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

Elife. 2020 Jun 2;9:e56991. 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.

Trial registration: ClinicalTrials.gov NCT02752672.

Keywords: AMPs; IL-36; anthralin; dithranol; human; immunology; inflammation; keratinocytes; mouse; psoriasis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthralin / pharmacology*
  • Chemokines, CXC / metabolism
  • Dermatologic Agents / pharmacology
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism*
  • Keratinocytes* / drug effects
  • Keratinocytes* / metabolism
  • Mice
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Pore Forming Cytotoxic Proteins / metabolism
  • Psoriasis* / immunology
  • Psoriasis* / metabolism
  • Serpins / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • Skin / drug effects
  • Skin / pathology

Substances

  • Chemokines, CXC
  • Dermatologic Agents
  • Interleukin-1
  • Pore Forming Cytotoxic Proteins
  • Serpins
  • Anthralin

Associated data

  • GEO/GSE145126
  • GEO/GSE145127
  • ClinicalTrials.gov/NCT02752672