Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

JAK/STAT Inhibition Normalizes Lipid Composition in 3D Human Epidermal Equivalents Challenged with Th2 Cytokines

Enrica Flori
ORCID logo ,
Alessia Cavallo
ORCID logo ,
Sarah Mosca
ORCID logo ,
Daniela Kovacs
,
Carlo Cota
,
Marco Zaccarini
,
Anna Di Nardo
,
Grazia Bottillo
,
Miriam Maiellaro
ORCID logo ,
Emanuela Camera
* ORCID logo ,
Giorgia Cardinali
ORCID logo
Version 1 : Received: 28 March 2024 / Approved: 28 March 2024 / Online: 29 March 2024 (11:24:27 CET)

How to cite: Flori, E.; Cavallo, A.; Mosca, S.; Kovacs, D.; Cota, C.; Zaccarini, M.; Nardo, A.D.; Bottillo, G.; Maiellaro, M.; Camera, E.; Cardinali, G. JAK/STAT Inhibition Normalizes Lipid Composition in 3D Human Epidermal Equivalents Challenged with Th2 Cytokines. Preprints 2024, 2024031794. https://doi.org/10.20944/preprints202403.1794.v1 Flori, E.; Cavallo, A.; Mosca, S.; Kovacs, D.; Cota, C.; Zaccarini, M.; Nardo, A.D.; Bottillo, G.; Maiellaro, M.; Camera, E.; Cardinali, G. JAK/STAT Inhibition Normalizes Lipid Composition in 3D Human Epidermal Equivalents Challenged with Th2 Cytokines. Preprints 2024, 2024031794. https://doi.org/10.20944/preprints202403.1794.v1

Abstract

Atopic dermatitis (AD) is a chronic inflammatory disorder presenting a dysregulated immune response and derangement of the epidermal barrier lipids. The Th2-type cytokines interleukin IL-4 and IL-13 play a prominent role in AD by activating the Janus Kinase/Signal Transduction and Activator of Transcription (JAK/STAT) intracellular signal axis. This study aimed to investigate the role of JAK/STAT in the lipid perturbations induced by Th2 signaling in 3D-epidermal equivalents. We used tofacitinib, a low-molecular-mass JAK inhibitor, to screen for the JAK/STAT-mediated deregulation of lipid metabolism. Th2 cytokines decreased the expression of elongases 1, 3, and 4, and serine-palmitoyl-transferase and increased that of sphingolipid delta(4)-desaturase, and carbonic anhydrase 2. Th2 cytokines inhibited the synthesis of palmitate and caused a depletion of triglycerides. This depletion was associated with altered PC profiles and fatty acid (FA) metabolism. Overall, the ceramide profiles were minimally affected. Except for most sphingolipids and very long chain FAs, the effects of Th2 on lipid pathways were reversed by co-treatment with tofacitinib. An increase in the mRNA levels of CPT1A and ACAT1, reduced by tofacitinib, suggests that Th2 cytokines promote FA beta-oxidation. In conclusion, pharmacological inhibition of JAK/STAT activation prevents the lipid disruption caused by halted homeostasis of FA metabolism.

Keywords

3D-Skin model; Th2 cytokines; skin lipidomics; JAK/STAT; Atopic Dermatitis

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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