Mechanistic insight to a therapy of psoriasis
Mechanistic insight to therapy of psoriasis. The combined calcipotriol/corticosteroid therapy effectively disrupts a positive feedback loop in the inflammation of plaque psoriasis at the two key nodes: calcipotriol acts on skin keratinocytes to suppress IL-36 through vitamin D receptor (VDR), while corticosteroid acts on immune cells to suppress IL-23/IL-17.
Jan. 24, 2019
Affecting 1 to 3% of the world's population, psoriasis is one of the most common, complex chronic inflammatory skin disorders. In this study, Mei Li’s team at the IGBMC (CNRS/INSERM/University of Strasbourg) revealed why calcipotriol, a vitamin D3 analogue, in combination with corticosteroids is an effective therapeutic treatment of patients with plaque psoriasis. Published the 24th January 2019, in JCI Insight, this discovery provide novel insights into the development of more powerful and targeted treatments for psoriasis.
In its most common form, psoriasis manifests as plaques of red, inflamed and scaly patches covered with a silvery white buildup of dead skin cells, and most often appears on the scalp, knees, elbows, and lower back. The exact cause of plaque psoriasis is unknown, but we do know that the immune system, environmental factors, and family history can all play a role. More recently we have recognized that the crosstalk between skin epidermal cells (called keratinocytes) and immune cells plays a central role in psoriasis pathogenesis: keratinocytes produce molecules called cytokines that drive abnormal immune response, and activated immune cells stimulate the abnormal proliferation and differentiation of keratinocytes. Since more than twenty years, calcipotriol, a vitamin D3 analogue, has been used to treat patients with mild to moderate plaque psoriasis and reached certain efficacy. Recently, various clinical studies have shown that the combination of calcipotriol with corticosteroids exhibits excellent and superior efficacy than calcipotriol alone, but without understanding why. Based on the clinical investigation, studies from Mei Li's team have now uncovered a mechanism underlying the action of this therapeutic combination.
Using an experimental psoriasis model and mouse genetic tools, the researchers revealed that in contrast to what was previously believed, calcipotriol acts on its receptor (vitamin D receptor, VDR) on keratinocytes to suppress the production of cytokine IL-36, a psoriasis signature molecule, and subsequently reduces the production of IL-23/IL-17 by immune cells in psoriasis. In collaboration with clinical researchers, they demonstrated the clinical relevance of their findings by performing studies using human biopsies from psoriasis patients and human cells. Their research also showed that the combined calcipotriol/corticosteroid therapy effectively disrupts the IL-36-IL-23/IL-17 positive feedback loop at the two key nodes: in keratinocytes (IL-36) by the action of calcipotriol and in immune cells (IL-23/IL-17) by the action of corticosteroid.
This study provides a better understanding of the therapeutic effects of calcipotriol in the treatment of plaque psoriasis and, in particular, a mechanistic insight to the superior efficacy of the calcipotriol/ corticosteroid combination. It raises the concept to target the IL-36-IL-23/IL-17 inflammatory loop to improve the effectiveness of treatment and prevent recurrences. This concept will be insightful for developing new therapeutic strategies not only for psoriasis, but also for other inflammatory and autoimmune diseases in which this inflammatory loop is implicated.
This study was supported by the ANR grants, Labex-INRT, the Foundation for Medical Research (FRM), the joint program of USIAS (Institute of Advanced Studies of the University of Strasbourg) ad FRIAS (the Freiburg Institute for Advanced Studies).