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Insights into innate immune activation via PS-ASO-protein-TLR9 interactions. | LitMetric

AI Article Synopsis

  • * Research found that pro-inflammatory PS-ASOs rely on TLR9 signaling, but their immune responses don't necessarily correlate with how well they bind to TLR9.
  • * Interactions between pro-inflammatory and non-inflammatory PS-ASOs affect immune responses through TLR9, and certain extracellular proteins enhance these responses, showing that changes in PS content can influence binding and activation.

Article Abstract

Non-CpG PS-ASOs can activate the innate immune system, leading to undesired outcomes. This response can vary-in part-as a function of 2'modifications and sequence. Here we investigated the molecular steps involved in the varied effects of PS-ASOs on the innate immune system. We found that pro-inflammatory PS-ASOs require TLR9 signaling based on the experimental systems used. However, the innate immunity of PS-ASOs does not correlate with their binding affinity with TLR9. Furthermore, the innate immune responses of pro-inflammatory PS-ASOs were reduced by coincubation with non-inflammatory PS-ASOs, suggesting that both pro-inflammatory and non-inflammatory PS-ASOs can interact with TLR9. We show that the kinetics of the PS-ASO innate immune responses can vary, which we speculate may be due to the existence of alternative PS-ASO binding sites on TLR9, leading to full, partial, or no activation of the pathway. In addition, we found that several extracellular proteins, including HMGB1, S100A8 and HRG, enhance the innate immune responses of PS-ASOs. Reduction of the binding affinity by reducing the PS content of PS-ASOs decreased innate immune responses, suggesting that PS-ASO-protein complexes may be sensed by TLR9. These findings thus provide critical information concerning how PS-ASOs can interact with and activate TLR9.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9371907PMC
http://dx.doi.org/10.1093/nar/gkac618DOI Listing

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