Zdhhc2 Is Essential for Plasmacytoid Dendritic Cells Mediated Inflammatory Response in Psoriasis
Résumé
Zdhhc family genes are composed of 24 members that regulate palmitoylation, a post-translational modification process for proteins. Mutations in genes that alter palmitoylation orde-palmitoylation could result in neurodegenerative diseases and inflammatory disorders. Inthis study, we found that Zdhhc2 was robustly induced in psoriatic skin and loss of Zdhhc2in mice by CRISPR/Cas9 dramatically inhibited pathology of the ear skin followingimiquimod treatment. As psoriasis is an inflammatory disorder, we analyzed tissueinfiltrating immune cells and cytokine production. Strikingly we found that a masterpsoriatic cytokine interferon-a(IFN-a) in the lesioned skin of wildtype (WT) mice was 23-fold higher than that in Zdhhc2 deficient counterparts. In addition, we found that CD45+white blood cells (WBC) infiltrating in the skin of Zdhhc2 deficient mice were also significantlyreduced. Amelioration in psoriasis and dramatically reduced inflammation of Zdhhc2deficient mice led us to analyze the cellular components that were affected by loss ofZdhhc2. We found that imiquimod induced plasmacytoid dendritic cell (pDC) accumulationin psoriatic skin, spleen, and draining lymph nodes (DLN) were drastically decreased inZdhhc2 deficient mice, and the expression of pDC activation marker CD80 also exhibitedsignificantly inhibited in psoriatic skin. In further experiments, we confirmed the cell intrinsiceffect of Zdhhc2 on pDCs as we found that loss of zDHHC2 in human CAL-1 pDCdampened both interferon regulatory factor 7 (IRF7) phosphorylation and IFN-aproduction.Therefore, we identified novel function of Zdhhc2 in controlling inflammatory response inpsoriasis in mice and we also confirmed that crucial role of Zdhhc2 in pDCs by regulatingIRF7 activity and production of the critical cytokine. Our resultsfinding the dependence ofIFN-aproduction on Zdhhc2 in inflamed murine skin and in human pDCs provide rationalefor targeting this new molecule in treatment of inflammation.
| Origine | Fichiers éditeurs autorisés sur une archive ouverte |
|---|
