Logical and experimental modeling of cytokine and eicosanoid signaling in psoriatic keratinocytes

Abstract

Psoriasis is characterized by chronic inflammation, perpetuated by a Th17-dependent signaling loop between the immune system and keratinocytes that could involve phospholipase A2 (PLA2)-dependent eicosanoid release. A prior knowledge network supported by experimental observations was used to encode the regulatory network of psoriatic keratinocytes in a computational model for studying the mode of action of a cytosolic (c) PLA2 inhibitor. A combination of evidence derived from the computational model and experimental data suggests that Th17 cytokines stimulate pro-inflammatory cytokine expression in psoriatic keratinocytes via activation of cPLA2-PGE2-EP4 signaling, which could be suppressed using the anti-psoriatic calcipotriol. cPLA2 inhibition and calcipotriol showed overlapping and distinct modes of action. Model analyses revealed the immunomodulatory role of Th1 cytokines, the modulation of the physiological states of keratinocytes by Th17 cytokines, and how Th1 and Th17 cells together promote the development of psoriasis. Model simulations additionally suggest novel drug targets, including EP4 and PRKACA, for treatment that may restore a normal phenotype. Our work illustrates how the study of complex diseases can benefit from an integrated systems approach.