Interleukin-18 Inhibition Aggravates Atherosclerosis in Jak2 Clonal Hematopoiesis

Clonal hematopoiesis (CH) driven by JAK2^V617F is known to accelerate atherosclerosis through inflammasome activation and release of interleukin (IL)-1β and -18; yet, the specific contribution of IL-18 has remained unclear. In this study, we demonstrate that antibody inhibition of IL-18 in JAK2^V617F CH mice increases plaque collagen but paradoxically promotes both early lesion growth and advanced necrotic core formation. Mechanistically, IL-18 blockade reverses absent in melanoma 2 inflammasome activation but shifts cell death toward apoptosis, and together with impaired efferocytosis, results in greater necrosis. These events are coordinated by reduced interferon gamma signaling, which enhances collagen deposition while decreasing expression of efferocytotic genes. Our findings challenge the prevailing notion that IL-18 inhibition stabilizes atherosclerotic plaques and provide new mechanistic insight into the interplay among inflammasome biology, adaptive immunity, and plaque stability.