Anti-IL-18 immunotherapy decreases inflammatory and vaso-occlusive responses in mice with sickle cell disease.

BACKGROUND Sickle cell disease (SCD) is characterized by inflammatory and vaso-occlusive processes that drive acute crises and progressive organ damage. Interleukin-18 (IL-18), elevated in SCD patients and mouse models, contributes to these pathological mechanisms. METHODS We evaluated the effects of acute and prolonged IL-18 blockade using the SK113AE-4 monoclonal antibody in Townes and Berkeley SCD mice. RESULTS Acute IL-18 neutralization reduced TNF-α-induced microvascular leukocyte recruitment and prevented hypoperfusion, indicating that modulation of inflammatory signaling improves physiological responses in SCD. Prolonged anti-IL-18 immunotherapy for 6 weeks decreased circulating TNF-α and IL-10 and reduced hepatic macrophage infiltration, but did not prevent liver fibrosis, iron deposition, or alter biochemical markers of hemolysis or hepatic/renal injury. As such, IL-18 blockade attenuates vascular inflammation and vaso-occlusive-like events, but may be insufficient to prevent SCD-related liver injury under the conditions tested. In contrast, in our previous study, anti-IL-1β immunotherapy provided added liver protection, highlighting potentially divergent cytokine pathways in SCD. CONCLUSIONS Collectively, these results support IL-18 as a therapeutic target to reduce vascular inflammation and vaso-occlusive processes, and suggest that combined inflammasome cytokine-targeted or multi-approach strategies may be required to prevent organ damage in SCD. TEASER ABSTRACT IL-18 is elevated in sickle cell disease (SCD) and contributes to inflammatory and vaso-occlusive pathways. Using two SCD mouse models, we show that acute IL-18 blockade improves microvascular responses and preserves skin perfusion after TNF-α challenge. Prolonged IL-18 inhibition reduces some inflammatory markers but does not prevent liver injury. These findings support IL-18 as a target to limit vascular inflammation in SCD, while indicating that preventing organ damage may require broader or combined approaches.

• Publication year

  2025

• Venue

  Experimental Hematology

• Publication date

  2025-12-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.1016/j.exphem.2025.105366PMID 41482116
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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