RTD-1 therapeutically normalizes synovial gene signatures in rat autoimmune arthritis and suppresses proinflammatory mediators in RA synovial fibroblasts

Abstract

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.

Antiarthritic effect of chitosan nanoparticle loaded with embelin against adjuvant‐induced arthritis in Wistar rats

“…IL‐1β and IL‐6 are other important pro‐inflammatory cytokines in the development of RA. The results of the present study demonstrated that CS‐embelin NPs decreased TNF‐α, IL‐1β, and IL‐6 release in the serum of CFA rats …”

“…The results of the present study demonstrated that CS-embelin NPs decreased TNF-α, IL-1β, and IL-6 release in the serum of CFA rats. 47,48 NF-kB is a key protein that mediates the inflammatory reaction during RA. NF-kB can induce proinflammatory cytokines, such as TNF-α and IL-6, which can increase arthritic inflammation.…”

A host-directed macrocyclic peptide therapeutic for MDR gram negative bacterial infections

“…RTD-1, the prototype θ-defensin, was identified as a broad-spectrum antimicrobial peptide in vitro 8 , 9 . Subsequent studies demonstrated that RTD-1 homeostatically regulates inflammation in infectious and non-infectious preclinical models 11 , 12 , 15 , 17 , 18 , 27 . Mechanisms implicated in the moderation of cytokine-driven inflammation include modulation of NFκB and MAPK pathways 13 , suppression of TNF release via the inhibition of the pro-TNF sheddase TACE (ADAM17) 26 , and disease resolution and normalization of gene signatures in models of rheumatoid arthritis 18 , 27 .…”

Integrated Transcriptome and Proteome Analyses Reveal the Regulatory Role of miR-146a in Human Limbal Epithelium via Notch Signaling

“…Differentially expressed genes were identified by combining two approaches that use different algorithms. A gene was called differentially expressed if it passed the false discovery rate (FDR) with adjusted p < 0.05 in DEseq2 [ 27 ] and employing the null model hypothesis [ 28 ], as has been detailed previously [ 29 ]. To investigate potential functional enrichment in differentially expressed genes of various biological pathways by RNA-seq, a ranked p value was computed for each pathway from the Fisher exact test based on the binomial distribution and independence for probability of any gene belonging to any enriched set [ 30 ].…”