Th17 cell differentiation pathway

Psoriasis has been considered an immune-mediated skin disease. Emerging evidence suggested the crucial role of Th17 cells in the pathogenesis of psoriasis. TGF-β in combination with proinflammatory cytokines, including IL-23, IL-6, and IL-1β, can drive the differentiation of naive T cells to Th17 cells. IL-23 further promotes the survival and proliferation of Th17 cells, as well as the migration of these cells into psoriatic skin lesions [23]. Th17 cells are considered a distinct subset of CD4⁺ Th cells by the ability to secrete IL-17, however, Th17 cells can also produce various inflammatory cytokines, such as IL-22, IL-21, IL-6, and TNF-α to promote inflammation and keratinocyte proliferation in psoriatic skin lesions [24]. Previous studies demonstrated that the serum levels of TGF-β, IL-17, IL-22, and IL-6 were significantly higher in patients with psoriasis compared with healthy subjects [25, 26].

Water-processed rosin from Pinus massoniana significantly reduced the proportion of Th17 cells in the spleen and inhibited the expression of Th17-related cytokines, including IL-17, IL-22, IL-23, and TNF-α in imiquimod (IMQ)-induced psoriasis-like mouse model [27]. Lavandula angustifolia essential oil and its component linalool showed significant decreases in IL-17 and IL-22 levels in IMQ-induced skin lesions [28]. Treatment with an ethanolic extract of Solanum xanthocarpum stem inhibited the skin expression of IL-17, IL-1β, IL-6, and TNF-α in the psoriasis mouse model [29]. Antrodia cinnamomea extract exerted inhibitory effects on Th17 cell differentiation and the production of IL-17, IL-22, and TNF-α in IMQ-treated mice [30]. Indigo naturalis, an extract from leaves of Baphicacanthus cusia (Ness) Bremek significantly decreased the expression of IL-1β, TNF-α, and IL-23 in keratinocytes, as well as inhibited the production of IL-17 and IL-22 in Jurkat T cells [31]. A methanolic extract of Euphorbia kansui root alleviated psoriasis symptoms by inhibiting the production of IL-23, IL-17, and IL-22 in lymph nodes from psoriatic mice [32].

Baicalin, the major flavonoid from Scutellaria baicalensis, inhibited IL-17 production in lymph nodes and decreased the expression of IL-23, TNF-α, IL-17, and IL-22 in skin lesions of IMQ-induced psoriatic mice [33]. Betulinic acid, a natural terpenoid, showed significant downregulation in the frequency of Th17 cells as well as the production of IL-17, TNF-α, and IL-6 in IMQ-treated mice [34]. Indigodole D extracted from Strobilanthes cusia suppressed IL-17 production in Th17 cells without any cytotoxicity [35]. Isogarcinol, a natural compound derived from Garcinia mangostana L. significantly inhibited Th17 cell differentiation and the expression of Th17-related cytokines, including IL-23, IL-6, TNF-α, IL-17, and IL-22 in a mouse model of psoriasis [36]. Vanillin, a phenolic aldehyde from Vanilla planifolia, suppressed the levels of IL-23 and IL-17 in psoriatic skin lesions [37]. Niazirin, sitosterol-3-O-β-d-glucoside, and marumoside A, three components of Moringa oleifera L., inhibited the production of IL-17, IL-22, and IL-23 in vitro, and reduced IL-17 messenger RNA (mRNA) level in vivo [38].

Gold lotion, an ethanolic extract of a mixture from peels of six citrus fruits, including Citrus sinensis (navel oranges), Citrus hassaku, Citrus limon, Citrus natsudaidai, Citrus miyauchi Iyo, and Citrus unshiu (Satsuma) decreased the ratio of Th17 cells in the spleen and reduced the expression of IL-23, IL-6, TNF-α, IL-17, and IL-22 at mRNA levels in skin lesions in IMQ-induced mouse model of psoriasis [39]. Bai Xuan Xia Ta Re Pian, a traditional herbal formula consisting of six herbs (Euphorbia Humifusae Herba, Chebula Fructus, Terminalia bellirica Fructus, Chebula Fructus Immaturus, Aloe, and Resina Scammoniae) significantly suppressed the expression of IL-23 and IL-17 in the skin of psoriatic mice [40].

NF-κB signaling pathway

NF-κB is a key transcription factor involved in the regulation of various cellular biological processes, including inflammatory responses [41]. Clinical studies in adult patients with moderate to severe psoriasis indicated that the level of the active form of NF-κB was significantly upregulated in psoriatic plaques, compared with non-lesional psoriatic skin and normal skin [42]. NF-κB transcription factor is a homodimer or heterodimer of NF-κB subunits (NFKBs), including p65 (RELA), RELB, p50, p52, and c-REL. In the baseline state, NF-κB dimers form a complex with the inhibitor of NF-κB (IκB) in the cytosol. Upon stimuli such as TNF-α, IκB kinase (IKK) phosphorylates IκB, leading to proteasomal degradation of IκB and releasing of NF-κB from the complex. Free NF-κB dimers translocate from the cytosol into the nucleus and bind to the promoter regions to regulate the transcription of various target genes [43]. NF-κB transcription factor is involved in the pathogenesis of psoriasis by regulating the expression of numerous cytokines, chemokines, and adhesion molecules to modulate inflammation, as well as keratinocyte proliferation and differentiation [42].

An ethanolic extract from leaves of Gynura pseudochina (L.) showed anti-psoriatic properties by inhibiting the translocation of NFKB RELB and suppressing the expression of IL-8 in TNF-α-stimulated HaCaT cells [44]. In vitro study suggested anti-psoriatic effect of three Thai medicinal herbs, including Alpinia galanga, Curcuma longa, and Annona squamosa by reducing the expression of NF-κB signaling-related genes, such as NF-κB1 (p50), NF-κB2 (p52), and RELA in HaCaT cells [45]. Oleoresin from Copaifera langsdorffii Desf. inhibited NF-κB nuclear translocation and decreased the production of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α in lipopolysaccharide (LPS)-stimulated THP-1 monocytes, suggesting its potential in psoriasis treatment [46]. Picea mariana extract decreased the expression of inflammatory molecules IL-6, IL-8, VEGF, and ICAM-1 by promoting phosphorylation and degradation of IκB, as well as suppressing phosphorylation of NF-κB in TNF-α-treated human keratinocytes [47]. Withania somnifera Dunal seed extract inhibited skin inflammation in 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced psoriasis in mice, reduced the expression of NF-κB and decreased the production of pro-inflammatory cytokines IL-6 and TNF-α in LPS-stimulated THP-1 cells [48].

Paeoniflorin, the major bioactive compound from Paeonia lactiflora Pall, alleviated psoriasis-like skin symptoms in IMQ-induced mice and inhibited hyperproliferation by suppressing phosphorylation of IκB-α and NF-κB in psoriatic keratinocytes [49]. cis-Khellactone, a common pyranocoumarin, reduced IMQ-induced psoriasis-like skin inflammation and decreased LPS-induced production of pro-inflammatory cytokines in macrophages by inhibiting phosphorylation of IKKα/β and NF-κB p65 [50]. Aloe polysaccharide, the main constituent of Aloe vera, decreased TNF-α-induced inflammation and proliferation in HaCaT cells by inhibiting phosphorylation of p65 and increasing the expression of IκB-α [51]. Luteolin, a common flavone, showed inhibitory effects on TNF-α-induced production of IL-6, IL-8, and VEGF, as well as hyperproliferation in HaCaT cells and NHEKs by decreasing mRNA levels of two genes (NFKB1 and RELA) and inhibiting nuclear translocation of NF-κB [52]. Chebulanin, a natural polyphenol derived from Terminalia chebula Retz., ameliorated IMQ-induced psoriatic skin lesions in mice and reduced inflammation and proliferation in HaCaT cells by decreasing phosphorylation of p65 at both mRNA and protein levels [53].

PAMs, a mixture of ethanolic extracts from Carthamus tinctorius, Lithospermum erythrorhizon, Solanum indicum, and Cymbopogon distans reduced skin symptoms in a psoriatic mouse model and inhibited the production of inflammatory cytokines and chemokines in HaCaT cells by suppressing nuclear translocation of NF-κB [54].

JAK/STAT signaling pathway

JAK/STAT pathway plays an important role in immune diseases by mediating various cytokine signalings to regulate inflammation and cell proliferation. JAK protein family includes four tyrosine kinases (TYKs): JAK1–3 and TYK2. The STAT family consists of seven members: STAT1–4, STAT5A, STAT5B, and STAT6. Upon binding of type I and II cytokines to their corresponding receptors, JAKs are activated and phosphorylated, leading to the recruitment and phosphorylation of STATs. Phosphorylated STATs can form dimers and translocate to the nucleus to regulate the transcription of various target genes involved in immune responses [55, 56]. Upregulated expression of JAK1 and STAT3 has been reported in skin lesions from patients with psoriasis, compared with normal skin. In addition, STAT3 expression had a positive correlation with the severity of psoriasis [57]. A variety of inflammatory cytokines related to psoriasis, such as IL-6, IL-23 can activate JAK/STAT signaling pathway to promote the development of psoriasis by triggering inflammatory response as well as keratinocyte proliferation in skin lesions [58]. Inhibition of JAK/STAT pathway by JAK inhibitors such as tofacitinib improved disease severity in patients with moderate-to-severe psoriasis [59], suggesting that modulation of JAK/STAT signaling pathway might a potential approach for psoriasis treatment.

An ethanolic extract of Illicium verum Hook. f. exhibited therapeutic potential for psoriasis by suppressing IFN-γ-induced ICAM-1 production in HaCaT cells via inhibiting JAK/STAT signaling pathway and decreasing the adhesion between T cells and keratinocytes [60]. Rehmannia glutinosa root extract alleviated epidermal thickening and skin levels of proinflammatory cytokines (IL-6, IL-17, IL-23, TNFα) in the IMQ-induced psoriasis mouse model by suppressing phosphorylation of JAK1, JAK2, STAT1, and STAT3 [61]. Multi-glycoside of Tripterygium wilfordii Hook. f. inhibited the expression of IL-17 and IL-22 in psoriasis mice by suppressing STAT3 signaling pathway [62]. Cryptotanshinone, a bioactive compound from Salvia miltiorrhiza Bunge. ameliorated psoriasis-like symptoms in IMQ-treated mice and reduced keratinocyte hyperproliferation by inhibiting STAT3 signaling pathway [63]. Shikonin, a main component of Leptospermum erythrorhizon improved skin severity in psoriasis mice and inhibited proliferation, promoted apoptosis, and decreased VEGF production in IL-17-stimulated HaCaT cells by suppressing activation of JAK/STAT3 signaling [64, 65].

JAK/STAT and related signaling pathways

Studies indicated the involvement of JAK/STAT, particularly STAT3 signaling pathway in Th17 differentiation from naive T cells, leading to the production of various inflammatory cytokines, such as TNF-α, IL-17, IL-21, and IL-22 [66, 67]. Hyperactivation of STAT3 signaling triggered Th17 differentiation, while STAT3-deficiency resulted in impairment of Th17 differentiation in T cells [67]. Tofacitinib, an inhibitor of JAK/STAT pathway significantly inhibited the production of Th17 cytokines (IL-17, IL-22) [68]. In turn, IL-22 binds to its receptor and activates several downstream pathways, including JAK/STAT3, MAPK, and PI3K/Akt/mTOR signaling pathways [69–71]. Other cytokines involved in Th17 differentiation, such as IL-6 and IL-23 also contributed to JAK/STAT activation [58].

A methanolic extract of root bark of Dictamnus dasycarpus Turcz. improved scaly skin lesions, reduced the number of inflammatory cell infiltration, and decreased epidermal thickness in IMQ-induced psoriasis mice by inhibiting STAT3 signaling pathway and reducing the number of Th17 cells as well as IL-17 production [72]. 9,19-cycloartenol glycosides G3, the main component of Cimicifuga simplex exhibited anti-psoriatic effects by suppressing the differentiation of CD4+ T cell into Th17 phenotype and inhibiting IFN-γ-induced JAK/STAT activation [73]. Withasteroid B isolated from Datura metel L. showed the inhibitory effects on JAK/STAT signaling pathway and reduced the ratio of Th17 cells as well as the production of Th17-related inflammatory cytokines [74]. Total glucosides extracted from Paeonia lactiflora Pall alleviated IMQ-induced psoriasis-like skin symptoms in mice, inhibited Th17 differentiation, and suppressed phosphorylation of STAT1 and STAT3 [75].

Dang Gui Liu Huang Tang, a traditional herbal formula consisting of Angelica acutiloba Kitag., Rehmannia glutinosa Libosch., Scutellaria baicalensis Georgi., Astragalus membranaceus Bunge., Coptis chinensis Franch., and Phellodendron amurense Rupr., improved psoriasis symptoms in IMQ-induced mice and reduced the production of inflammatory cytokines and chemokines, as well as suppressed hyperproliferation in human keratinocytes by inhibiting the activation of STAT3 and MAPK signaling pathways [76]. PSORI-CM02, a traditional formula including five herbs, Smilax glabra Roxb., Sarcandra glabra (Thunb.) Nakai, Paeonia lactiflora Pall, Curcuma phaeocaulis Val., and Prunus mume Sieb. et Zucc., showed anti-psoriatic effects by suppressing STAT1/6 and PI3K/Akt/mTOR signaling pathways in keratinocytes and immune cells [77, 78].

NF-κB and related signaling pathways

NF-κB pathway can be activated by several upstream pathways, including PI3K/Akt and MAPK signalings to regulate inflammation [79, 80]. Nrf2 signaling can attenuate NF-κB activation, and in contrast, NF-κB could suppress Nrf2 activity [81]. NF-κB and JAK/STAT signaling pathways are involved in the regulation of inflammatory response in psoriasis. A previous study demonstrated that JAK/STAT signaling synergized with NF-κB to activate the transcription of various inflammatory genes in response to stimuli [82]. NF-κB activation also modulates many downstream signaling pathways which are involved in the pathogenesis of psoriasis. NF-κB signaling shows intrinsic and extrinsic effects on Th17 differentiation [83]. VEGF signaling, which is important in regulating angiogenesis (a hallmark of psoriasis), is also a downstream pathway of NF-κB [84]. Moreover, NF-κB pathway was suggested to be involved in NLRP3 inflammasome activation in psoriasis [85].

Astragalus sinicus L. extract suppressed the production of inflammatory molecules in TNF-α/IFN-γ-stimulated human keratinocytes and IL-23-induced psoriasis-like mouse model by inhibiting NF-κB, STAT1/3, and PI3K/Akt signaling pathways [86]. An aqueous extract of Actinidia arguta shows inhibitory effects on IMQ-induced cutaneous inflammation and cytokine-induced inflammation and hyperproliferation in HaCaT cells by suppressing phosphorylation of NF-κB p65 and STAT1/3 [87]. Extracts from Sinapis Alba Linn and Datura metel L. exerted anti-psoriatic effect by inhibiting NF-κB and NLRP3 inflammasome signaling pathways [88–90].

Chrysin, a common flavone found in various natural sources, such as honey, passion flowers, or propolis, alleviated IMQ-induced psoriasis symptoms in mice and inhibited the production of inflammatory cytokines, chemokines, and antimicrobial peptides in keratinocytes by suppressing NF-κB, MAPK, and JAK/STAT signaling pathways [91]. Glycyrrhizin, a major component of Glycyrrhiza glabra, improved psoriasis-like skin lesions in IMQ-induced mice and reduced ICAM-1 production in TNF-α-stimulated HaCaT cells by inhibiting NF-κB/MAPK signaling [92]. Tussilagonone, a natural compound derived from Tussilago farfara, alleviated psoriasis symptoms in IMQ-treated mice and TNF-α-treated keratinocytes via Nrf2 activation and NF-κB/STAT3 inhibition [93]. Curcumin, a main compound of Curcuma longa, attenuated psoriasis pathology by inhibiting and NF-κB and Th17 differentiation pathways in keratinocytes and immune cells [94–96]. Honokiol (a lignan isolated from Magnolia officinalis) and gambogic acid (a xanthone from Garcinia harburyi) showed the anti-psoriatic effect by suppressing NF-κB/VEGF signaling pathway [97, 98]. Saikosaponin A, a component of Bupleurum chinense, reduced psoriasis area and severity index (PASI) scores and epidermal hyperplasia in IMQ-induced mice and attenuated cytokine-induced inflammation in human keratinocytes by suppressing the phosphorylation of NF-κB and the expression of NLRP3 [99].

PSORI-CM01, a herbal formula consisting of seven plants Curcuma zedoaria, Sarcandra glabra, Smilax glabra Roxb., Prunus mume, Arnebia euchroma (Royle) Johnst., Paeonia lactiflora, and Glycyrrhiza uralensis, exerted the anti-psoriatic effect by suppressing the translocation of NF-κB p65 and inhibiting Th17 differentiation signaling [100]. Psoriasis 1, a mixture of 12 herbs including Smilacis glabrae, Folium isatidis, Isatis tinctoria L., Angelica sinensis, Hedyotis diffusa, Ligusticum striatum, Plantago major, Kochia scoparia, Lobelia chinensis, Alisma orientale, Dictamnus dasycarpus Turcz., and Glycyrrhiza uralensis, alleviated psoriasis inflammation by inhibiting the phosphorylation of IKK, NF-κB p65, STAT3, and STAT4 in keratinocytes and T cells [101, 102].