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December 8, 2025Blood

Neutrophil-TLR9 is a therapeutic target for acute chest syndrome in sickle cell disease

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Authors

ASAyyanar SivananthamSHS HoweNSNicholas Swendrowski

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Overview

Experiment shows type I interferon and neutrophil extracellular traps are linked to lung injury in sickle cell disease, suggesting TLR9 is a therapeutic target.

Key Points

  • To examine the role of neutrophil-intrinsic TLR9 signaling in lung injury and acute chest syndrome in sickle cell disease.
  • Utilized humanized SCD mice and control mice for IV challenge with oxyhemoglobin
  • Assessed lung injury and vaso-occlusion via histology and intravital lung microscopy
  • Isolated neutrophils from SCD patients and healthy controls using density gradient method
  • Conducted gene expression analysis, immunoprecipitation, and western blotting
  • Oxy-Hb challenge caused significant lung injury in SCD mice that was prevented by TLR9 blockade
  • Increased levels of neutrophil extracellular traps were observed in both SCD mice and patients with acute chest syndrome
  • TLR9 blockade reduced severe IRF7 phosphorylation and type I interferon signaling in neutrophils

Cite This Study

Sivanantham et al. (2025) studied this question.

synapsesocial.com/papers/69362f744fa91c937236e339https://doi.org/10.1182/blood-2025-839
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Deep neutrophil phenotyping uncovers complement-mediated neutrophil dysregulation in sickle cell disease2025
  2. 2Sickle red blood cell/Siglec-9 interactions contribute to neutrophil activation in SCD and are associated with survival2026
  3. 3S100A9 deletion ameliorates acute lung injury by attenuating excessive neutrophil activation via activating the NRF2/HO-1 signaling axis2026
  4. 4C26-15 Mild Flu Promotes Platelet-RIG1 Dependent Lung Injury in Sickle Cell Disease2026
  5. 5Loss of erythrocyte sialic acid in sepsis disrupts inhibitory Siglec interactions, driving neutrophil hyperactivation and NET outspread2026 · 1 citations