracted from Artemisia annua L., is the most widely used natural compound against malaria and plays a vital role in the treatment of malaria worldwide (Ma et al., 2020). Cruciferous vegetables have been considered sanatory, and can reduce the risk of chronic diseases (Raiola et al., 2017). The bioactive compounds that have been reported are ascorbic acid, phenolics, carotenoids, and glucosinolates (Peluso and Palmery, 2014). Sulforaphane, also known as isothiocyanate 1-isothiocyanato-(4R)-(methylsulfinyl) butane (Figure 1A), is a kind of isothiocyanate that is a hydrolysate of glucosinolates produced by the enzyme myrosinase in cruciferous vegetables (Raiola et al., 2017). Sulforaphane has been reported to exhibit the anti-inflammatory, antioxidant, and antitumour activities. Sulforaphane exerted an anti-inflammatory effect by regulating MAPK signaling in lipopolysaccharide (LPS)-induced microglia (Subedi et al., 2019). Furthermore, sulforaphane exerts therapeutic effects on diabetic nephropathy by upregulating nuclear factor-like 2 (Nrf2) antioxidant signaling (Li et al., 2020). In addition, the antitumour effects of sulforaphane in clinical therapy range from the attenuation of DNA damage to regulation of the cell cycle by activating the transcription factor Nrf2 (Russo et al., 2018). However, whether sulforaphane has therapeutic effects on inflammatory or autoimmune skin diseases, including psoriasis and systemic lupus erythematosus (SLE), is unclear.

Psoriasis is a chronic inflammatory immune-related skin disease characterized by erythema, scales, epidermal hyperplasia, and infiltration of inflammatory cells (Beek and van Reede, 1977). The release of proinflammatory mediators and cytokines has been identified in the skin and systemically (Nickoloff et al., 2007). Dysfunction of T lymphocytes, especially Th1 and Th17 subtypes, causes the overexpression of interferon-γ, interleukins, and tumor necrosis factor (Wu et al., 2018). Notably, oxidative stress is involved in the pathogenesis of psoriasis. A number of oxidative stress-related markers are increased in the plasma or serum of psoriatic patients, such as ischaemia-modified albumin (Kirmit et al., 2020), catalase (Kirmit et al., 2020), malondialdehyde (Kadam et al., 2010), and nitric oxide (Gabr and Al-Ghadir, 2012). Furthermore, the elevated levels of reactive oxygen species (ROS) are caused by active oxidative stress and initially trigger the abnormal activation of Th1 and Th17 cells (Lai et al., 2018). Moreover, ROS act as secondary messengers that induce activation of the MAPK, NF-κB, and JAK-STAT signaling pathways, amplifying the inflammatory response (Lin and Huang, 2016). Therefore, targeting oxidative stress may be a therapeutic strategy for psoriasis. IMQ-induced psoriasis-like skin inflammation is characterized by acanthosis, parakeratosis, and infiltration of inflammatory cells, which resemble human psoriasis. The mouse model uses the daily topical application of imiquimod (IMQ), a TLR7/8 ligand, to induce the inflammation of skin (Singh et al., 2019). The model is used to investigate the molecular and cellular pathogenesis of psoriasis in preclinical studies, as well as in the evaluation of potential therapies.

SLE is a systemic autoimmune disease that affects multiple organs, including the skin, kidney, and joints. The pathogenesis of SLE has not yet been clarified. The loss of immunologic tolerance causes the aberrant activation of autoreactive T cells and B cells, inducing massive autoantibodies production. Eventually, complement activation and the deposition of immune complexes lead to organ damage. In SLE, neutrophil extracellular traps released by neutrophils enhance the activation of inflammasomes and accumulate due to impaired degradation, causing increased anti-dsDNA production (Yu and Su, 2013). Dysfunction of dendritic cells is associated with the development of SLE. Inappropriate antigen presentation by dendritic cells promotes the loss of immunologic tolerance, accelerating the progression of SLE (Tsokos et al., 2016). Oxidative stress is closely related to the progression of SLE. Excessive production and impaired clearance of ROS induce dysfunction in T cells (Perl, 2013). In addition, oxidative modification of self-antigens triggers autoimmunity, leading to the acceleration of SLE (Perl, 2013). Studies have demonstrated that blocking the antioxidant signaling pathway reduces lifespan and increases autoantibodies, aggravating renal damage (Yoh et al., 2001). The elevated oxidative stress correlates with disease activity and organ damage. Thus, antioxidant therapy might provide an important strategy to ameliorate SLE. MRL/MpJ-Fas^lpr/lpr (MRL/lpr) mice are the defect of Fas gene on MRL/MpJ background, which fail to eliminate autoreactive lymphocytes, inducing spontaneous autoimmune phenotypes. The clinical manifestations of MRL/lpr mice resemble human SLE, including skin lesion, glomerulonephritis, arthritis, circulating anti-nuclear antibodies (ANA), and depositions of immune complexes and complements (Watanabe-Fukunaga et al., 1992). MRL/lpr mice are used to study molecular and cellular pathogenesis of SLE in preclinical studies and evaluation of potential therapies.

To clarify the effects of sulforaphane on psoriasis, we studied the differences in skin inflammation and changes in Th subtypes in IMQ-induced psoriasis-like mice treated with sulforaphane or vehicle control Our findings suggested that sulforaphane reduced the percentages of Th1 and Th17 cells to inhibit skin inflammation. Moreover, we investigated the potential therapeutic effect of sulforaphane on SLE. Sulforaphane increased the lifespan and reduced the renal damage in lupus-like mice and decreased the percentages of plasma cells, Tfh cells, neutrophils, and dendritic cells. These results indicated that sulforaphane is a natural compound with therapeutic effects on skin inflammation and autoimmune diseases.

We found that the administration of sulforaphane ameliorated the IMQ-induced psoriasis-like skin inflammation and renal damage in lupus-prone MRL/lpr mice. In IMQ-induced psoriasis-like mice, sulforaphane reduced the proportions of Th1 and Th17 cells and induced the expression of the antioxidant gene Prdx1. Furthermore, our results demonstrated that sulforaphane increased the lifespan and reduced renal damage in lupus-prone MRL/lpr mice, decreased the proportions of plasma cells, Tfh cells, neutrophils, dendritic cells, and the concentration of MDA and induced the expression of antioxidant gene Prdx1.

Sulforaphane, which is found in cruciferous vegetables, is an activator of nuclear factor E2-related factor 2 (Nrf2). The antioxidant Nrf2 can suppress lupus nephritis by reducing oxidative stress and the NF-κB signaling pathway (Jiang et al., 2014). Peroxiredoxin 1 (Prdx1) is a member of the peroxiredoxin family that acts as an antioxidant enzyme to catalyze the reduction of hydrogen peroxide (Park et al., 2016). Studies have shown that Prdx1 decreased ROS to protect against oxidative stress (Ding et al., 2017). Quinone oxidoreductase (NQO1), which belongs to the Phase II detoxification enzyme family, catalyzes the two-electron reduction of quinone to the redox-stable hydroquinone (Luo et al., 2019). Nqo1, which exerts antioxidant activity to protect against oxidative stress, is induced by sulforaphane and reduces the neuro-cytotoxicity of DA quinone (Han et al., 2007). Haem oxygenase-1 (Hmox1) and glutathione synthetase (Gss) are also antioxidant enzymes, downstream of the Nrf2 signaling pathway (Lu, 2009; Zhao et al., 2019). We found that Prdx1 expression was upregulated in IMQ-induced psoriasis-like mice and MRL/lpr mice after treatment with sulforaphane, suggesting that sulforaphane exerted the antioxidant effects dependent on the activation of Prdx1.

Psoriasis is a chronic hyperplastic skin disease induced by multiple genetic and environmental factors that affects approximately 0.1–3% of the global population (Boehncke, 2018; Rendon and Schakel, 2019). The abnormally differentiated Th1 and Th17 cells release proinflammatory cytokines, including IFN-γ, IL-17, IL-22, and TNF-α, to increase the cutaneous inflammatory response (Benhadou et al., 2019). Th1 cells increase the production of IL-2, TNF-α, and IFN-γ, participating in the development of psoriasis (Rodriguez-Cerdeira et al., 2019). The enhanced Th1 response increases inflammation by upregulating many cytokines, including IL-1, IL-6, IL-8, IL-12, IL-15, interferon-inducible protein-10, and iNOS, to promote keratinocyte proliferation (Grossman et al., 1989; Xie et al., 1993; Rich and Kupper, 2001; Behnam et al., 2005). IL-17 targets innate immune cells, keratinocytes, and endothelial cells, and is the major effector cytokine that drives the pathogenesis of psoriasis (Blauvelt and Chiricozzi, 2018). In this study, our results demonstrated that sulforaphane reduced the percentages of Th1 and Th17 cells to ameliorate acanthosis and dermal inflammatory cell infiltration in IMQ-induced psoriasis-like skin inflammation. ROS-mediated oxidative stress is involved in numerous signaling pathways related to the inflammatory response, contributing to the progression of psoriasis (Briganti and Picardo, 2003). As an antioxidant therapy, dimethylfumarate (DMF) has been used for the treatment of psoriasis and has shown a high degree of efficacy (Rostami and Mrowietz, 2008). Sulforaphane, as an antioxidant, induces the expression of antioxidant gene Prdx1, contributing to the recovery of psoriasis.

SLE is a complicated multifactorial autoimmune disease. The molecular mechanisms remain voluminously unknown. An imbalance in the production and degradation of ROS causes the oxidative modification of DNA, inducing DNA damage (Shah et al., 2014). Dendritic cells recognize the self-antigens and present them to B cells, triggering the autoimmune response and excessive production of autoantibodies (Herrada et al., 2019). Tfh cells assist B cells in inducing autoimmune response, playing an important role in the pathogenesis of SLE (Blanco et al., 2016). The deposition of immune complexes recruits neutrophils, inducing local inflammation and damage (Kaplan, 2011). In our study, the administration of sulforaphane decreased the percentages of plasma cells, Tfh cells, neutrophils, and dendritic cells. Moreover, sulforaphane induced the expression of Prdx1 to protect against oxidative stress. N-acetyl cysteine has been reported to attenuate oxidative stress in SLE, suggesting that the antioxidant therapy might be a promising strategy for the treatment of SLE.

In this study, we found that sulforaphane reduced the proportions of Th1 and Th17 cells and the concentration of MDA. Similarly, sulforaphane decreased the proportions of plasma cells, Tfh cells, neutrophils, and dendritic cells. We also found that the expression of antioxidative gene Prdx1 was upregulated in the sulforaphane-treated group. It was reported that CYP11A1-derived vitamin D3- and lumisterol-hydroxy derivatives protected primary human keratinocytes against radiation and UVB-induced damage, which is associated with Nrf2-regulated antioxidants responses (Chaiprasongsuk et al., 2019; Slominski et al., 2020). Previous study showed that the oxidative stress and molecular modifications induced by oxidative stress caused the massive activation of immune cells (Lightfoot et al., 2017). We speculated that the activation of NRF2 signaling and reduced oxidative stress contributed to inhibition of activation of immune cells. Moreover, there are other possible mechanisms that sulforaphane ameliorate skin lesion and renal damage. 20(OH)D₃ and 20,23(OH)₂D₃ play as antagonists of RORα and RORγ to inhibit the activity of IL17 promoter (Slominski et al., 2014). In addition, we suppose that sulforaphane functions as a ligand of transcription factor to inhibit differentiation of immune cells. We conducted the macromolecular docking using the crystal structure of RORγT and sulforaphane. Interestingly, the docking score revealed that sulforaphane might bind to RORγT as a ligand (Supplementary Figure S4 and Supplementary Table 2). We will further study the underlying molecular mechanisms of sulforaphane-induced antioxidation and repression of autoimmune activities in psoriasis and SLE. Moreover, because this condition involves a local inflammatory response, sulforaphane might have a higher degree of efficacy when administered locally in IMQ-induced psoriasis-like skin inflammation.

In conclusion, the results of this study showed that sulforaphane improve the skin lesion of IMQ-induced psoriasis-like mice and the renal damage in lupus-like mice by inhibiting inflammatory and autoimmune responses and oxidative stress. This evidence suggests the potential value of sulforaphane in treating psoriasis and SLE and highlights the use of antioxidant therapy in inflammatory and autoimmune diseases.