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.