Abstract
SummaryPsoriasis is a chronic skin disease, in which immune cells and keratinocytes keep each other in a state of inflammation. It is believed that phospholipase A2 (PLA2)-dependent eicosanoid release plays a key role in this. T-helper (Th) 1-derived cytokines are established activators of phospholipases in keratinocytes, whereas Th17-derived cytokines have largely unknown effects. Logical model simulations describing the function of cytokine and eicosanoid signaling networks combined with experimental data suggest that Th17 cytokines stimulate proinflammatory cytokine expression in psoriatic keratinocytes via activation of cPLA2α-Prostaglandin E2-EP4 signaling, which could be suppressed using the anti-psoriatic calcipotriol. cPLA2α inhibition and calcipotriol distinctly regulate expression of key psoriatic genes, possibly offering therapeutic advantage when applied together. Model simulations additionally suggest EP4 and protein kinase cAMP-activated catalytic subunit alpha as drug targets that may restore a normal phenotype. Our work illustrates how the study of complex diseases can benefit from an integrated systems approach.
Highlights
Psoriasis is a chronic inflammatory disease that affects 2%–3% of the world’s population
Logical model simulations describing the function of cytokine and eicosanoid signaling networks combined with experimental data suggest that Th17 cytokines stimulate proinflammatory cytokine expression in psoriatic keratinocytes via activation of cPLA2a-Prostaglandin E2-EP4 signaling, which could be suppressed using the anti-psoriatic calcipotriol. cPLA2a inhibition and calcipotriol distinctly regulate expression of key psoriatic genes, possibly offering therapeutic advantage when applied together
The subsequent maturation of plasmacytoid DCs (pDCs) is marked by the production of high levels of interferon (IFN)-a. pDC-derived IFNa or RNA-LL-37 released by KCs activate myeloid DCs, which in turn directly influence the differentiation of naive T cells (Albanesi et al, 2018; Benhadou et al, 2019; Rendon and Schakel, 2019; Wang and Bai, 2020)
Summary
Psoriasis is a chronic inflammatory disease that affects 2%–3% of the world’s population. Th1 cells release IFNg and tumor necrosis factor alpha (TNFa), whereas Th17 cells produce interleukin-17 (IL-17) and IL-22, partially overlapping with the role of Th22 cells that produce IL-22 (Benham et al, 2013) Together, these cytokines stimulate hyperproliferation, premature differentiation, and resistance to apoptosis in KCs, largely through the activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-kB) transcription factors (Albanesi et al, 2018). These cytokines stimulate hyperproliferation, premature differentiation, and resistance to apoptosis in KCs, largely through the activation of signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappa B (NF-kB) transcription factors (Albanesi et al, 2018) Their effects are, not limited to changing keratinocyte physiology and include the stimulation of KCs to produce antimicrobial peptides (AMPs), proinflammatory cytokines, and chemoattractants, which together results in neutrophil recruitment and the maintenance of the same Th-cell populations.
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