Noncanonical Roles of Caspase-4 and Caspase-5 in Heme-Driven IL-1β Release and Cell Death.
Alarmins
/ metabolism
Anemia, Sickle Cell
/ metabolism
Caspases
/ metabolism
Caspases, Initiator
/ metabolism
Cell Death
Cells, Cultured
Erythrocytes
/ physiology
Heme
/ metabolism
Hemolysis
Humans
Inflammasomes
/ metabolism
Inflammation
/ metabolism
Interleukin-1beta
/ metabolism
Macrophages
/ immunology
Up-Regulation
Journal
Journal of immunology (Baltimore, Md. : 1950)
ISSN: 1550-6606
Titre abrégé: J Immunol
Pays: United States
ID NLM: 2985117R
Informations de publication
Date de publication:
15 04 2021
15 04 2021
Historique:
received:
02
03
2020
accepted:
28
01
2021
pubmed:
21
3
2021
medline:
24
8
2021
entrez:
20
3
2021
Statut:
ppublish
Résumé
Excessive release of heme from RBCs is a key pathophysiological feature of several disease states, including bacterial sepsis, malaria, and sickle cell disease. This hemolysis results in an increased level of free heme that has been implicated in the inflammatory activation of monocytes, macrophages, and the endothelium. In this study, we show that extracellular heme engages the human inflammatory caspases, caspase-1, caspase-4, and caspase-5, resulting in the release of IL-1β. Heme-induced IL-1β release was further increased in macrophages from patients with sickle cell disease. In human primary macrophages, heme activated caspase-1 in an inflammasome-dependent manner, but heme-induced activation of caspase-4 and caspase-5 was independent of canonical inflammasomes. Furthermore, we show that both caspase-4 and caspase-5 are essential for heme-induced IL-1β release, whereas caspase-4 is the primary contributor to heme-induced cell death. Together, we have identified that extracellular heme is a damage-associated molecular pattern that can engage canonical and noncanonical inflammasome activation as a key mediator of inflammation in macrophages.
Identifiants
pubmed: 33741688
pii: jimmunol.2000226
doi: 10.4049/jimmunol.2000226
pmc: PMC8026643
mid: NIHMS1669212
doi:
Substances chimiques
Alarmins
0
Inflammasomes
0
Interleukin-1beta
0
Heme
42VZT0U6YR
CASP4 protein, human
EC 3.4.22.-
CASP5 protein, human
EC 3.4.22.-
Caspases
EC 3.4.22.-
Caspases, Initiator
EC 3.4.22.-
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
1878-1889Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM121389
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL136415
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL114567
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA125123
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK060445
Pays : United States
Organisme : NICHD NIH HHS
ID : P50 HD103555
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK121479
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008231
Pays : United States
Organisme : NCRR NIH HHS
ID : S10 RR024574
Pays : United States
Informations de copyright
Copyright © 2021 by The American Association of Immunologists, Inc.
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