Dithranol targets keratinocytes, their crosstalk with neutrophils and inhibits the IL-36 inflammatory loop in psoriasis

With the development and market introduction of biologics, much progress has been made in recent years in the systemic treatment of psoriasis. Currently, targeted therapy with antibodies against IL-17 or IL-23 exhibits high efficacy and allows complete or almost complete clinical clearance of psoriasis lesions in a high percentage of cases (Blauvelt et al., 2017; Langley et al., 2014; Papp et al., 2017; Reich et al., 2018). However, patients with limited body area involvement (i.e. mild forms of psoriasis) who represent the majority of psoriasis patients with up to 90% (Stern et al., 2004) have been neglected. Not much innovation has occurred in the past few years on topical treatment of psoriasis that is mainly prescribed to these patients. Steroids, vitamin D3 and vitamin A analogues are most commonly used as topical agents in such patients, but besides changes in their pharmaceutical formulation, they have not been developed further in recent years (de Korte et al., 2008; Krueger et al., 2001; Langley et al., 2011; Schaarschmidt et al., 2015). Short courses of dithranol (1,8-dihydroxy-9-anthracenone or anthralin) have been successfully used as intermittent topical treatment of psoriasis since 1916 (Nast et al., 2012; Sehgal et al., 2014; Vleuten et al., 1996). Despite its numerous disadvantages like brown staining and irritation of perilesional skin, dithranol has remained one of the most effective topical treatment modalities in psoriasis. Analogous to the most recent generation of biologics (including anti-IL-17 and anti-IL-23 antibodies), dithranol delivers PASI75 rates in 66–82.5% of patients with fast action and clearance of skin lesion within very few weeks (Kemény et al., 1990; Painsi et al., 2015b; Sehgal et al., 2014; van de Kerkhof, 2015). Although dithranol has been used for many years, its exact mechanism of action has remained largely unknown (Holstein et al., 2017; Kemény et al., 1990; Kucharekova et al., 2006; Sehgal et al., 2014).

With the aim of unraveling dithranol’s therapeutic mechanisms and to possibly uncover new targets for topical treatment of psoriasis, we conducted a clinical trial and employed several mouse models including the c-Jun/JunB knockout model (Zenz et al., 2005) and the imiquimod psoriasis model (van der Fits et al., 2009) in order to address this issue and elucidate dithranol's effects. In this study, we demonstrate that dithranol exerts its anti-psoriatic effects by directly targeting keratinocytes and their crosstalk with neutrophils, as well as disrupting the IL-36 inflammatory loop. Consistent with this finding, we observed that dithranol’s therapeutic activity was completely independent of its pro-inflammatory effect mainly on perilesional skin, thus overthrowing the long-believed paradigm that dithranol-induced irritation is crucial for its anti-psoriatic action and unraveling irritation merely as a bystander effect of treatment.

This study demonstrates that topical dithranol directly targets keratinocytes (in particular their differentiation regulators and AMPs), keratinocyte-neutrophil crosstalk and inhibits the IL-36 inflammatory loop in psoriasis, thus unraveling after over 100 years of use, the therapeutic mechanism of one of the most effective topical treatments of psoriasis. Dithranol significantly diminished mRNA expression of pro-psoriatic IL-1 family members (IL36A, IL36G and IL36RN) (Supplementary file 1 and Figure 4). At day 6 after start of dithranol treatment, PASI had decreased by 33%, but at week 2–3 we saw a reduction of 58%, an effect that was paralleled by reduced expression of IL-36-related genes in psoriasis patients. The therapeutic importance of reduction of IL-1 family members in human skin was substantiated by results generated in the keratinocyte-based c-Jun/JunB mouse psoriasis model (Zenz et al., 2005). Expression of IL36RN (murine Il1f5) and IL36B (Il1f8) was significantly reduced in dithranol-treated psoriatic c-Jun/JunB lesions compared to controls (Figure 4) and among the top differentially expressed genes in our human and mouse dataset were genes involved in keratinocyte and epidermal differentiation (Table 4, Table 7). Dithranol strongly reduced mRNA expression of the keratinocyte differentiation regulator involucrin (IVL) and members of the serpin family (SERPBINB7, SERBINB13) both in lesional skin of patients and c-Jun/JunB knockout mice (Figure 4). Moreover, dithranol downregulated expression of AMPs such as ß-defensins (DEFB4A and DEFB4B) produced by keratinocytes (Liu et al., 2002; Schröder and Harder, 1999) within 6 days and chemotactic factors for neutrophils (such as CXCL5 and CXCL8) (Albanesi et al., 2018; Table 2) and neutrophilic infiltration (as determined by MPO staining) within 2–3 weeks of treatment in human psoriatic skin (Figure 2).

Surprisingly, there were no significant changes in overall T cell numbers including CD4+ and CD8+ T cells, as well as FoxP3 positivity indicative for regulatory T cells in the skin in the early phase (within 6 days) during dithranol treatment. Reflecting dithranol’s primary effect on the epidermal compartment, the reduction of T cell numbers in the epidermis preceded that in the dermis. Whereas dithranol had decreased T cell counts in the epidermis at week 2–3, an effect on T cell numbers in the dermis was only evident at the follow-up visit, 4–6 weeks after the end of dithranol treatment (Figure 2), in agreement with previous reports favoring dithranol’s effect on keratinocytes (Holstein et al., 2017; Swinkels et al., 2002a; Vleuten et al., 1996; Yamamoto and Nishioka, 2003).

Vleuten et al., 1996 and Swinkels et al., 2002a applied immunohistochemistry to analyze differentiation and proliferation markers as well as T cell numbers in the skin and observed, as we did, a decrease in keratin 16, restoration of filaggrin and a decrease of Ki67 in the epidermis after 2 weeks of dithranol treatment. However, their data on the effect of dithranol on dermal T cell numbers at 4 weeks was controversial (Swinkels et al., 2002a; Vleuten et al., 1996). The group of Eberle recently tested the effects of dithranol using primary keratinocytes, a 3D psoriasis tissue model and some biopsy samples from psoriasis patients and reported on a reduction in Ki67 and keratin 16 positive cells in the epidermis using immunostaining and an inhibition of the antimicrobial peptide DEFB4 using qPCR analysis. However, based on their observations, they concluded that dithranol’s anti-psoriatic effects cannot be explained by direct effects on keratinocyte differentiation or cytokine expression (Holstein et al., 2017).

Our genome-wide expression analysis indicates that dithranol primarily targets keratinocytes and that this is crucial for response to treatment, considering that differentially regulated genes in histological responders compared to non-responders belonged to pathways like keratinocyte differentiation, cornification and keratin filament formation (Supplementary file 3). The importance of dithranol’s direct effect on keratinocytes has been further substantiated by our findings generated using the mouse-tail model, a simple in vivo model to analyze effects of topical preparations on keratinocyte differentiation and parakeratosis (Bosman et al., 1992; Sebök et al., 2000; Wu et al., 2015). Similar to previous studies (Bosman et al., 1992; Hofbauer et al., 1988; Sebök et al., 2000; Wrench and Britten, 1975), we observed a strong increase in orthokeratosis after dithranol application in the mouse-tail test, reflecting its keratinocyte differentiation-inducing activity (Figure 3—figure supplement 1). Our transcriptional analysis indicated that the effect of dithranol in the mouse-tail test was linked to a strong upregulation of keratinocyte differentiation markers and several AMPs, while the pro-psoriatic antimicrobial peptide Camp/LL37 was downregulated, as well as Cxcl5, a chemotactic factor for neutrophils (Figure 3—figure supplement 2), but not other pro-psoriatic AMPs (Fritz et al., 2017; Wang et al., 2018) such as Defb3, S100a8 or S100a9. Although the mouse-tail test has evidently limitations since the disturbed cell differentiation of this model only reflects one of many aspects of psoriasis, it supports the primary effect of dithranol on keratinocytes with induced induction of orthokeratosis.

In contrast to its therapeutic effect in both keratinocyte-driven psoriasis models, the c-Jun/JunB model and mouse-tail test, dithranol did aggravate psoriatic lesions in the imiquimod model that has been solely shown to be immunologically mediated and dependent on the IL-17/IL-23 axis (van der Fits et al., 2009). In the latter model, biologics such as etanercept and anti-IL-17a agents (Liu et al., 2018), topical steroids (Sun et al., 2014) and vitamin d3 analogues (Germán et al., 2019) but also UVB and PUVA (Shirsath et al., 2018) were shown to have a beneficial effect. In contrast, dithranol significantly enhanced overall macroscopic skin thickness, consistent with a slight increase in epidermal hyperplasia and worsened inflammation (as measured by the density of cellular infiltrate in the dermis) (Figure 3—figure supplement 3). Dithranol treatment of healthy murine skin led to similar effects upon irritation, as it increased epidermal thickness and cellular infiltrate of the skin (data not shown). However, the irritant effect of dithranol may remain without functional anti-psoriatic relevance in human psoriasis (as indicated by the clinical results depicted in Figure 1—figure supplement 2 and discussed below) but might be crucial in the agent's therapeutic action in alopecia areata (Nasimi et al., 2019; Ngwanya et al., 2017).

Together, these data unambiguously demonstrate that dithranol directly acts on keratinocytes, their crosstalk with neutrophils and IL-36 signaling, with AMPs being the potential link (Figure 5). This goes also in line with the observation that Langerhans cells as another type of immune cells showed a delayed response to dithranol, with no changes during treatment and an evident increase in numbers only later on (at the follow-up visit 4–6 weeks after end of treatment). These results are consistent with previous studies performed by Swinkels et al., showing that there was no significant change in T cells or Langerhans cells during twelve days of dithranol treatment (Swinkels et al., 2002a).

Figure 5

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Our findings on dithranol’s effect on members of the IL-1 family, being beneficial for its anti-psoriatic efficacy, are well in line with recent work on blockade of IL-36 pathway as a novel strategy for the treatment of pustular psoriasis (Bachelez et al., 2019) as well as plaque-type psoriasis (Benezeder and Wolf, 2019; Mahil et al., 2017). Notably, human keratinocytes express IL-1 family members (IL-36α, IL-36β, IL-36γ, IL-36Ra) and their receptor IL-36R (D'Erme et al., 2015; Foster et al., 2014; Johnston et al., 2017). Furthermore, normal human keratinocytes show increased expression of IL-1 group mRNA after treatment with psoriasis-associated cytokines (TNFα, IL-1α, IL-17,IL-22) (Johnston et al., 2011). Genome-wide association studies revealed that deficiency in interleukin-36 receptor antagonist due to IL36RN mutations was associated with generalized pustular psoriasis (GPP) (Marrakchi et al., 2011; Sugiura et al., 2013). Supporting this notion, blocking IL-36 receptor was effective in reducing epidermal hyperplasia and showed comparable effects to etanercept in a psoriatic skin xenotransplantation model (Blumberg et al., 2010). Furthermore, successful treatment of psoriasis with the anti-psoriatic standard treatment etanercept is accompanied by a decrease in IL36A, IL36G and IL36RN expression (Johnston et al., 2011). A recent clinical phase one study provided proof-of-concept for the efficacy of BI 655130, a monoclonal antibody against the interleukin-36 receptor in the treatment of generalized pustular psoriasis (Bachelez et al., 2019). Intriguingly, topical short-contact dithranol therapy is efficacious not only in plaque-type psoriasis, but under certain conditions (i.e. after stabilization of disease activity with bland emollients) reportedly also in pustular psoriasis (Farber and Nall, 1993; Gerritsen, 1999). In this neutrophilic-driven condition, in which one might expect that dithranol worsens a heavy inflammatory state, it may have beneficial capacity by targeting the IL-36 pathway and neutrophils, both playing a most crucial role in this type of psoriasis (Bachelez, 2018; Bachelez et al., 2019; Johnston et al., 2017; Marrakchi et al., 2011; Sugiura et al., 2013).

As outlined above, we observed a strong effect of dithranol on keratinocyte-neutrophil crosstalk. Importantly, early response to anti-IL-17a blockade, as one of the most effective biological treatments currently available, has been linked to inhibition of keratinocyte-neutrophil crosstalk (Reich et al., 2015). Similar to our observation, anti-IL-17a treatment with secukinumab significantly reduced epidermal hyperproliferation after 2 weeks, decreased mRNA expression of keratinocyte-derived chemotactic factors and led to a strong decrease in IL-17a positive neutrophils. Apparently, disrupting the crosstalk between keratinocytes and neutrophils may be a crucial early effect in the clinical efficacy of secukinumab in psoriasis (Reich et al., 2015). In addition, decreased expression of AMPs like ß-defensin and S100 proteins was observed after only 1 week of anti-IL-17a treatment with secukinumab (Krueger et al., 2019) and after 2 weeks of ixekizumab treatment (Krueger et al., 2012), well in line with our observed early effect of dithranol on AMPs. Krueger et al. concluded that clinical efficacy of anti-IL-17a treatment is closely linked to early inhibition of keratinocyte-derived products such as chemokines and AMPs. Together this suggests that dithranol’s direct action on keratinocytes at the molecular level may disrupt IL-17 pathway dysregulation (without directly blocking IL-17 or its receptor), leading in turn to similar downstream effects as treatment with anti-IL-17 antagonists.

Our study also negates the paradigm that dithranol-induced irritation is crucial for its anti-psoriatic action (Gerritsen, 1999; Kucharekova et al., 2005; Prins et al., 1998; van de Kerkhof, 1991; Wiegrebe and Müller, 1995). As depicted in Figure 1—figure supplement 2, there was no correlation between dithranol-induced perilesional as well as lesional erythema and its anti-psoriatic effect, indicating that dithranol’s irritation (Prins et al., 1998; Swinkels et al., 2002c; Swinkels et al., 2002b) is a treatment side-effect unrelated to its therapeutic mechanism. However, this irritant effect of dithranol may be crucial for its action in alopecia areata, a condition, in which it was shown to be greatly effective, leading to hair regrowth in a high percentage of cases (Ngwanya et al., 2017). Similar to other topical treatment options (Nasimi et al., 2019; Yoshimasu and Furukawa, 2016), an initial irritant reaction to dithranol is followed by regrowth of hair within weeks after treatment.

What our work does not answer, is how dithranol exactly acts at the molecular level. Cell culture studies have shown that dithranol targets mitochondria (McGill et al., 2005), alters cellular metabolism (Hollywood et al., 2015) and induces apoptosis in keratinocytes (George et al., 2013; McGill et al., 2005). Dithranol also inhibits human monocytes in vitro, inhibiting secretion of IL-6, IL-8 and TNFα (Mrowietz et al., 1992; Mrowietz et al., 1997). Its effects on neutrophils were also shown in vitro, where dithranol leads to an increase in superoxide generation and a decrease in leukotriene production in neutrophils (Kavanagh et al., 1996; Schröder, 1986). Moreover, the potential receptor of dithranol remains undefined. Anti-psoriatic effects of other topical treatment options have recently been linked to modulation of the aryl hydrocarbon receptor (AhR) (Smith et al., 2017) and AhR may play a role in pathogenesis of psoriasis (Di Meglio et al., 2014). However, it appears that dithranol does not act via modulation of AhR, as we did not observe differences in the response of skin to dithranol comparing AhR knockout mice to controls (data not shown). There is need for further studies investigating how dithranol exactly acts on the molecular level, which receptor it potentially binds to or inhibits or whether it acts through modulation of a specific transcription factor such as NF-kB or STATs. Another question is whether the effect of dithranol is specific compared to other topical treatments such as steroids and vitamin D3 analogues. There seem to be some overlapping mechanisms between dithranol and vitamin D3 analogues such as calcipotriol that has been shown to act on keratinocytes to repress the expression of IL-36α/γ, an effect mediated through keratinocytic vitamin D receptor (Germán et al., 2019). Moreover, similar to dithranol, calcipotriol decreased expression of AMPs such as ß-defensins in keratinocytes of psoriatic plaques (Peric et al., 2009). At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased IL-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. Calcipotriol also directly targets Th17 cells (Fujiyama et al., 2016) and CD8+IL-17+ cells (Dyring-Andersen et al., 2015), whereas we found that dithranol only has delayed effects on T cells. Moreover, cathelicidin (LL37) expression was increased by calcipotriol (Peric et al., 2009), juxtaposing the results of dithranol treatment at least in the mouse-tail test of present study. That dithranol and vitamin D3 analogues may have similar basic mechanisms of action is also supported by the notion that depending on the concentration, both dithranol (Nasimi et al., 2019; Ngwanya et al., 2017) and calcipotriol (El Taieb et al., 2019; Fullerton et al., 1998; Molinelli et al., 2020) can be irritant to the skin and induce hair regrowth in alopecia areata. Compared to vitamin D3 analogues topical steroids have an even broader mechanisms of action in psoriasis linked to their anti-inflammatory, antiproliferative, vasoconstrictive (Uva et al., 2012) and immunomodulatory properties, in particular suppressing the IL-23/IL-17 axis, with IL-23 produced by dendritic cells/macrophages and IL-17 produced by Th17 cells/γδ T cells/innate lymphoid cells (Germán et al., 2019).

Another question that this study does not answer is, whether topical dithranol therapy has any effects on systemic psoriatic inflammation. However nowadays, treatment with dithranol is mainly administered in refractory, circumscribed psoriatic lesions in patients who do not have significant systemic inflammation how it may be otherwise the case in patients with moderate to severe forms of psoriasis.

Together our work opens up several avenues for novel topical (and potentially also systemic) treatment strategies in psoriasis. Not only targeting the IL-36 pathway, but also keratinocyte differentiation regulators (e.g. involucrin), keratinocyte-produced AMPs (ß-defensins like DEFB4A, DEFB4B, DEFB103A, S100 proteins like S100A7, S100A12), and neutrophils and their chemotactic factors (CXCL5 and CXCL8) or members of the serpin family (SERPINB7 and SERPINB13), are promising approaches. Such approaches may not only be helpful for chronic plaque-psoriasis, but also for pustular psoriasis, in which a vicious loop between AMPs such as cathelicidin (LL-37) and IL-36 signaling may drive psoriatic disease (Benezeder and Wolf, 2019; Furue et al., 2018; Li et al., 2014; Madonna et al., 2019; Ngo et al., 2018).

All microarray data has been deposited at the public repository Gene Expression Omnibus (GEO) (http://www.ncbi.nlm.nih.gov/geo/) with accession numbers GSE145126 and GSE145127.

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Author details

1. Theresa Benezeder

   Department of Dermatology, Medical University of Graz, Graz, Austria

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration

   Contributed equally with

   Clemens Painsi

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-6218-2792

2. Clemens Painsi

   State Hospital Klagenfurt, Klagenfurt am Wörthersee, Austria

   Contribution

   Conceptualization, Data curation, Investigation, Project administration

   Contributed equally with

   Theresa Benezeder

   Competing interests

   No competing interests declared

3. VijayKumar Patra

   Department of Dermatology, Medical University of Graz, Graz, Austria

   Contribution

   Visualization, Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7161-7767

4. Saptaswa Dey

   Department of Dermatology, Medical University of Graz, Graz, Austria

   Contribution

   Methodology

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7532-7858

5. Martin Holcmann

   Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

   Contribution

   Resources, Methodology

   Competing interests

   No competing interests declared

6. Bernhard Lange-Asschenfeldt

   State Hospital Klagenfurt, Klagenfurt am Wörthersee, Austria

   Contribution

   Resources, Project administration

   Competing interests

   No competing interests declared

7. Maria Sibilia

   Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria

   Contribution

   Resources, Writing - review and editing

   Competing interests

   No competing interests declared

8. Peter Wolf

   Department of Dermatology, Medical University of Graz, Graz, Austria

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing - review and editing

   For correspondence

   peter.wolf@medunigraz.at

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7777-9444

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