title: Endogenous IRAK-M attenuates postinfarction remodeling through effects on macrophages and fibroblasts.
abstract: OBJECTIVE
  Effective postinfarction repair requires timely suppression of innate immune signals to prevent the catastrophic consequences of uncontrolled inflammation on cardiac geometry and function. In macrophages, interleukin-1 receptor-associated kinase (IRAK)-M acts as a functional decoy preventing uncontrolled toll-like receptor /interleukin-1-mediated responses. Our study investigates the role of IRAK-M as a negative regulator of the postinfarction inflammatory response and as a modulator of cardiac remodeling.
  
  
  RESULTS
  In wild-type mouse infarcts IRAK-M was upregulated in infiltrating macrophages and fibroblasts exhibiting a biphasic response. When compared with wild-type animals, infarcted IRAK-M(-/-) mice had enhanced adverse remodeling and worse systolic dysfunction; however, acute infarct size was comparable between groups. Adverse remodeling in IRAK-M(-/-) animals was associated with enhanced myocardial inflammation and protease activation. The protective actions of IRAK-M involved phenotypic modulation of macrophages and fibroblasts. IRAK-M(-/-) infarcts showed increased infiltration with proinflammatory CD11b+/Ly6C(hi) monocytes; leukocytes harvested from IRAK-M-null infarcts exhibited accentuated cytokine expression. In vitro, IRAK-M expression was upregulated in cytokine-stimulated murine cardiac fibroblasts and suppressed their matrix-degrading properties without affecting their inflammatory activity.
  
  
  CONCLUSIONS
  Endogenous IRAK-M attenuates adverse postinfarction remodeling suppressing leukocyte inflammatory activity, while inhibiting fibroblast-mediated matrix degradation.
authors.affiliation: The Wilf Family Cardiovascular Research Institute, Albert Einstein College of Medicine, 1300 Morris Park Avenue Forchheimer G46B, Bronx, NY 10461, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Amit
authors.initials: A
authors.lastname: Saxena
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Jinyu
authors.initials: J
authors.lastname: Sun
authors.forename: Amit
authors.initials: A
authors.lastname: Gupta
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Lee
authors.forename: Qi
authors.initials: Q
authors.lastname: Tian
authors.forename: Marcin
authors.initials: M
authors.lastname: Dobaczewski
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D007113:Immunity, Innate; D007249:Inflammation / Q000000981:diagnostic imaging / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D009206:Myocardium / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D020556:Neutrophil Infiltration; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014463:Ultrasonography; D015854:Up-Regulation; D020257:Ventricular Remodeling
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D012333:RNA, Messenger; D003094:Collagen; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse