IL-18 Inhibition Aggravates Atherosclerosis in Jak2V617F Clonal Hematopoiesis

Clonal hematopoiesis (CH) driven by Jak2V617F is known to accelerate atherosclerosis through inflammasome activation and release of IL-1ß and IL-18, yet the specific contribution of IL-18 has remained unclear. In this study, we demonstrate that antibody inhibition of IL-18 in Jak2V617F CH mice increases plaque collagen but paradoxically promotes both early lesion growth and advanced necrotic core formation. Mechanistically, IL-18 blockade reverses AIM2 inflammasome activation but shifts cell death toward apoptosis, and together with impaired efferocytosis, results in greater necrosis. These events appear to be coordinated by reduced IFN-? signaling, which enhanced collagen deposition while decreasing expression of efferocytotic genes.Our findings challenge the prevailing notion that IL-18 inhibition stabilizes atherosclerotic plaques in CH and provide new mechanistic insight into the interplay between inflammasome biology, adaptive immunity, and plaque stability.