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Hemin and Cobalt Protoporphyrin Inhibit NLRP3 Inflammasome Activation by Enhancing Autophagy : A Novel Mechanism of Inflammasome Regulation

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  • معلومة اضافية
    • Contributors:
      Department of Geosciences and Geography; Clinicum; Department of Bacteriology and Immunology; Medicum; Department of Medicine; Reumatologian yksikkö; University of Helsinki; HUS Internal Medicine and Rehabilitation; HUS Inflammation Center
    • بيانات النشر:
      Karger
    • الموضوع:
      2020
    • Collection:
      Helsingfors Universitet: HELDA – Helsingin yliopiston digitaalinen arkisto
    • نبذة مختصرة :
      Inflammasomes are intracellular protein platforms, which, upon activation, produce the highly proinflammatory cytokines interleukin (IL)-1 beta and IL-18. Heme, hemin and their degradation products possess significant immunomodulatory functions. Here, we studied whether hemin regulates inflammasome function in macrophages. Both hemin and its derivative, cobalt protoporphyrin (CoPP), significantly reduced IL-1 beta secretion by cultured human primary macrophages, the human monocytic leukemia cell line and also mouse bone marrow-derived and peritoneal macrophages. Intraperitoneal administration of CoPP to mice prior to urate crystal-induced peritonitis alleviated IL-1 beta secretion to the peritoneal cavity. In cultured macrophages, hemin and CoPP inhibited NLRP3 inflammasome assembly by reducing the amount of intracellular apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). The reduction of ASC was associated with enhanced autophagosome formation and autophagic flux. Inhibition of autophagy prevented the CoPP-induced depletion of ASC, implying that the depletion was caused by increased autophagy. Our data indicate that hemin functions as an endogenous negative regulator of the NLRP3 inflammasome. The inhibition is mediated via enhanced autophagy that results in increased degradation of ASC. This regulatory mechanism may provide a novel approach for the treatment of inflammasome-related diseases. (C) 2016 S. Karger AG, Basel ; Peer reviewed
    • File Description:
      application/pdf
    • Relation:
      The authors gratefully acknowledge Maij a Atuegwu, Mari Jokinen, Paivi Alander and Santtu Hirvikorpi for excellent technical assistance, Anna-Kaisa Ruotsalainen (MSc) for expert assistance in animal breeding and Andrea Dichlberger for expertise in the quantitative real-time RT-PCR and primer design. Biomedicum FACS core facilities are acknowledged for providing flow cytometric services. This work was supported by the Wihuri Research Institute, maintained by the Jenny and Antti Wihuri Foundation, and also by grants from the Ida Montin Foundation, the Maire Lisko Foundation, the Aarne Koskelo Foundation, the Finnish Foundation for Cardiovascular Research, the Paulo Foundation, the Veritas Foundation and the Meilahti Foundation (to K.N.), the Sigrid Juselius Foundation and the Academy of Finland (to A.L.L.), the Stockmann Foundation, the Arthritis Society of Canada, the Canadian Institutes of Health Research (THC 135230) and Helsinki University Central Hospital research funds (to K.K.E.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.; Nurmi , K , Kareinen , I , Virkanen , J , Rajamaki , K , Kouri , V-P , Vaali , K , Levonen , A-L , Fyhrquist , N , Matikainen , S , Kovanen , P T & Eklund , K K 2017 , ' Hemin and Cobalt Protoporphyrin Inhibit NLRP3 Inflammasome Activation by Enhancing Autophagy : A Novel Mechanism of Inflammasome Regulation ' , Journal of innate immunity , vol. 9 , no. 1 , pp. 65-82 . https://doi.org/10.1159/000448894; http://hdl.handle.net/10138/312772; 342416f6-03a3-4f85-b4bd-fd8dcb0d92fe; 84988613648; 000392166700007
    • الدخول الالكتروني :
      http://hdl.handle.net/10138/312772
    • Rights:
      info:eu-repo/semantics/openAccess ; openAccess
    • الرقم المعرف:
      edsbas.DF15DF56