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

Theresa Benezeder,Peter Wolf,Martin Holcmann,Saptaswa Dey,Vijaykumar Patra,Bernhard Lange-Asschenfeldt,Maria Sibilia,Clemens Painsi

doi:10.7554/elife.56991

Abstract

Despite the introduction of biologics, topical dithranol (anthralin) has remained one of the most effective anti-psoriatic agents. Serial biopsies from human psoriatic lesions and both the c-Jun/JunB and imiquimod psoriasis mouse model allowed us to study the therapeutic mechanism of this drug. Top differentially expressed genes in the early response to dithranol belonged to keratinocyte and epidermal differentiation pathways and IL-1 family members (i.e. IL36RN) but not elements of the IL-17/IL-23 axis. In human psoriatic response to dithranol, rapid decrease in expression of keratinocyte differentiation regulators (e.g. involucrin, SERPINB7 and SERPINB13), antimicrobial peptides (e.g. ß-defensins like DEFB4A, DEFB4B, DEFB103A, S100 proteins like S100A7, S100A12), chemotactic factors for neutrophils (e.g. CXCL5, CXCL8) and neutrophilic infiltration was followed with much delay by reduction in T cell infiltration. Targeting keratinocytes rather than immune cells may be an alternative approach in particular for topical anti-psoriatic treatment, an area with high need for new drugs.

Highlights

With the development and market introduction of biologics, much progress has been made in recent years in the systemic treatment of psoriasis
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
Different set-ups were tested, but similar effects were observed. These results demonstrate that dithranol primarily targets keratinocytes and only has delayed effects on other immune cells such as T cells belonging to the IL-17/IL-23 axis in psoriatic skin

Summary

Introduction

With the development and market introduction of biologics, much progress has been made in recent years in the systemic treatment of psoriasis. 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). 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 (Kemeny et al, 1990; Painsi et al, 2015b; Sehgal et al, 2014; van de Kerkhof, 2015). Dithranol has been used for many years, its exact mechanism of action has remained

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