Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C

Laura F. Bennett, Chang Liao, Michael D. Quickel, Beng San Yeoh, Matam Vijay-Kumar, Pamela Hankey Giblin, Kumble Sandeep Prabhu, Robert Paulson

Research output: Contribution to journalArticle

Abstract

Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also induced stress erythropoiesis in the absence of hypoxia. Using a mouse model of sterile inflammation, we demonstrated that signaling through Toll-like receptors (TLRs) paradoxically increased the phagocytosis of erythrocytes (erythrophagocytosis) by macrophages in the spleen, which enabled expression of the heme-responsive gene encoding the transcription factor SPI-C. Increased amounts of SPI-C coupled with TLR signaling promoted the expression of Gdf15 and Bmp4, both of which encode ligands that initiate the expansion of stress erythroid progenitors (SEPs) in the spleen. Furthermore, despite their inhibition of steady-state erythropoiesis in the bone marrow, the proinflammatory cytokines TNF-α and IL-1β promoted the expansion and differentiation of SEPs in the spleen. These data suggest that inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.

Original languageEnglish (US)
Article numbereaap7336
JournalScience signaling
Volume12
Issue number598
DOIs
StatePublished - Sep 10 2019

Fingerprint

Erythropoiesis
Heme
Chemical activation
Inflammation
Toll-Like Receptors
Spleen
Erythrocytes
Bone
Anemia
Homeostasis
Cytokines
Bone Marrow
Gene encoding
Macrophages
Interleukin-1
Hematopoiesis
Phagocytosis
Transcription Factors
Chronic Disease
Ligands

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Bennett, Laura F. ; Liao, Chang ; Quickel, Michael D. ; Yeoh, Beng San ; Vijay-Kumar, Matam ; Giblin, Pamela Hankey ; Prabhu, Kumble Sandeep ; Paulson, Robert. / Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C. In: Science signaling. 2019 ; Vol. 12, No. 598.
@article{b6e06ca21dd248809ceea2227d809d65,
title = "Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C",
abstract = "Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also induced stress erythropoiesis in the absence of hypoxia. Using a mouse model of sterile inflammation, we demonstrated that signaling through Toll-like receptors (TLRs) paradoxically increased the phagocytosis of erythrocytes (erythrophagocytosis) by macrophages in the spleen, which enabled expression of the heme-responsive gene encoding the transcription factor SPI-C. Increased amounts of SPI-C coupled with TLR signaling promoted the expression of Gdf15 and Bmp4, both of which encode ligands that initiate the expansion of stress erythroid progenitors (SEPs) in the spleen. Furthermore, despite their inhibition of steady-state erythropoiesis in the bone marrow, the proinflammatory cytokines TNF-α and IL-1β promoted the expansion and differentiation of SEPs in the spleen. These data suggest that inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.",
author = "Bennett, {Laura F.} and Chang Liao and Quickel, {Michael D.} and Yeoh, {Beng San} and Matam Vijay-Kumar and Giblin, {Pamela Hankey} and Prabhu, {Kumble Sandeep} and Robert Paulson",
year = "2019",
month = "9",
day = "10",
doi = "10.1126/scisignal.aap7336",
language = "English (US)",
volume = "12",
journal = "Science Signaling",
issn = "1937-9145",
publisher = "American Association for the Advancement of Science",
number = "598",

}

Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C. / Bennett, Laura F.; Liao, Chang; Quickel, Michael D.; Yeoh, Beng San; Vijay-Kumar, Matam; Giblin, Pamela Hankey; Prabhu, Kumble Sandeep; Paulson, Robert.

In: Science signaling, Vol. 12, No. 598, eaap7336, 10.09.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inflammation induces stress erythropoiesis through heme-dependent activation of SPI-C

AU - Bennett, Laura F.

AU - Liao, Chang

AU - Quickel, Michael D.

AU - Yeoh, Beng San

AU - Vijay-Kumar, Matam

AU - Giblin, Pamela Hankey

AU - Prabhu, Kumble Sandeep

AU - Paulson, Robert

PY - 2019/9/10

Y1 - 2019/9/10

N2 - Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also induced stress erythropoiesis in the absence of hypoxia. Using a mouse model of sterile inflammation, we demonstrated that signaling through Toll-like receptors (TLRs) paradoxically increased the phagocytosis of erythrocytes (erythrophagocytosis) by macrophages in the spleen, which enabled expression of the heme-responsive gene encoding the transcription factor SPI-C. Increased amounts of SPI-C coupled with TLR signaling promoted the expression of Gdf15 and Bmp4, both of which encode ligands that initiate the expansion of stress erythroid progenitors (SEPs) in the spleen. Furthermore, despite their inhibition of steady-state erythropoiesis in the bone marrow, the proinflammatory cytokines TNF-α and IL-1β promoted the expansion and differentiation of SEPs in the spleen. These data suggest that inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.

AB - Inflammation alters bone marrow hematopoiesis to favor the production of innate immune effector cells at the expense of lymphoid cells and erythrocytes. Furthermore, proinflammatory cytokines inhibit steady-state erythropoiesis, which leads to the development of anemia in diseases with chronic inflammation. Acute anemia or hypoxic stress induces stress erythropoiesis, which generates a wave of new erythrocytes to maintain erythroid homeostasis until steady-state erythropoiesis can resume. Although hypoxia-dependent signaling is a key component of stress erythropoiesis, we found that inflammation also induced stress erythropoiesis in the absence of hypoxia. Using a mouse model of sterile inflammation, we demonstrated that signaling through Toll-like receptors (TLRs) paradoxically increased the phagocytosis of erythrocytes (erythrophagocytosis) by macrophages in the spleen, which enabled expression of the heme-responsive gene encoding the transcription factor SPI-C. Increased amounts of SPI-C coupled with TLR signaling promoted the expression of Gdf15 and Bmp4, both of which encode ligands that initiate the expansion of stress erythroid progenitors (SEPs) in the spleen. Furthermore, despite their inhibition of steady-state erythropoiesis in the bone marrow, the proinflammatory cytokines TNF-α and IL-1β promoted the expansion and differentiation of SEPs in the spleen. These data suggest that inflammatory signals induce stress erythropoiesis to maintain erythroid homeostasis when inflammation inhibits steady-state erythropoiesis.

UR - http://www.scopus.com/inward/record.url?scp=85072029059&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85072029059&partnerID=8YFLogxK

U2 - 10.1126/scisignal.aap7336

DO - 10.1126/scisignal.aap7336

M3 - Article

C2 - 31506384

AN - SCOPUS:85072029059

VL - 12

JO - Science Signaling

JF - Science Signaling

SN - 1937-9145

IS - 598

M1 - eaap7336

ER -