👤 Percio S Gulko

Psoriasis is a chronic inflammatory skin disease characterised by keratinocyte hyperproliferation and immune cell infiltration driven by cytokines such as IL-17A. The dual-specificity phosphatase 6 (DUSP6) is a negative regulator of MAPK signalling and was previously reported to be a key mediator of arthritis severity. Here, we examine the role of DUSP6 in a mouse model of psoriasis. Psoriasis was studied in the imiquimod-induced model (IMQ). The skin of DUSP6+/+ and DUSP6-/- mice was treated with IMQ cream. Disease severity was assessed using well-established clinical and histologic systems. Skin inflammatory genes were quantified by qPCR.DUSP6-/- mice exhibited significantly reduced skin inflammation with lower PASI clinical scores (mean DUSP6-/- 1.8 and DUSP6+/+ 8.4; p < 0.0001). Histologic scores for epidermal thickening, parakeratosis and immune cell infiltration were decreased in the DUSP6-/- mice (p < 0.0005), and mRNA levels of IL1β, IL17A and STAT3 were lower in DUSP6-/- skin (p ≤ 0.05) compared with DUSP6+/+. In conclusion, DUSP6 is required for the development of psoriasis-like skin inflammation in mice. In the absence of DUSP6, mice were protected and had significantly lower levels of pathogenic genes, suggesting a new and central role for DUSP6 in skin inflammation and a potential therapeutic target in psoriasis. Show less

The dual specificity phosphatase 6 (DUSP6) was recently implicated in autoimmune arthritis pathogenesis. However, it remains unclear which cell mediates its pathogenic activity in a mouse model of rheumatoid arthritis (RA). Bone marrow (BM) CD11b + Gr1 + cells were isolated from DUSP6 +/+ mice and transferred into DUSP6 -/- recipients. Six weeks later mice were administered the KRN serum to induce arthritis (KSIA), and analyzed for arthritis severity clinical scores. The same strategy was used in the opposite direction with cells from DUSP6-/- cells transferred in DUSP6 +/+ mice. BM CD11b + Gr1 + cells from DUSP6 +/+ and DUSP6 -/ - were stimulated with PMA and used for RNA sequencing, and also used for real-time measurements of mitochondrial respiration with the Seahorse XF Analyzer. Transfer of CD11 + Gr1 + cells DUSP6 We describe a new arthritogenic role for DUSP6, which is mediated by CD11b + Gr1 + cells and their glycolytic activity and oxidative burst. Our findings also implicate these myeloid cells in arthritis pathogenesis and raise the possibility that DUSP6 may be a good target for the development of new therapies for RA. Show less

Receptor tyrosine kinases (RTKs) have an important role in arthritis severity and in models of rheumatoid arthritis (RA), but their regulation is not fully understood. The dual specificity phosphatase 6 (DUSP6) has been implicated in the regulation of RTK signaling, but never in the context of arthritis and autoimmunity. We used the KRN serum-induced arthritis (KSIA) model of RA and showed that DUSP6 Show less

Rhesus theta defensin-1 (RTD-1), a macrocyclic immunomodulatory host defense peptide from Old World monkeys, is therapeutic in pristane-induced arthritis (PIA) in rats, a model of rheumatoid arthritis (RA). RNA-sequence (RNA-Seq) analysis was used to interrogate the changes in gene expression in PIA rats, which identified 617 differentially expressed genes (DEGs) in PIA synovial tissue of diseased rats. Upstream regulator analysis showed upregulation of gene expression pathways regulated by TNF, IL1B, IL6, proinflammatory cytokines, and matrix metalloproteases (MMPs) involved in RA. In contrast, ligand-dependent nuclear receptors like the liver X-receptors NR1H2 and NR1H3 and peroxisome proliferator-activated receptor gamma (PPARG) were downregulated in arthritic synovia. Daily RTD-1 treatment of PIA rats for 1-5 days following disease presentation modulated 340 of the 617 disease genes, and synovial gene expression in PIA rats treated 5 days with RTD-1 closely resembled the gene signature of naive synovium. Systemic RTD-1 inhibited proinflammatory upstream regulators such as TNF, IL1, and IL6 and activated antiarthritic ligand-dependent nuclear receptor pathways, including PPARG, NR1H2, and NR1H3, that were suppressed in untreated PIA rats. RTD-1 also inhibited proinflammatory responses in IL-1β-stimulated human RA fibroblast-like synoviocytes (FLS) in vitro and diminished expression of human orthologs of disease genes that are induced in rat PIA synovium. Thus, the antiarthritic mechanisms of systemic RTD-1 include homeostatic regulation of arthritogenic gene networks in a manner that correlates temporally with clinical resolution of rat PIA. Show less