Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter

Abstract

Interleukin-18 (IL18) participates in atherogenesis through several putative mechanisms1,2. Interruption of IL18 action reduces atherosclerosis in mice3,4. This study shows that the absence of IL18 receptor (IL18r) does not affect atherosclerosis in apolipoprotein E-deficient (Apoe−/−) mice, nor does it affect IL18 cell surface binding or signaling. IL18 antibody-mediated immunoprecipitation identified an interaction between IL18 and Na-Cl co-transporter (NCC), a 12-transmembrane-domain ion transporter protein preferentially expressed in the kidney5. Yet, we find NCC expression and colocalization with IL18r in atherosclerotic lesions and both molecules form a complex. IL18 also binds to the cell surface and induces cell signaling and down-stream cytokine expression in NCC-transfected COS-7 cells that do not express IL18r. In Apoe−/− mice, combined deficiency of IL18r and NCC, but not single deficiency, protects mice from atherosclerosis. Peritoneal macrophages from Apoe−/− mice or those lacking IL18r or NCC respond to IL18 binding or IL18 induction of cell signaling and cytokine and chemokine production, but those with combined deficiency of IL18r and NCC do not. This study identifies NCC as an IL18-binding protein that coordinates with IL18r in cell signaling, inflammatory molecule expression, and experimental atherogenesis.

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

“…Several lines of evidence suggest that IL-18 participates in atherogenesis (91–93) This cytokine also deserves consideration for therapeutic targeting in atherothrombosis. As the inflammasome pathway activates the immature precursors of both IL-1β and IL-18, inhibition of the NLRP3 inflammasome could offer an approach to simultaneous limitation of the action of this pair of pro-inflammatory cytokines.…”

Assessment of IL‐18 Serum Level and Its Promoter Polymorphisms in the Saudi Coronary Artery Disease (CAD) Patients

“…Moreover, IL‐18 and 12 mutually mediates inflammatory signaling cascade which promotes T‐lymphocyte differentiation, production of IFN‐γ, natural killer cells as well as subsets of macrophages [Wawrocki et al, ]. In addition, IL‐18 also induces the production of other inflammatory cytokines, chemokines, and vascular adhesion molecules [Wang et al, ]. Increased expression of IL‐18 and its possible association with clinical presentations of atherosclerosis have been reported in several studies [Nakamura et al, ; Trøseid et al, ; Dezayee, ].…”

The Role of High Mobility Group Box 1 Protein in Interleukin-18-Induced Myofibroblastic Transition of Valvular Interstitial Cells

“…IL-18 has been demonstrated to play important roles in the pathogenesis of atherosclerosis and cardiac fibrosis [3,14]. A previous study also showed that IL-18 immunoreactivity was found mainly in macrophages in nonrheumatic stenotic AVs.…”

“…Interleukin-18 (IL-18) is a member of the IL-1 family of cytokines and plays an important role in the pathogenesis of atherosclerosis [3]. IL-18 also induces cardiac fibroblast migration and differentiation to myofibroblasts [4].…”