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Phosphodiesterase-4 Inhibition Reduces Cutaneous Inflammation and IL-1β Expression in a Psoriasiform Mouse Model but Does Not Inhibit Inflammasome Activation

Authors :
Meier-Schiesser, Barbara
Mellett, Mark
Ramirez-Fort, Marigdalia K
Maul, Julia-Tatjana
Klug, Annika
Winkelbeiner, Nicola
Fenini, Gabriele
Schafer, Peter
Contassot, Emmanuel
French, Lars E
University of Zurich
Meier-Schiesser, Barbara
Source :
International Journal of Molecular Sciences, International Journal of Molecular Sciences, Vol 22, Iss 12878, p 12878 (2021)
Publication Year :
2021

Abstract

Apremilast (Otezla®) is an oral small molecule phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis, psoriatic arthritis, and oral ulcers associated with Behçet’s disease. While PDE4 inhibition overall is mechanistically understood, the effect of apremilast on the innate immune response, particularly inflammasome activation, remains unknown. Here, we assessed the effect of apremilast in a psoriasis mouse model and primary human cells. Psoriatic lesion development in vivo was studied in K5.Stat3C transgenic mice treated with apremilast for 2 weeks, resulting in a moderate (2 mg/kg/day) to significant (6 mg/kg/day) resolution of inflamed plaques after 2-week treatment. Concomitantly, epidermal thickness dramatically decreased, the cutaneous immune cell infiltrate was reduced, and proinflammatory cytokines were significantly downregulated. Additionally, apremilast significantly inhibited lipopolysaccharide- or anti-CD3-induced expression of proinflammatory cytokines in peripheral mononuclear cells (PBMCs). Notably, inflammasome activation and secretion of IL-1β were not inhibited by apremilast in PBMCs and in human primary keratinocytes. Collectively, apremilast effectively alleviated the psoriatic phenotype of K5.Stat3 transgenic mice, further substantiating PDE4 inhibitor-efficiency in targeting key clinical, histopathological and inflammatory features of psoriasis. Despite lacking direct effect on inflammasome activation, reduced priming of inflammasome components upon apremilast treatment reflected the indirect benefit of PDE4 inhibition in reducing inflammation.

Details

Language :
English
Database :
OpenAIRE
Journal :
International Journal of Molecular Sciences, International Journal of Molecular Sciences, Vol 22, Iss 12878, p 12878 (2021)
Accession number :
edsair.pmid.dedup....29d2d05e9d0226e583c857dc1092523f