Kristiina Rajamäki1, Mikko I Mäyränpää1, Ana Risco1, Jarno Tuimala1, Katariina Nurmi1, Ana Cuenda1, Kari K Eklund1, Katariina Öörni1, Petri T Kovanen2. 1. 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.). 2. 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.
Abstract
OBJECTIVE: 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. APPROACH AND RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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 humanatherosclerotic lesions. APPROACH AND RESULTS: 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 necroticlipid 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. CONCLUSIONS: 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: Laura Barrio; Sara Román-García; Ester Díaz-Mora; Ana Risco; Rodrigo Jiménez-Saiz; Yolanda R Carrasco; Ana Cuenda Journal: Front Cell Dev Biol Date: 2020-03-24
Authors: Muhammad Torequl Islam; Sanaa K Bardaweel; Mohammad S Mubarak; Wojciech Koch; Katarzyna Gaweł-Beben; Beata Antosiewicz; Javad Sharifi-Rad Journal: Front Immunol Date: 2020-09-25 Impact factor: 7.561
Authors: Abby C Lee; Jaideep Chakladar; Wei Tse Li; Chengyu Chen; Eric Y Chang; Jessica Wang-Rodriguez; Weg M Ongkeko Journal: Int J Mol Sci Date: 2020-07-31 Impact factor: 5.923