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Jaewoo Lee1, Jang Wook Sohn, Ying Zhang

  • 1Duke Translational Research Institute, Duke University Medical Center, Durham, NC 27710, USA. jaewoo.lee@duke.edu

Proceedings of the National Academy of Sciences of the United States of America
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Novel polymers neutralize extracellular nucleic acids, preventing inflammatory responses and autoimmune diseases. These agents act as molecular scavengers, inhibiting toll-like receptor activation and protecting against toxic shock.

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Area of Science:

  • Immunology
  • Molecular Biology
  • Pharmacology

Background:

  • Extracellular nucleic acids from dead cells activate inflammatory pathways.
  • Activation of toll-like receptors (TLRs) by nucleic acids can lead to inflammatory and autoimmune diseases.
  • The TLR family's redundancy necessitates broad-acting inhibitors.

Purpose of the Study:

  • To identify materials that neutralize the proinflammatory effects of diverse nucleic acids.
  • To investigate the potential of nucleic acid-binding polymers as anti-inflammatory agents.

Main Methods:

  • Testing nucleic acid-binding polymers for their ability to inhibit TLR activation.
  • Evaluating the efficacy of systemic polymer administration in a mouse model of toxic shock.

Main Results:

  • Certain nucleic acid-binding polymers inhibited all tested nucleic acid-sensing TLRs (TLR3, 7, 8, 9).
  • Inhibition occurred regardless of nucleic acid sequence, structure, or chemistry (ssRNA, dsRNA, hypomethylated DNA).
  • Systemic polymer administration prevented fatal liver injury in a mouse toxic shock model.

Conclusions:

  • Nucleic acid-binding polymers are effective molecular scavengers of proinflammatory nucleic acids.
  • These polymers represent a novel class of anti-inflammatory agents.
  • Potential therapeutic applications in inflammatory and autoimmune conditions.