Discussion
The dynamic interplay between keratinocytes and T cell-derived cytokines is crucial in the initiation and maintenance phases of psoriatic alterations, perpetuating inflammation in a vicious cycle(Jiang et al. , 2020). Keratinocytes play multiple roles in psoriatic skin lesions as the target cell of IL-17 and the producer of cytokines, leading to the infiltration of inflammatory cells. More importantly, keratinocytes are the main initiator of pathological changes in psoriatic skin due to uncontrolled proliferation and differentiation. Our study demonstrates that blocking the feedback between keratinocytes and inflammatory factors is a promising approach for treating psoriasis.
Although traditional treatment therapies are effective, psoriasis is not cured and is often recurrent, emphasizing the importance of long-term safe and effective drugs. Accordingly, nontoxic, widely accessible, and inexpensive natural products have gained momentum as a novel strategy in recent years. Diallyl trisulfide, a sulfur compound found in garlic, has been developed and approved to treat fungal and bacterial infections. The anti-inflammatory, antiviral, and anticancer properties of allicin prompt us to explore its potential in psoriasis. Based on our in vitro and in vivo results, allicin alleviates psoriasis by suppressing inflammation and hyperproliferation. Indeed, the influence of the topical application of allicin on the systemic immune system was negligible compared to systemic administration. Our data identified that allicin treatment did not induce significant changes in body weight and immune organ index values, indicating that allicin treatment was safe, with no significant side effects on mice. The present study substantiates that allicin is a promising natural drug candidate for psoriasis.
We used the first-line drugs corticosteroids (TAE) and topical vitamin D corticosteroid (calcitriol) in the present study as positive control drugs. We demonstrated that allicin treatment has therapeutic effects on inflammation comparable to the positive groups; moreover, improvement of erythema and scales showed higher therapeutic efficacy with allicin than with positive drugs. This finding may be attributed to the fact that current first-line drugs merely inhibit inflammation and suppress proliferation and differentiation of keratinocytes, while the anti-psoriasis effect of allicin is multifaceted. Our results showed that allicin not only decreased IL-17 secretion but also triggered inhibition of keratinocyte viability and cell cycle progression and promoted apoptosis, which directly relieved epidermal swelling.
Keratinocytes are actively involved in the pathogenesis and maintenance of psoriasis by producing various pro-inflammatory factors and chemokines. S100A8/9 and CCL20 are additional factors during IL-17-driven dermal inflammation, which are strongly induced preferentially during the early maturation of keratinocytes(Christmann et al. , 2020; Elnabawi et al. , 2021). Overwhelming evidence substantiates that S100A8/9 and CCL20 are overexpressed in human psoriatic lesions, whereas serum concentrations of S100A8/S100A9 and CCL20 are reliable biomarkers for monitoring disease activity in psoriasis, including psoriatic arthritis or infections, underlining their clinical relevance(Benoit et al. , 2006; Schonthaler et al. , 2013; Austermann et al. , 2017; Dey et al. , 2017; Freise et al. , 2019). Consistent with previous reports, we identified upregulated expression of IL-17-dependent CCL20 and S100a8/9, both in HaCaT cells and in mice psoriatic skin lesions. Our study corroborated that allicin inhibited immune cell infiltration in skin lesions; however, we did not investigate the effect of allicin on systemic immune cells in depth. Mechanistically, allicin inhibited transcription of NF-κB induced by IL-17, which triggered the expression of psoriasis-relevant target genes encoding for CCL20 and S100A8/9. Overall, our data suggest that interfering with IL-17 signaling in keratinocytes is a promising strategy for treating psoriasis. Targeting the IL-17 signaling pathway may improve treatment response and prevent treatment resistance.
Interestingly, it has been reported that allicin inhibits the activation of the MAPK/NF-κB pathway and NLRP3 inflammasome to improve acrylamide-induced hepatotoxicity(Li et al. , 2020). Furthermore, allicin alleviated reticuloendotheliosis virus infection-induced inflammation and oxidative damage by blocking the ERK/MAPK pathway(Wang et al. , 2017). In addition, alliin ameliorated gut inflammation by suppressing MAPKs-PPAR-γ/NF-κB/AP-1/STAT-1 signaling pathways(Shi et al. , 2017). These studies corroborated that allicin yields superior anti-inflammatory effects by regulating MAPKs and NF-κB. During the transcriptome analysis of allicin-treated and IMQ-treated mice lesions, we observed dramatic changes in IL-17-dependent genes expression following IL-17A/F gene expression down-graduation, and substantial enrichment in IL-17 signaling pathways, confirming the in vivo molecular mechanisms of allicin are related to IL-17 signaling in psoriasis. Hyperactivity of the IL-17 signaling pathway in psoriatic lesions further exacerbates the inflammatory response. Importantly, the inhibition of IL-17 and IL-17 signaling blocks various signaling pathways in keratinocytes. In this study, we documented the pivotal role of allicin in blocking the IL-17 signaling pathway, including TRAF6, MAPKs (ERK1/2, P38, JNK), STAT3, and NF-κB (P65).