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).