PMID- 38000727
OWN - NLM
STAT- MEDLINE
DCOM- 20240108
LR  - 20240127
IS  - 1873-6424 (Electronic)
IS  - 0269-7491 (Print)
IS  - 0269-7491 (Linking)
VI  - 341
DP  - 2024 Jan 15
TI  - Molecular mechanisms underlying NLRP3 inflammasome activation and IL-1beta 
      production in air pollution fine particulate matter (PM(2.5))-primed macrophages.
PG  - 122997
LID - S0269-7491(23)01999-1 [pii]
LID - 10.1016/j.envpol.2023.122997 [doi]
LID - 122997
AB  - Exposure to air pollution fine particulate matter (PM(2.5)) aggravates 
      respiratory and cardiovascular diseases. It has been proposed that PM(2.5) uptake 
      by alveolar macrophages promotes local inflammation that ignites a systemic 
      response, but precise underlying mechanisms remain unclear. Here, we demonstrate 
      that PM(2.5) phagocytosis leads to NLRP3 inflammasome activation and subsequent 
      release of the pro-inflammatory master cytokine IL-1beta. Inflammasome priming and 
      assembly was time- and dose-dependent in inflammasome-reporter THP-1-ASC-GFP 
      cells, and consistent across PM(2.5) samples of variable chemical composition. 
      While inflammasome activation was promoted by different PM(2.5) surrogates, 
      significant IL-1beta release could only be observed after stimulation with 
      transition-metal rich Residual Oil Fly Ash (ROFA) particles. This effect was 
      confirmed in primary human monocyte-derived macrophages and murine bone 
      marrow-derived macrophages (BMDMs), and by confocal imaging of 
      inflammasome-reporter ASC-Citrine BMDMs. IL-1beta release by ROFA was dependent on 
      the NLRP3 inflammasome, as indicated by lack of IL-1beta production in ROFA-exposed 
      NLRP3-deficient (Nlrp3(-/-)) BMDMs, and by specific NLRP3 inhibition with the 
      pharmacological compound MCC950. In addition, while ROFA promoted the 
      upregulation of pro-inflammatory gene expression and cytokines release, MCC950 
      reduced TNF-alpha, IL-6, and CCL2 production. Furthermore, inhibition of TNF-alpha with a 
      neutralizing antibody decreased IL-1beta release in ROFA-exposed BMDMs. Using 
      electron tomography, ROFA particles were observed inside intracellular vesicles 
      and mitochondria, which showed signs of ultrastructural damage. Mechanistically, 
      we identified lysosomal rupture, K(+) efflux, and impaired mitochondrial function 
      as important prerequisites for ROFA-mediated IL-1beta release. Interestingly, 
      specific inhibition of superoxide anion production (O(2)(*-)) from mitochondrial 
      respiratory Complex I, but not III, blunted IL-1beta release in ROFA-exposed BMDMs. 
      Our findings unravel the mechanism by which PM(2.5) promotes IL-1beta release in 
      macrophages and provide a novel link between innate immune response and exposure 
      to air pollution PM(2.5).
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.
FAU - Caceres, Lourdes
AU  - Caceres L
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany; Universidad de Buenos Aires, 
      Facultad de Farmacia y Bioquimica, Departamento de Ciencias Quimicas, C1113AAD, 
      Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, Instituto de 
      Bioquimica y Medicina Molecular Prof. Alberto Boveris (IBIMOL), C1113AAD, Buenos 
      Aires, Argentina.
FAU - Abogunloko, Tijani
AU  - Abogunloko T
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany; Spemann Graduate School of 
      Biology and Medicine (SGBM), University of Freiburg, 79104, Freiburg, Germany.
FAU - Malchow, Sara
AU  - Malchow S
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany.
FAU - Ehret, Fabienne
AU  - Ehret F
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany; Faculty of Biology, University 
      of Freiburg, 79104, Freiburg im Breisgau, Germany.
FAU - Merz, Julian
AU  - Merz J
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany.
FAU - Li, Xiaowei
AU  - Li X
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany.
FAU - Sol Mitre, Lucia
AU  - Sol Mitre L
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany; Spemann Graduate School of 
      Biology and Medicine (SGBM), University of Freiburg, 79104, Freiburg, Germany.
FAU - Magnani, Natalia
AU  - Magnani N
AD  - Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Departamento de 
      Ciencias Quimicas, C1113AAD, Buenos Aires, Argentina; CONICET - Universidad de 
      Buenos Aires, Instituto de Bioquimica y Medicina Molecular Prof. Alberto Boveris 
      (IBIMOL), C1113AAD, Buenos Aires, Argentina.
FAU - Tasat, Deborah
AU  - Tasat D
AD  - Universidad Nacional de General San Martin, Escuela de Ciencia y Tecnologia, 
      B1650, General San Martin, Argentina.
FAU - Mwinyella, Timothy
AU  - Mwinyella T
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany.
FAU - Spiga, Lisa
AU  - Spiga L
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany.
FAU - Suchanek, Dymphie
AU  - Suchanek D
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany.
FAU - Fischer, Larissa
AU  - Fischer L
AD  - Faculty of Biology, University of Freiburg, 79104, Freiburg im Breisgau, Germany; 
      Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106, 
      Freiburg, Germany.
FAU - Gorka, Oliver
AU  - Gorka O
AD  - Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106, 
      Freiburg, Germany.
FAU - Colin Gissler, Mark
AU  - Colin Gissler M
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany.
FAU - Hilgendorf, Ingo
AU  - Hilgendorf I
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany.
FAU - Stachon, Peter
AU  - Stachon P
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany.
FAU - Rog-Zielinska, Eva
AU  - Rog-Zielinska E
AD  - Institute for Experimental Cardiovascular Medicine, University Heart Center, 
      Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, 
      Germany.
FAU - Gross, Olaf
AU  - Gross O
AD  - Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106, 
      Freiburg, Germany.
FAU - Westermann, Dirk
AU  - Westermann D
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany.
FAU - Evelson, Pablo
AU  - Evelson P
AD  - Universidad de Buenos Aires, Facultad de Farmacia y Bioquimica, Departamento de 
      Ciencias Quimicas, C1113AAD, Buenos Aires, Argentina; CONICET - Universidad de 
      Buenos Aires, Instituto de Bioquimica y Medicina Molecular Prof. Alberto Boveris 
      (IBIMOL), C1113AAD, Buenos Aires, Argentina.
FAU - Wolf, Dennis
AU  - Wolf D
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany. Electronic address: 
      dennis.wolf@uniklinik-freiburg.de.
FAU - Marchini, Timoteo
AU  - Marchini T
AD  - Department of Cardiology and Angiology, University Heart Center, University of 
      Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University 
      of Freiburg, 79110, Freiburg im Breisgau, Germany; Universidad de Buenos Aires, 
      Facultad de Farmacia y Bioquimica, Departamento de Ciencias Quimicas, C1113AAD, 
      Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, Instituto de 
      Bioquimica y Medicina Molecular Prof. Alberto Boveris (IBIMOL), C1113AAD, Buenos 
      Aires, Argentina.
LA  - eng
PT  - Journal Article
DEP - 20231122
PL  - England
TA  - Environ Pollut
JT  - Environmental pollution (Barking, Essex : 1987)
JID - 8804476
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (Particulate Matter)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 0 (Cytokines)
RN  - 0 (Coal Ash)
SB  - IM
MH  - Humans
MH  - Animals
MH  - Mice
MH  - *Inflammasomes/metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/genetics
MH  - Particulate Matter/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Macrophages/metabolism
MH  - Cytokines/metabolism
MH  - Coal Ash/pharmacology
MH  - *Air Pollution
PMC - PMC10804998
OTO - NOTNLM
OT  - Inflammation
OT  - K(+) efflux
OT  - Lysosomal disruption
OT  - Macrophages
OT  - Mitochondria
OT  - Particulate matter
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/11/25 07:42
MHDA- 2024/01/08 06:41
PMCR- 2024/01/15
CRDT- 2023/11/24 19:30
PHST- 2023/09/01 00:00 [received]
PHST- 2023/11/10 00:00 [revised]
PHST- 2023/11/17 00:00 [accepted]
PHST- 2024/01/08 06:41 [medline]
PHST- 2023/11/25 07:42 [pubmed]
PHST- 2023/11/24 19:30 [entrez]
PHST- 2024/01/15 00:00 [pmc-release]
AID - S0269-7491(23)01999-1 [pii]
AID - 122997 [pii]
AID - 10.1016/j.envpol.2023.122997 [doi]
PST - ppublish
SO  - Environ Pollut. 2024 Jan 15;341:122997. doi: 10.1016/j.envpol.2023.122997. Epub 
      2023 Nov 22.