Noncanonical Roles of Caspase-4 and Caspase-5 in Heme-Driven IL-1β Release and Cell Death

Beatriz E. Bolívar; Alexandra N. Brown-Suedel; Brittany A. Rohrman; Chloé I. Charendoff; Vanda Yazdani; John D. Belcher; Gregory M. Vercellotti; Jonathan M. Flanagan; Lisa Bouchier-Hayes

doi:10.4049/jimmunol.2000226

Noncanonical Roles of Caspase-4 and Caspase-5 in Heme-Driven IL-1β Release and Cell Death

Beatriz E. Bolívar, Alexandra N. Brown-Suedel, Brittany A. Rohrman, Chloé I. Charendoff, Vanda Yazdani, John D. Belcher, Gregory M. Vercellotti, Jonathan M. Flanagan, Lisa Bouchier-Hayes

Medicine - Hematology, Oncology, Transplant

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1878-1889
Number of pages	12
Journal	Journal of Immunology
Volume	206
Issue number	8
DOIs	https://doi.org/10.4049/jimmunol.2000226
State	Published - Apr 15 2021

Bibliographical note

Funding Information:
We thank the members of L.B.-H.’s laboratory, past and present, for helpful discussions and careful reading of the manuscript. We thank Doug Green and the members of his laboratory for valuable suggestions. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with the assistance of Joel M. Sederstrom. The graphical abstract was drawn using BioRender software.

Funding Information:
This work was supported by National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant T32DK060445 (to B.E.B., B.A.R.), NIH, NIDDK F32DK121479 (to B.E.B.), NIH, National Institute of General Medical Sciences (NIGMS) Grant T32GM008231 (to A.N.B.-S.), NIH, NIGMS Grant R01GM121389 (to L.B.-H.), NIH, National Heart, Lung, and Blood Institute (NHLBI) R01HL114567 (to J.D.B., G.M.V.), NIH, NHLBI R01-HL136415 (to J.M.F.), and CPRIT-RP180672, NIHCA125123, and NIHRR024574 (to the Cytometry and Cell Sorting Core at Baylor College of Medicine).

Publisher Copyright:
Copyright Ó 2021 by The American Association of Immunologists, Inc. 0022-1767/21/$37.50

Keywords

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

PubMed: MeSH publication types

Research Support, Non-U.S. Gov't
Journal Article
Research Support, N.I.H., Extramural

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.4049/jimmunol.2000226

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@article{00ab15784fe94daabfcc6c000b5cd648,

title = "Noncanonical Roles of Caspase-4 and Caspase-5 in Heme-Driven IL-1β Release and Cell Death",

abstract = "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.",

keywords = "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",

author = "Bol{\'i}var, {Beatriz E.} and Brown-Suedel, {Alexandra N.} and Rohrman, {Brittany A.} and Charendoff, {Chlo{\'e} I.} and Vanda Yazdani and Belcher, {John D.} and Vercellotti, {Gregory M.} and Flanagan, {Jonathan M.} and Lisa Bouchier-Hayes",

note = "Funding Information: We thank the members of L.B.-H.{\textquoteright}s laboratory, past and present, for helpful discussions and careful reading of the manuscript. We thank Doug Green and the members of his laboratory for valuable suggestions. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with the assistance of Joel M. Sederstrom. The graphical abstract was drawn using BioRender software. Funding Information: This work was supported by National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant T32DK060445 (to B.E.B., B.A.R.), NIH, NIDDK F32DK121479 (to B.E.B.), NIH, National Institute of General Medical Sciences (NIGMS) Grant T32GM008231 (to A.N.B.-S.), NIH, NIGMS Grant R01GM121389 (to L.B.-H.), NIH, National Heart, Lung, and Blood Institute (NHLBI) R01HL114567 (to J.D.B., G.M.V.), NIH, NHLBI R01-HL136415 (to J.M.F.), and CPRIT-RP180672, NIHCA125123, and NIHRR024574 (to the Cytometry and Cell Sorting Core at Baylor College of Medicine). Publisher Copyright: Copyright {\'O} 2021 by The American Association of Immunologists, Inc. 0022-1767/21/$37.50",

year = "2021",

month = apr,

day = "15",

doi = "10.4049/jimmunol.2000226",

language = "English (US)",

volume = "206",

pages = "1878--1889",

journal = "Journal of Immunology",

issn = "0022-1767",

publisher = "American Association of Immunologists",

number = "8",

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TY - JOUR

T1 - Noncanonical Roles of Caspase-4 and Caspase-5 in Heme-Driven IL-1β Release and Cell Death

AU - Bolívar, Beatriz E.

AU - Brown-Suedel, Alexandra N.

AU - Rohrman, Brittany A.

AU - Charendoff, Chloé I.

AU - Yazdani, Vanda

AU - Belcher, John D.

AU - Vercellotti, Gregory M.

AU - Flanagan, Jonathan M.

AU - Bouchier-Hayes, Lisa

N1 - Funding Information: We thank the members of L.B.-H.’s laboratory, past and present, for helpful discussions and careful reading of the manuscript. We thank Doug Green and the members of his laboratory for valuable suggestions. This project was supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with the assistance of Joel M. Sederstrom. The graphical abstract was drawn using BioRender software. Funding Information: This work was supported by National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grant T32DK060445 (to B.E.B., B.A.R.), NIH, NIDDK F32DK121479 (to B.E.B.), NIH, National Institute of General Medical Sciences (NIGMS) Grant T32GM008231 (to A.N.B.-S.), NIH, NIGMS Grant R01GM121389 (to L.B.-H.), NIH, National Heart, Lung, and Blood Institute (NHLBI) R01HL114567 (to J.D.B., G.M.V.), NIH, NHLBI R01-HL136415 (to J.M.F.), and CPRIT-RP180672, NIHCA125123, and NIHRR024574 (to the Cytometry and Cell Sorting Core at Baylor College of Medicine). Publisher Copyright: Copyright Ó 2021 by The American Association of Immunologists, Inc. 0022-1767/21/$37.50

PY - 2021/4/15

Y1 - 2021/4/15

N2 - 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.

AB - 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.

KW - Alarmins/metabolism

KW - Anemia, Sickle Cell/metabolism

KW - Caspases/metabolism

KW - Caspases, Initiator/metabolism

KW - Cell Death

KW - Cells, Cultured

KW - Erythrocytes/physiology

KW - Heme/metabolism

KW - Hemolysis

KW - Humans

KW - Inflammasomes/metabolism

KW - Inflammation/metabolism

KW - Interleukin-1beta/metabolism

KW - Macrophages/immunology

KW - Up-Regulation

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UR - http://www.scopus.com/inward/citedby.url?scp=85103992679&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.2000226

DO - 10.4049/jimmunol.2000226

M3 - Article

C2 - 33741688

AN - SCOPUS:85103992679

SN - 0022-1767

VL - 206

SP - 1878

EP - 1889

JO - Journal of Immunology

JF - Journal of Immunology

IS - 8

ER -

Noncanonical Roles of Caspase-4 and Caspase-5 in Heme-Driven IL-1β Release and Cell Death

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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