title: IL-1 Signaling Is Critically Required in Stromal Cells in Kawasaki Disease Vasculitis Mouse Model: Role of Both IL-1α and IL-1β.
abstract: OBJECTIVE
  Kawasaki disease (KD) is the most common cause of acute vasculitis and acquired cardiac disease among US children. We have previously shown that both TLR2/MyD88 and interleukin (IL)-1β signaling are required for the Lactobacillus casei cell wall extract-induced KD vasculitis mouse model. The objectives of this study were to investigate the cellular origins of IL-1 production, the role of CD11c(+) dendritic cells and macrophages, and the relative contribution of hematopoietic and stromal cells for IL-1 responsive cells, as well the MyD88 signaling, in Lactobacillus casei cell wall extract-induced KD mouse model of vasculitis.
  
  
  RESULTS
  Using mouse knockout models and antibody depletion, we found that both IL-1α and IL-1β were required for Lactobacillus casei cell wall extract-induced KD. Both dendritic cells and macrophages were necessary, and we found that MyD88 signaling was required in both hematopoietic and stromal cells. However, IL-1 response and signaling were critically required in nonendothelial stromal cells, but not in hematopoietic cells.
  
  
  CONCLUSIONS
  Our results suggest that IL-1α and IL-1β, as well as CD11c(+) dendritic cells and macrophages, are essential for the development of KD vasculitis and coronary arteritis in this mouse model. Bone marrow chimera experiments suggest that MyD88 signaling is important in both hematopoietic and stromal cells, whereas IL-1 signaling and response are required only in stromal cells, but not in endothelial cells. Determining the role of IL-1α and IL-1β and of specific cell types in the KD vasculitis mouse model may have important implications for the design of more targeted therapies and understanding of the molecular mechanisms of KD immunopathologies.
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).
authors.forename: Youngho
authors.initials: Y
authors.lastname: Lee
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).
authors.forename: Daiko
authors.initials: D
authors.lastname: Wakita
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).
authors.forename: Jargalsaikhan
authors.initials: J
authors.lastname: Dagvadorj
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).
authors.forename: Kenichi
authors.initials: K
authors.lastname: Shimada
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).
authors.forename: Shuang
authors.initials: S
authors.lastname: Chen
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).
authors.forename: Ganghua
authors.initials: G
authors.lastname: Huang
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).
authors.forename: Thomas J A
authors.initials: TJ
authors.lastname: Lehman
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).
authors.forename: Hal M
authors.initials: HM
authors.lastname: Hoffman
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.).
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Crother
authors.affiliation: From the Division of Pediatric Infectious Diseases and Immunology, Department of Pediatric, Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA (Y.L., D.W., J.D., K.S., S.C., G.H., T.R.C., M.A.); Department of Rheumatology, Pediatric Rheumatology, Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY (T.J.A.L.); Department of Pathology, David Geffen School of Medicine at UCLA (M.C.F.); and Department of Pediatrics, Pediatric Rheumatology, University of California, San Diego, La Jolla (H.M.H.). moshe.arditi@cshs.org.
authors.forename: Moshe
authors.initials: M
authors.lastname: Arditi
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001025:Aortitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002352:Carrier Proteins / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D002473:Cell Wall; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D007780:Lacticaseibacillus casei; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009080:Mucocutaneous Lymph Node Syndrome / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology; D018183:Transplantation Chimera
chemical_list: C540422:Aim2 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C587672:IL1B protein, mouse; C583355:IL1R1 protein, mouse; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D053573:Receptors, Interleukin-1 Type I; D020170:Caspase 1
keywords: MyD88; dendritic cells; endothelial cells; interleukin-1; mucocutaneous lymph node syndrome; protein