Introduction
Psoriasis is a chronic inflammatory mediated autoimmune skin disease in which keratinocytes and immune cells play central roles. The characteristic histological findings of psoriasis mainly include the aberrant proliferation of keratinocytes and brisk immune cells infiltration. Erythema and scaling appearance of psoriasis lesions severely impact the patient’s quality of life. At present, the most advanced therapy currently includes neutralizing antibodies and immunosuppressors for treating psoriasis, which is effective but has many disadvantages, including high cost and systemic side effects such as infection of the upper respiratory tract(Hawkes et al. , 2017; Armstrong et al. , 2020). Therefore, there remains a need for novel drugs with improved efficacy and less toxicity.
At present, the pathogenesis of psoriasis remains unclear. Many studies have confirmed that the development and maintenance of psoriasis occur through the interplay between inflammatory factors and keratinocytes(Pasquali et al. , 2019; Ghoreschi et al. , 2021). An increasing body of evidence suggests that IL-17A is a critical inflammatory mediator that mainly targets keratinocytes and drives changes within psoriatic lesions(Martinet al. , 2013; Kirkham et al. , 2014; Blauvelt et al. , 2018). In keratinocytes, IL-17 activates a series of signal transduction factors to induce the production of chemokines (CXCL1, CXCL8, and CCL20) and other inflammatory factors such as antimicrobial peptides (AMPs, including S100A8, S100A9), which recruit T cells and myeloid dendritic cells to the psoriatic lesions(Blauvelt et al. , 2018; Christmann et al. , 2020). The positive feedback loop of inflammation in the local skin lesions amplifies and exacerbates the chronic inflammatory process of psoriasis. Although monoclonal antibodies that block IL-17 are effective for psoriasis, the benefits of reducing the interaction between IL-17 and keratinocytes have not been widely studied.
It is widely acknowledged that inflammation response is initiated by multiple signaling pathways, including the mitogen-activated protein kinase (MAPK) and nuclear factor-kB (NF-κB) signaling(Zhao et al. , 2021). The critical contribution of the MAPK and NF-κB pathways in psoriasis has been documented in multiple studies(Zhanget al. , 2018; Wang et al. , 2021). NF-κB is a critical transcription factor of inflammatory genes, which responds to inflammation by binding to specific promoter elements in target genes. Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6) has been reported to be a signaling adaptor that can regulate the activation of MAPK and NF-κB(Matsumotoet al. , 2018). Ample evidence suggests that IL-17 promotes the expression of inflammatory chemokines and AMPs through NF-κB in keratinocytes(Harper et al. , 2009; Wang et al. , 2013). IL-17 can also induce the signal transducer and activator of transcription 3 (STAT3) phosphorylation to activate the NF-κB(Kimet al. , 2017). Therefore, blocking the IL-17-induced activation of NF-κB is a promising way to alleviate psoriatic dermatitis. The significance of blocking the downstream signal of IL-17 targeting keratinocytes and thus inhibiting the progression of psoriasis warrants further studies.
Natural medicine have become new therapeutic options for the treatment of psoriasis given their good efficacy and few side effects. Garlic is a dietary additive rich in organic sulfur-containing organosulfur compounds, with specific pharmacological properties, such as antioxidant(Zhang et al. , 2006), anti-inflammatory(Wang et al. , 2017), anti-tumor(Sarvizadeh et al. , 2021), immune regulation, and anti-fungal[15](Caporaso et al. , 1983). Allicin (diallylthiosulfinate) is the main active ingredient of garlic, rapidly produced from the non-proteinogenic amino acid S-allyl cysteine sulfoxide (alliin) catalyzed by the alliinase enzyme in the presence of water (Borlinghaus et al. , 2014; Rose et al. , 2019). Given that allicin is not chemically stable and has a short half-life, we extracted stable precursors alliin and alliinase from garlic, which can continuously produce allicin in situ when mixed with an appropriative solvent on the skin tissue. However, the involved mechanism of allicin on anti-inflammatory response in psoriasis has not been documented.
The present study showed that allicin ameliorates imiquimod (IMQ)-induced psoriatic lesions by inhibiting IL-17A expression and abnormal proliferation of keratinocytes. Mechanistically, allicin inhibits IL-17A/IMQ induced NF-κB signaling transcriptional activation and downregulates the expression of chemokines and AMPs in keratinocytes. Our data substantiate the hitherto undocumented therapeutic potential of allicin in alleviating psoriasis.