title: p38δ MAPK: A Novel Regulator of NLRP3 Inflammasome Activation With Increased Expression in Coronary Atherogenesis.
abstract: Activation of the inflammasome pathway in macrophages results in the secretion of 2 potent proinflammatory and proatherogenic cytokines, interleukin (IL)-1β, and IL-18. Atherosclerotic lesions are characterized by the presence of various endogenous activators of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, including cholesterol crystals and extracellular ATP. The aim of this study was to comprehensively characterize the expression of inflammasome pathway components and regulators in human atherosclerotic lesions.
  
  
  
  Twenty human coronary artery RNA samples from 10 explanted hearts were analyzed using an inflammasome pathway-focused quantitative polymerase chain reaction array. Advanced atherosclerotic plaques, when compared with early-to-intermediate lesions from the same coronary trees, displayed significant upregulation of 12 target genes, including the key inflammasome components apoptosis-associated speck-like protein containing a CARD domain, caspase-1, and IL-18. Immunohistochemical stainings of the advanced plaques revealed macrophage foam cells positive for NLRP3 inflammasome components around the necrotic lipid cores. The polymerase chain reaction array target p38δ mitogen-activated protein kinase was upregulated in advanced plaques and strongly expressed by lesional macrophage foam cells. In cultured human monocyte-derived macrophages, the p38δ mitogen-activated protein kinase was activated by intracellular stress signals triggered during ATP- and cholesterol crystal-induced NLRP3 inflammasome activation and was required for NLRP3-mediated IL-1β secretion.
  
  
  
  Increased expression of the key inflammasome components in advanced coronary lesions implies enhanced activity of the inflammasome pathway in progression of coronary atherosclerosis. The p38δ mitogen-activated protein kinase was identified as a novel regulator of NLRP3 inflammasome activation in primary human macrophages, and thus, represents a potential target for modulation of atherosclerotic inflammation.
authors.affiliation: From the Wihuri Research Institute, Helsinki, Finland (K.R., K.N., K.Ö., P.T.K.); University of Helsinki, Clinicum, Helsinki, Finland (K.R., K.K.E.); Department of Pathology, University of Helsinki, Helsinki, Finland (M.I.M.); Division of Pathology, HUSLAB, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland (M.I.M.); Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CNB/CSIC), Madrid, Spain (A.R., A.C.); RS-koulutus, Helsinki, Finland (J.T.); and Helsinki University Central Hospital, Department of Rheumatology, Helsinki, Finland (K.K.E.).
authors.forename: Kristiina
authors.initials: K
authors.lastname: Rajamäki
authors.affiliation: From the Wihuri Research Institute, Helsinki, Finland (K.R., K.N., K.Ö., P.T.K.); University of Helsinki, Clinicum, Helsinki, Finland (K.R., K.K.E.); Department of Pathology, University of Helsinki, Helsinki, Finland (M.I.M.); Division of Pathology, HUSLAB, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland (M.I.M.); Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CNB/CSIC), Madrid, Spain (A.R., A.C.); RS-koulutus, Helsinki, Finland (J.T.); and Helsinki University Central Hospital, Department of Rheumatology, Helsinki, Finland (K.K.E.).
authors.forename: Mikko I
authors.initials: MI
authors.lastname: Mäyränpää
authors.affiliation: From the Wihuri Research Institute, Helsinki, Finland (K.R., K.N., K.Ö., P.T.K.); University of Helsinki, Clinicum, Helsinki, Finland (K.R., K.K.E.); Department of Pathology, University of Helsinki, Helsinki, Finland (M.I.M.); Division of Pathology, HUSLAB, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland (M.I.M.); Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CNB/CSIC), Madrid, Spain (A.R., A.C.); RS-koulutus, Helsinki, Finland (J.T.); and Helsinki University Central Hospital, Department of Rheumatology, Helsinki, Finland (K.K.E.).
authors.forename: Ana
authors.initials: A
authors.lastname: Risco
authors.affiliation: From the Wihuri Research Institute, Helsinki, Finland (K.R., K.N., K.Ö., P.T.K.); University of Helsinki, Clinicum, Helsinki, Finland (K.R., K.K.E.); Department of Pathology, University of Helsinki, Helsinki, Finland (M.I.M.); Division of Pathology, HUSLAB, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland (M.I.M.); Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CNB/CSIC), Madrid, Spain (A.R., A.C.); RS-koulutus, Helsinki, Finland (J.T.); and Helsinki University Central Hospital, Department of Rheumatology, Helsinki, Finland (K.K.E.).
authors.forename: Jarno
authors.initials: J
authors.lastname: Tuimala
authors.affiliation: From the Wihuri Research Institute, Helsinki, Finland (K.R., K.N., K.Ö., P.T.K.); University of Helsinki, Clinicum, Helsinki, Finland (K.R., K.K.E.); Department of Pathology, University of Helsinki, Helsinki, Finland (M.I.M.); Division of Pathology, HUSLAB, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland (M.I.M.); Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CNB/CSIC), Madrid, Spain (A.R., A.C.); RS-koulutus, Helsinki, Finland (J.T.); and Helsinki University Central Hospital, Department of Rheumatology, Helsinki, Finland (K.K.E.).
authors.forename: Katariina
authors.initials: K
authors.lastname: Nurmi
authors.affiliation: From the Wihuri Research Institute, Helsinki, Finland (K.R., K.N., K.Ö., P.T.K.); University of Helsinki, Clinicum, Helsinki, Finland (K.R., K.K.E.); Department of Pathology, University of Helsinki, Helsinki, Finland (M.I.M.); Division of Pathology, HUSLAB, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland (M.I.M.); Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CNB/CSIC), Madrid, Spain (A.R., A.C.); RS-koulutus, Helsinki, Finland (J.T.); and Helsinki University Central Hospital, Department of Rheumatology, Helsinki, Finland (K.K.E.).
authors.forename: Ana
authors.initials: A
authors.lastname: Cuenda
authors.affiliation: From the Wihuri Research Institute, Helsinki, Finland (K.R., K.N., K.Ö., P.T.K.); University of Helsinki, Clinicum, Helsinki, Finland (K.R., K.K.E.); Department of Pathology, University of Helsinki, Helsinki, Finland (M.I.M.); Division of Pathology, HUSLAB, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland (M.I.M.); Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CNB/CSIC), Madrid, Spain (A.R., A.C.); RS-koulutus, Helsinki, Finland (J.T.); and Helsinki University Central Hospital, Department of Rheumatology, Helsinki, Finland (K.K.E.).
authors.forename: Kari K
authors.initials: KK
authors.lastname: Eklund
authors.affiliation: From the Wihuri Research Institute, Helsinki, Finland (K.R., K.N., K.Ö., P.T.K.); University of Helsinki, Clinicum, Helsinki, Finland (K.R., K.K.E.); Department of Pathology, University of Helsinki, Helsinki, Finland (M.I.M.); Division of Pathology, HUSLAB, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland (M.I.M.); Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CNB/CSIC), Madrid, Spain (A.R., A.C.); RS-koulutus, Helsinki, Finland (J.T.); and Helsinki University Central Hospital, Department of Rheumatology, Helsinki, Finland (K.K.E.).
authors.forename: Katariina
authors.initials: K
authors.lastname: Öörni
authors.affiliation: From the Wihuri Research Institute, Helsinki, Finland (K.R., K.N., K.Ö., P.T.K.); University of Helsinki, Clinicum, Helsinki, Finland (K.R., K.K.E.); Department of Pathology, University of Helsinki, Helsinki, Finland (M.I.M.); Division of Pathology, HUSLAB, Meilahti Laboratories of Pathology, Helsinki University Central Hospital, Helsinki, Finland (M.I.M.); Department of Immunology and Oncology, Centro Nacional de Biotecnología/Consejo Superior de Investigaciones Cientificas (CNB/CSIC), Madrid, Spain (A.R., A.C.); RS-koulutus, Helsinki, Finland (J.T.); and Helsinki University Central Hospital, Department of Rheumatology, Helsinki, Finland (K.K.E.). petri.kovanen@wri.fi.
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D003331:Coronary Vessels / Q000201:enzymology* / Q000473:pathology; D003460:Crystallization; D004789:Enzyme Activation; D005487:Foam Cells / Q000201:enzymology* / Q000473:pathology; D020869:Gene Expression Profiling / Q000379:methods; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D048292:Mitogen-Activated Protein Kinase 13 / Q000235:genetics / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D009687:Nuclear Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D058226:Plaque, Atherosclerotic; D061251:Primary Cell Culture; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000949:Histocompatibility Antigens Class II; D058847:Inflammasomes; C083728:MHC class II transactivator protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D009687:Nuclear Proteins; D015534:Trans-Activators; D000255:Adenosine Triphosphate; D002784:Cholesterol; D048292:Mitogen-Activated Protein Kinase 13
keywords: coronary artery disease; inflammation; innate immunity; interleukin; macrophage