Zdhhc2 Is Essential for Plasmacytoid Dendritic Cells Mediated Inflammatory Response in Psoriasis

Abstract

Zdhhc family genes are composed of 24 members that regulate palmitoylation, a post-translational modification process for proteins. Mutations in genes that alter palmitoylation or de-palmitoylation could result in neurodegenerative diseases and inflammatory disorders. In this study, we found that Zdhhc2 was robustly induced in psoriatic skin and loss of Zdhhc2 in mice by CRISPR/Cas9 dramatically inhibited pathology of the ear skin following imiquimod treatment. As psoriasis is an inflammatory disorder, we analyzed tissue infiltrating immune cells and cytokine production. Strikingly we found that a master psoriatic cytokine interferon-α (IFN-α) 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 significantly reduced. Amelioration in psoriasis and dramatically reduced inflammation of Zdhhc2 deficient mice led us to analyze the cellular components that were affected by loss of Zdhhc2. We found that imiquimod induced plasmacytoid dendritic cell (pDC) accumulation in psoriatic skin, spleen, and draining lymph nodes (DLN) were drastically decreased in Zdhhc2 deficient mice, and the expression of pDC activation marker CD80 also exhibited significantly inhibited in psoriatic skin. In further experiments, we confirmed the cell intrinsic effect of Zdhhc2 on pDCs as we found that loss of zDHHC2 in human CAL-1 pDC dampened both interferon regulatory factor 7 (IRF7) phosphorylation and IFN-α production. Therefore, we identified novel function of Zdhhc2 in controlling inflammatory response in psoriasis in mice and we also confirmed that crucial role of Zdhhc2 in pDCs by regulating IRF7 activity and production of the critical cytokine. Our results finding the dependence of IFN-α production on Zdhhc2 in inflamed murine skin and in human pDCs provide rationale for targeting this new molecule in treatment of inflammation.

Mannan‐binding lectin exacerbates the severity of psoriasis by promoting plasmacytoid dendritic cell differentiation via the signal transducer and activator of transcription 3–interferon regulatory factor 8 axis

“…Psoriasis is a chronic inflammatory skin disorder that mainly manifests as erythema, scales, and thickness of the affected skin 1 . According to its clinical characteristics, the severity of psoriasis is always evaluated by the PASI and BSA scores 2 .…”

“…Psoriasis is a chronic autoimmune skin disease characterized by erythema with silver scales, affecting 2–3% of the general population 1 . The effectiveness of tumor necrosis factor (TNF)‐α inhibitors in treating psoriasis implies the activation of the innate immune response in psoriasis 2 .…”

Emerging Roles of Post-Translational Modifications in Skin Diseases: Current Knowledge, Challenges and Future Perspectives

“… 52 Palmitoylation, a reversible PTM which is catalyzed by palmitoyltransferases and depalmitoylating enzymes, is a process that transfers a 16-carbon palmitoyl group onto the protein target. Recently, Zhou et al 53 reported the role of a palmitoyltransferase ZDHHC2 in the progress of psoriasis. In IMQ-induced psoriasis mouse models, Zdhhc2 deficiency significantly reduced the pathological grade and the infiltration of pDC by interfering with IRF7 activity to reduce the secretion of pro-inflammatory cytokine IFN-α.…”

“…In IMQ-induced psoriasis mouse models, Zdhhc2 deficiency significantly reduced the pathological grade and the infiltration of pDC by interfering with IRF7 activity to reduce the secretion of pro-inflammatory cytokine IFN-α. 53 Thus, the upregulated expression of Zdhhc2 in the epidermis of psoriasis-mouse model provides insights into the role of palmitoylation in the pathogenesis of psoriasis.…”

Antigen-Presenting Cells in Psoriasis

“…Post-translational modifications also seem to influence IFNα production by pDCs. The palmitoylating agent Zdhhc2 is required for pDC accumulation in psoriatic skin by controlling the phosphorylation of IRF7 that is a key transcription factor regulating IFNα production of pDCs [39]. The H4 histamine receptor is highly expressed on pDCs in psoriasis and histamine regulates the cytokine production and migration of pDCs [40], supporting the role of neuroimmune interactions in psoriasis progression.…”