Oxidized hemoglobin forms contribute to NLRP3 inflammasome-driven IL-1β production upon intravascular hemolysis

Benard Bogonko Nyakundi, Andrea Tóth, Enikő Balogh, Béla Nagy, Judit Erdei, Bernhard Ryffel, György Paragh, Mario D. Cordero, V. Jeney

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Damage associated molecular patterns (DAMPs) are released form red blood cells (RBCs) during intravascular hemolysis (IVH). Extracellular heme, with its pro-oxidant, pro-inflammatory and cytotoxic effects, is sensed by innate immune cells through pattern recognition receptors such as toll-like receptor 4 and nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3), while free availability of heme is strictly controlled. Here we investigated the involvement of different hemoglobin (Hb) forms in hemolysis-associated inflammatory responses. We found that after IVH most of the extracellular heme molecules are localized in oxidized Hb forms. IVH was associated with caspase-1 activation and formation of mature IL-1β in plasma and in the liver of C57BL/6 mice. We showed that ferrylHb (FHb) induces active IL-1β production in LPS-primed macrophages in vitro and triggered intraperitoneal recruitment of neutrophils and monocytes, caspase-1 activation and active IL-1β formation in the liver of C57BL/6 mice. NLRP3 deficiency provided a survival advantage upon IVH, without influencing the extent of RBC lysis or the accumulation of oxidized Hb forms. However, both hemolysis-induced and FHb-induced pro-inflammatory responses were largely attenuated in Nlrp3−/− mice. Taken together, FHb is a potent trigger of NLRP3 activation and production of IL-1β in vitro and in vivo, suggesting that FHb may contribute to hemolysis-induced inflammation. Identification of RBC-derived DAMPs might allow us to develop new therapeutic approaches for hemolytic diseases.

Original languageEnglish
Pages (from-to)464-475
Number of pages12
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1865
Issue number2
DOIs
Publication statusPublished - Feb 1 2019

Fingerprint

Inflammasomes
Hemolysis
Interleukin-1
Hemoglobins
Heme
Caspase 1
Erythrocytes
Inbred C57BL Mouse
Pattern Recognition Receptors
Toll-Like Receptor 4
Neutrophil Infiltration
Liver
Leucine
Monocytes
Reactive Oxygen Species
Nucleotides
Macrophages
Inflammation
ferrylhemoglobin

Keywords

  • Ferryl hemoglobin
  • Heme
  • Hemolysis
  • IL-1β
  • Macrophage
  • NLRP3 inflammasome activation

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Oxidized hemoglobin forms contribute to NLRP3 inflammasome-driven IL-1β production upon intravascular hemolysis. / Nyakundi, Benard Bogonko; Tóth, Andrea; Balogh, Enikő; Nagy, Béla; Erdei, Judit; Ryffel, Bernhard; Paragh, György; Cordero, Mario D.; Jeney, V.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1865, No. 2, 01.02.2019, p. 464-475.

Research output: Contribution to journalArticle

Nyakundi, Benard Bogonko ; Tóth, Andrea ; Balogh, Enikő ; Nagy, Béla ; Erdei, Judit ; Ryffel, Bernhard ; Paragh, György ; Cordero, Mario D. ; Jeney, V. / Oxidized hemoglobin forms contribute to NLRP3 inflammasome-driven IL-1β production upon intravascular hemolysis. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2019 ; Vol. 1865, No. 2. pp. 464-475.
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AU - Nyakundi, Benard Bogonko

AU - Tóth, Andrea

AU - Balogh, Enikő

AU - Nagy, Béla

AU - Erdei, Judit

AU - Ryffel, Bernhard

AU - Paragh, György

AU - Cordero, Mario D.

AU - Jeney, V.

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AB - Damage associated molecular patterns (DAMPs) are released form red blood cells (RBCs) during intravascular hemolysis (IVH). Extracellular heme, with its pro-oxidant, pro-inflammatory and cytotoxic effects, is sensed by innate immune cells through pattern recognition receptors such as toll-like receptor 4 and nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3), while free availability of heme is strictly controlled. Here we investigated the involvement of different hemoglobin (Hb) forms in hemolysis-associated inflammatory responses. We found that after IVH most of the extracellular heme molecules are localized in oxidized Hb forms. IVH was associated with caspase-1 activation and formation of mature IL-1β in plasma and in the liver of C57BL/6 mice. We showed that ferrylHb (FHb) induces active IL-1β production in LPS-primed macrophages in vitro and triggered intraperitoneal recruitment of neutrophils and monocytes, caspase-1 activation and active IL-1β formation in the liver of C57BL/6 mice. NLRP3 deficiency provided a survival advantage upon IVH, without influencing the extent of RBC lysis or the accumulation of oxidized Hb forms. However, both hemolysis-induced and FHb-induced pro-inflammatory responses were largely attenuated in Nlrp3−/− mice. Taken together, FHb is a potent trigger of NLRP3 activation and production of IL-1β in vitro and in vivo, suggesting that FHb may contribute to hemolysis-induced inflammation. Identification of RBC-derived DAMPs might allow us to develop new therapeutic approaches for hemolytic diseases.

KW - Ferryl hemoglobin

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KW - NLRP3 inflammasome activation

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