Native and oxidised lipoproteins negatively regulate the serum amyloid A-induced NLRP3 inflammasome activation in human macrophages

Katariina Nurmi; Katri Niemi; Ilona Kareinen; Kristiina Silventoinen; Martina B Lorey; Yan Chen; Vesa-Petteri Kouri; Jukka Parantainen; Timo Juutilainen; Katariina Öörni; Petri T Kovanen; Dan Nordström; Sampsa Matikainen; Kari K Eklund

doi:10.1002/cti2.1323

Native and oxidised lipoproteins negatively regulate the serum amyloid A-induced NLRP3 inflammasome activation in human macrophages

Clin Transl Immunology. 2021 Aug 3;10(8):e1323. doi: 10.1002/cti2.1323. eCollection 2021.

Authors

Katariina Nurmi¹, Katri Niemi², Ilona Kareinen², Kristiina Silventoinen¹, Martina B Lorey^{1

2}, Yan Chen¹, Vesa-Petteri Kouri¹, Jukka Parantainen¹, Timo Juutilainen³, Katariina Öörni², Petri T Kovanen², Dan Nordström^{1

4}, Sampsa Matikainen¹, Kari K Eklund^{1

5

6}

Affiliations

¹ Helsinki Rheumatic Diseases and Inflammation Research Group Translational Immunology Research Program University of Helsinki Helsinki University Clinicum Helsinki Finland.
² Wihuri Research Institute Helsinki Finland.
³ Division of Orthopedics Department of Surgery Helsinki University Central Hospital Vantaa Finland.
⁴ Internal Medicine and Rehabilitation University of Helsinki and Helsinki University Hospital Helsinki Finland.
⁵ Division of Rheumatology Department of Medicine Helsinki University Hospital Helsinki Finland.
⁶ Orton Orthopaedic Hospital Helsinki Finland.

Abstract

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)-1β and tumor necrosis factor by reducing their transcription. Oxidised forms of these lipoproteins reduced the secretion of mature IL-1β 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-1β 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.

Keywords: NLRP3 inflammasome activation; extracellular vesicle; high‐density lipoprotein; low‐density lipoprotein; oxidised lipoprotein; serum amyloid A.