APOL1 risk variants in individuals of African genetic ancestry drive endothelial cell defects that exacerbate sepsis.
Animals
Apolipoprotein L1
/ blood
Black People
/ genetics
COVID-19
/ genetics
DNA, Mitochondrial
/ metabolism
Endothelial Cells
/ metabolism
Genetic Predisposition to Disease
/ genetics
Humans
Inflammation
/ genetics
Membrane Proteins
/ antagonists & inhibitors
Mice
Mice, Knockout
Mitophagy
/ genetics
NLR Family, Pyrin Domain-Containing 3 Protein
/ antagonists & inhibitors
Risk Factors
Sepsis
/ genetics
Severity of Illness Index
White People
/ genetics
APOL1
COVID-19
endothelial cell
mitophagy
sepsis
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
09 11 2021
09 11 2021
Historique:
received:
26
02
2021
revised:
18
06
2021
accepted:
06
10
2021
pubmed:
30
10
2021
medline:
24
11
2021
entrez:
29
10
2021
Statut:
ppublish
Résumé
The incidence and severity of sepsis is higher among individuals of African versus European ancestry. We found that genetic risk variants (RVs) in the trypanolytic factor apolipoprotein L1 (APOL1), present only in individuals of African ancestry, were associated with increased sepsis incidence and severity. Serum APOL1 levels correlated with sepsis and COVID-19 severity, and single-cell sequencing in human kidneys revealed high expression of APOL1 in endothelial cells. Analysis of mice with endothelial-specific expression of RV APOL1 and in vitro studies demonstrated that RV APOL1 interfered with mitophagy, leading to cytosolic release of mitochondrial DNA and activation of the inflammasome (NLRP3) and the cytosolic nucleotide sensing pathways (STING). Genetic deletion or pharmacological inhibition of NLRP3 and STING protected mice from RV APOL1-induced permeability defects and proinflammatory endothelial changes in sepsis. Our studies identify the inflammasome and STING pathways as potential targets to reduce APOL1-associated health disparities in sepsis and COVID-19.
Identifiants
pubmed: 34715018
pii: S1074-7613(21)00410-6
doi: 10.1016/j.immuni.2021.10.004
pmc: PMC9338439
mid: NIHMS1815073
pii:
doi:
Substances chimiques
APOL1 protein, human
0
Apolipoprotein L1
0
DNA, Mitochondrial
0
Membrane Proteins
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
Nlrp3 protein, mouse
0
Sting1 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2632-2649.e6Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL137006
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL137915
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK087635
Pays : United States
Organisme : CSRD VA
ID : I01 CX001897
Pays : United States
Organisme : NHLBI NIH HHS
ID : K24 HL155804
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK076077
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK105821
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2021. Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of interests The Susztak lab is supported by Boehringer Ingelheim, Regeneron, Bayer, GSK, Novartis, and Novo Nordisk for work that is not related to the current manuscript. K.S. is on the advisory board of Jnana.
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