Daiko Wakita1, Yosuke Kurashima1, Timothy R Crother1, Magali Noval Rivas1, Youngho Lee1, Shuang Chen1, Wen Fury1, Yu Bai1, Shawn Wagner1, Debiao Li1, Thomas Lehman1, Michael C Fishbein1, Hal M Hoffman1, Prediman K Shah1, Kenichi Shimada1, Moshe Arditi2. 1. From the Division of Infectious Diseases and Immunology, Department of Biomedical Sciences and Pediatrics (D.W., T.R.C., M.N.R., Y.L., S.C., K.S., M.A.), Infectious and Immunologic Diseases Research Center, Department of Biomedical Sciences (T.R.C., S.C., K.S., M.A.), Biomedical Imaging Research Institute, Department of Biomedical Sciences (S.W., D.L.), and Division of Cardiology, Oppenheimer Atherosclerosis Research Center Cedars-Sinai Heart Institute (P.K.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan (Y.K.); Regeneron Pharmaceuticals, Tarrytown, NY (W.F., Y.B.); Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.L.); Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA (M.C.F.); Departments of Pediatrics (H.M.H.) and Medicine (H.M.H.), University of California, San Diego, La Jolla; and Department of Pediatrics, Rady Children's Hospital, San Diego, CA (H.M.H.). 2. From the Division of Infectious Diseases and Immunology, Department of Biomedical Sciences and Pediatrics (D.W., T.R.C., M.N.R., Y.L., S.C., K.S., M.A.), Infectious and Immunologic Diseases Research Center, Department of Biomedical Sciences (T.R.C., S.C., K.S., M.A.), Biomedical Imaging Research Institute, Department of Biomedical Sciences (S.W., D.L.), and Division of Cardiology, Oppenheimer Atherosclerosis Research Center Cedars-Sinai Heart Institute (P.K.S.), Cedars-Sinai Medical Center, Los Angeles, CA; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan (Y.K.); Regeneron Pharmaceuticals, Tarrytown, NY (W.F., Y.B.); Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.L.); Department of Pathology, David Geffen School of Medicine at UCLA, Los Angeles, CA (M.C.F.); Departments of Pediatrics (H.M.H.) and Medicine (H.M.H.), University of California, San Diego, La Jolla; and Department of Pediatrics, Rady Children's Hospital, San Diego, CA (H.M.H.). moshe.arditi@cshs.org.
Abstract
OBJECTIVE: Kawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell-wall extract (LCWE)-induced KD vasculitis mouse model. METHODS AND RESULTS: We discovered that in addition to aortitis, coronary arteritis and myocarditis, the LCWE-induced KD mouse model is also associated with abdominal aorta dilatation and AAA, as well as renal and iliac artery aneurysms. AAA induced in KD mice was exclusively infrarenal, both fusiform and saccular, with intimal proliferation, myofibroblastic proliferation, break in the elastin layer, vascular smooth muscle cell loss, and inflammatory cell accumulation in the media and adventitia. Il1r(-/-), Il1a(-/-), and Il1b(-/-) mice were protected from KD associated AAA. Infiltrating CD11c(+) macrophages produced active caspase-1, and caspase-1 or NLRP3 deficiency inhibited AAA formation. Treatment with interleukin (IL)-1R antagonist (Anakinra), anti-IL-1α, or anti-IL-1β mAb blocked LCWE-induced AAA formation. CONCLUSIONS: Similar to clinical KD, the LCWE-induced KD vasculitis mouse model can also be accompanied by AAA formation. Both IL-1α and IL-1β play a key role, and use of an IL-1R blocking agent that inhibits both pathways may be a promising therapeutic target not only for KD coronary arteritis, but also for the other systemic arterial aneurysms including AAA that maybe seen in severe cases of KD. The LCWE-induced vasculitis model may also represent an alternative model for AAA disease.
OBJECTIVE:Kawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell-wall extract (LCWE)-induced KD vasculitismouse model. METHODS AND RESULTS: We discovered that in addition to aortitis, coronary arteritis and myocarditis, the LCWE-induced KDmouse model is also associated with abdominal aorta dilatation and AAA, as well as renal and iliac artery aneurysms. AAA induced in KDmice was exclusively infrarenal, both fusiform and saccular, with intimal proliferation, myofibroblastic proliferation, break in the elastin layer, vascular smooth muscle cell loss, and inflammatory cell accumulation in the media and adventitia. Il1r(-/-), Il1a(-/-), and Il1b(-/-) mice were protected from KD associated AAA. Infiltrating CD11c(+) macrophages produced active caspase-1, and caspase-1 or NLRP3 deficiency inhibited AAA formation. Treatment with interleukin (IL)-1R antagonist (Anakinra), anti-IL-1α, or anti-IL-1β mAb blocked LCWE-induced AAA formation. CONCLUSIONS: Similar to clinical KD, the LCWE-induced KD vasculitismouse model can also be accompanied by AAA formation. Both IL-1α and IL-1β play a key role, and use of an IL-1R blocking agent that inhibits both pathways may be a promising therapeutic target not only for KD coronary arteritis, but also for the other systemic arterial aneurysms including AAA that maybe seen in severe cases of KD. The LCWE-induced vasculitis model may also represent an alternative model for AAA disease.
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