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

Abstract

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 patients with SCD and mouse models, contributes to these pathological mechanisms. We evaluated the effects of acute and prolonged IL-18 blockade using the SK113AE-4 monoclonal antibody in Townes and Berkeley SCD mice. Acute IL-18 neutralization reduced tumor necrosis factor-alpha (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. 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 multiapproach strategies may be required to prevent organ damage in SCD.