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Updated: May 25, 2025
Screening Bioactive Nanoparticles in Phagocytic Immune Cells for Inhibitors of Toll-like Receptor Signaling
Published on: July 26, 2017
Suppressed activation of the IRF7 and TLR9 by JAK2V617F gold nanoparticles
Berkay Tokcan1,2, Esra Nur Demirtaş1,2, Selçuk Sözer3
1Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Gureba Str., Capa Campus, No:69, 34093, Sehremini/Istanbul, Türkiye.
Abstract:
Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) are characterized by the overproduction of myeloid cells and a lack of response to cytokine signaling, along with genomic instability and the accumulation of nucleic acids in the cytoplasm. In this study, we investigated the effects of oligonucleotide-gold nanoparticle conjugates (ON-GNPs) targeting JAK2 or JAK2V617F mRNAs on nucleic acid-sensing pathways in HEL, SET2, and K562 cell lines. We evaluated changes in gene expression related to TLR9 and cGAS/STING pathways, RAGE/TLR9 receptor dynamics, and inflammatory cytokine release over short-term (0.5-2 h) and long-term (24-72 h) exposures. Our results demonstrated that ON-GNPs transiently suppressed TLR9, IRF7, and NFKB1 expression during the short term, followed by significant upregulation after 24 h, persisting up to 72 h. Notably, JAK2V617F-targeting ON-GNPs induced heightened IRF7 activation in HEL and SET2 cells after 24 h without affecting TLR9/RAGE expression. Additionally, IL-8 secretion increased in HEL and SET2 culture media after 72 h, correlating with interferon pathway activation. This study reveals that complementary ON-GNPs can modulate nucleic acid-sensing pathways, suppressing IL-8 and inflammatory signaling in the short term while inducing delayed activation of TLR9 and IRF7 in the presence of JAK2V617F. These findings provide a promising foundation for developing ON-GNP-based therapeutic strategies to manage inflammation and disease progression in Ph-MPNs.
Insights
Oligonucleotide-gold nanoparticle conjugates (ON-GNPs) targeting JAK2 in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) initially suppressed inflammation but later activated immune pathways. This suggests potential for new Ph-MPN therapies.
Area of Science:
- Molecular Biology
- Immunology
- Nanotechnology
- Oncology
Background:
- Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) involve myeloid overproduction and cytokine signaling defects.
- Genomic instability in Ph-MPNs leads to cytoplasmic nucleic acid accumulation.
- Nucleic acid-sensing pathways, including TLR9 and cGAS/STING, are implicated in Ph-MPN pathogenesis.
Purpose of the Study:
- To investigate the effects of oligonucleotide-gold nanoparticle conjugates (ON-GNPs) targeting JAK2 or JAK2V617F mRNA.
- To evaluate the impact of ON-GNPs on nucleic acid-sensing pathways and inflammatory cytokine release in Ph-MPN cell lines.
- To assess short-term and long-term responses to ON-GNP treatment.
Main Methods:
- Utilized HEL, SET2, and K562 cell lines, characteristic of Ph-MPNs.
- Administered ON-GNPs targeting JAK2 or JAK2V617F mRNA.
- Analyzed gene expression of TLR9, cGAS/STING pathway components, RAGE, and inflammatory cytokines (e.g., IL-8) at various time points (0.5-72 hours).
Main Results:
- ON-GNPs transiently suppressed TLR9, IRF7, and NFKB1 expression in the short term (0.5-2h).
- A delayed, significant upregulation of TLR9, IRF7, and NFKB1 was observed after 24h, persisting up to 72h.
- JAK2V617F-targeting ON-GNPs specifically induced IRF7 activation and increased IL-8 secretion in HEL and SET2 cells after 72h, correlating with interferon pathway activation.
Conclusions:
- Complementary ON-GNPs can modulate nucleic acid-sensing pathways in Ph-MPN models.
- Short-term ON-GNP treatment suppresses inflammatory signaling, but long-term exposure induces delayed activation of TLR9 and IRF7, particularly with JAK2V617F targeting.
- These findings offer a basis for developing novel ON-GNP-based therapeutic strategies to manage inflammation and disease progression in Ph-MPNs.
