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

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 languageEnglish (US)
Pages (from-to)1878-1889
Number of pages12
JournalJournal of Immunology
Issue number8
StatePublished - 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


  • 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


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