نبذة مختصرة : Objectives The NLRP3 inflammasome plays a key role in arterial wall inflammation. In this study, we elucidated the role of serum lipoproteins in the regulation of NLRP3 inflammasome activation by serum amyloid A (SAA) and other inflammasome activators. Methods The effect of lipoproteins on the NLRP3 inflammasome activation was studied in primary human macrophages and THP-1 macrophages. The effect of oxidised low-density lipoprotein (LDL) was examined in an in vivo mouse model of SAA-induced peritoneal inflammation. Results Native and oxidised high-density lipoproteins (HDL3) and LDLs inhibited the interaction of SAA with TLR4. HDL3 and LDL inhibited the secretion of interleukin (IL)-1 beta and tumor necrosis factor by reducing their transcription. Oxidised forms of these lipoproteins reduced the secretion of mature IL-1 beta also by inhibiting the activation of NLRP3 inflammasome induced by SAA, ATP, nigericin and monosodium urate crystals. Specifically, oxidised LDL was found to inhibit the inflammasome complex formation. No cellular uptake of lipoproteins was required, nor intact lipoprotein particles for the inhibitory effect, as the lipid fraction of oxidised LDL was sufficient. The inhibition of NLRP3 inflammasome activation by oxidised LDL was partially dependent on autophagy. Finally, oxidised LDL inhibited the SAA-induced peritoneal inflammation and IL-1 beta secretion in vivo. Conclusions These findings reveal that both HDL3 and LDL inhibit the proinflammatory activity of SAA and this inhibition is further enhanced by lipoprotein oxidation. Thus, lipoproteins possess major anti-inflammatory functions that hinder the NLRP3 inflammasome-activating signals, particularly those exerted by SAA, which has important implications in the pathogenesis of cardiovascular diseases. ; Peer reviewed
Relation: We thank Maija Atuegwu, Mari Jokinen, Jarmo Koponen and Suvi M?kinen at Wihuri Research Institute for the excellent technical assistance. This work was supported by Helsinki University Hospital research funds, Stockmann?s Foundation, Finska L?kares?llskapet and an independent research grant from Roche (KKE), the Academy of Finland (#315568, #332564 K?), the Novo Nordisk Fonden (#NNF19OC0057411 K?) and the Finnish Foundation for Cardiovascular Research (K? and MBL). KNu is a recipient of grants from P?ivikki and Sakari Sohlberg Foundation, Yrj? Jahnsson Foundation, Maire Lisko Foundation and Reumatautien tutkimuss??ti?. KNi is a recipient of grants from Orion Research Foundation and Aarne Koskelo Foundation. IK is a recipient of a grant from the Finnish Foundation of Veterinary Research. KS is a recipient of a grant from Orion Research Foundation. The Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation. We thank Maija Atuegwu, Mari Jokinen, Jarmo Koponen and Suvi Mäkinen at Wihuri Research Institute for the excellent technical assistance. This work was supported by Helsinki University Hospital research funds, Stockmann’s Foundation, Finska Läkaresällskapet and an independent research grant from Roche (KKE), the Academy of Finland (#315568, #332564 KÖ), the Novo Nordisk Fonden (#NNF19OC0057411 KÖ) and the Finnish Foundation for Cardiovascular Research (KÖ and MBL). KNu is a recipient of grants from Päivikki and Sakari Sohlberg Foundation, Yrjö Jahnsson Foundation, Maire Lisko Foundation and Reumatautien tutkimussäätiö. KNi is a recipient of grants from Orion Research Foundation and Aarne Koskelo Foundation. IK is a recipient of a grant from the Finnish Foundation of Veterinary Research. KS is a recipient of a grant from Orion Research Foundation. The Wihuri Research Institute is maintained by the Jenny and Antti Wihuri Foundation.; Nurmi , K , Niemi , K , Kareinen , I , Silventoinen , K , Lorey , M B , Chen , Y , Kouri , VP , Parantainen , J , Juutilainen , T , Öörni , K , Kovanen , P T , Nordström , D , Matikainen , S & Eklund , K K 2021 , ' Native and oxidised lipoproteins negatively regulate the serum amyloid A‐induced NLRP3 inflammasome activation in human macrophages ' , Clinical Translational Immunology , vol. 10 , 1323 . https://doi.org/10.1002/cti2.1323; Bibtex: Nurmi2021; ORCID: /0000-0002-9525-0250/work/99661228; ORCID: /0000-0001-5605-6714/work/99661454; ORCID: /0000-0002-6791-198X/work/146909688; http://hdl.handle.net/10138/334096; 27a01514-9c65-41a9-891e-f35c14d06e21; 000688354300002
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