IL-33 promotes anemia during chronic inflammation by inhibiting differentiation of erythroid progenitors

J Exp Med. 2020 Sep 7;217(9):e20200164. doi: 10.1084/jem.20200164.

Abstract

An important comorbidity of chronic inflammation is anemia, which may be related to dysregulated activity of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM). Among HSPCs, we found that the receptor for IL-33, ST2, is expressed preferentially and highly on erythroid progenitors. Induction of inflammatory spondyloarthritis in mice increased IL-33 in BM plasma, and IL-33 was required for inflammation-dependent suppression of erythropoiesis in BM. Conversely, administration of IL-33 in healthy mice suppressed erythropoiesis, decreased hemoglobin expression, and caused anemia. Using purified erythroid progenitors in vitro, we show that IL-33 directly inhibited terminal maturation. This effect was dependent on NF-κB activation and associated with altered signaling events downstream of the erythropoietin receptor. Accordingly, IL-33 also suppressed erythropoietin-accelerated erythropoiesis in vivo. These results reveal a role for IL-33 in pathogenesis of anemia during inflammatory disease and define a new target for its treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anemia / complications
  • Anemia / pathology*
  • Animals
  • Annexin A5 / metabolism
  • Bone Marrow / pathology
  • Cell Differentiation*
  • Chronic Disease
  • Erythroid Precursor Cells / metabolism*
  • Erythroid Precursor Cells / pathology*
  • Erythropoiesis
  • Erythropoietin / pharmacology
  • Hematopoiesis
  • Inflammation / complications
  • Inflammation / pathology*
  • Injections
  • Interleukin-1 Receptor-Like 1 Protein / metabolism
  • Interleukin-33 / metabolism*
  • Ki-67 Antigen / metabolism
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Models, Biological
  • Myelopoiesis
  • NF-kappa B / metabolism
  • Phosphorylation
  • Receptors, Erythropoietin / metabolism
  • Signal Transduction
  • Spondylarthritis / pathology
  • beta-Glucans

Substances

  • Annexin A5
  • Il1rl1 protein, mouse
  • Interleukin-1 Receptor-Like 1 Protein
  • Interleukin-33
  • Ki-67 Antigen
  • NF-kappa B
  • Receptors, Erythropoietin
  • beta-Glucans
  • Erythropoietin
  • curdlan