Randialic acid B and tomentosolic acid block formyl peptide receptor 1 in human neutrophils and attenuate psoriasis-like inflammation in vivo

Biochem Pharmacol. 2021 Aug:190:114596. doi: 10.1016/j.bcp.2021.114596. Epub 2021 May 6.

Abstract

Psoriasis is a long-lasting inflammatory skin disease lacking proper cure. Dysregulated activation of neutrophils is a major pathogenic factor in psoriasis. Formyl peptide receptor 1 (FPR1) triggers neutrophil activation in response to bacteria- or mitochondria-derived N-formyl peptides, but its significance in neutrophilic psoriasis remains unknown. In this study, we discovered two derivatives of ursolic acid, 3β-hydroxyurs-12,18-dien-28-oic acid (randialic acid B, RAB) and 3β-hydroxyurs-12,19-dien-28-oic acid (tomentosolic acid, TA), as FPR1 inhibitors in human neutrophils with ability to suppress psoriatic symptoms in mice. Both RAB and TA, triterpenoids of traditional medicinal plant Ilex kaushue, selectively inhibited reactive oxygen species production, elastase release, and CD11b expression in human neutrophils activated by FPR1, but not non-FPR1 agonists. Importantly, RAB and TA inhibited the binding of N-formyl peptide to FPR1 in human neutrophils, neutrophil-like THP-1 cells, and hFPR1-transfected HEK293 cells, indicating FPR1 antagonism. Moreover, in assays induced by various concentrations of FPR1 agonist, both RAB and TA acted competitively for its binding to the FPR1 receptor. The FPR1-downstream signaling such as Ca2+ mobilisation and activation of Akt and MAPKs was also competitively inhibited. In addition, imiquimod-induced psoriasis-like symptoms, including epidermal hyperplasia, desquamation with scaling, neutrophil skin infiltration, and transepidermal water loss were significantly reduced by both RAB and TA. The results illustrate a possible role of human neutrophils FPR1 receptor in psoriasis-like inflammation. Accordingly, triterpenoids RAB and TA represent novel FPR1 antagonists and exhibit therapeutic potential for treating neutrophilic inflammatory skin diseases.

Keywords: FPR1 antagonist; Ilex kaushue; Neutrophilic inflammation; Psoriasis; Triterpene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Cell Line
  • Cells, Cultured
  • Female
  • HEK293 Cells
  • Humans
  • Imiquimod / toxicity
  • Inflammation / chemically induced
  • Inflammation / metabolism
  • Inflammation / prevention & control
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neutrophils / drug effects*
  • Neutrophils / metabolism
  • Psoriasis / chemically induced
  • Psoriasis / metabolism
  • Psoriasis / prevention & control*
  • Receptors, Formyl Peptide / antagonists & inhibitors*
  • Receptors, Formyl Peptide / metabolism
  • Triterpenes / chemistry
  • Triterpenes / pharmacology
  • Triterpenes / therapeutic use*
  • Ursolic Acid
  • Young Adult

Substances

  • FPR1 protein, human
  • Receptors, Formyl Peptide
  • Triterpenes
  • randialic acid B
  • Imiquimod